Methods for percutaneous delivery of an agent to the heart

Abstract

Provided herein are methods for delivering an agent (e.g., a therapeutic agent) preferentially to the heart, e.g., percutaneously, of a patient under conditions of cardiac arrest and isolation of cardiac circulation from systemic circulation. Also disclosed are methods of treating a cardiac condition in a patient using the methods of delivery.

Description

[0001]Attorney Docket No.: DTJ-006PC METHODS FOR PERCUTANEOUS DELIVERY OF AN AGENT TO THE HEART RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 672,063, filed on July 16, 2024, the entire contents of which are incorporated by reference in its entirety. BACKGROUND Recent years have brought about trailblazing advancements in gene therapy and genetic medicine. However, clinical trials in cardiac gene therapy are delayed due to difficulties with efficiently transfecting and transducing cardiomyocytes. There currently are no validated approaches for achieving highly efficient delivery and expression of therapeutic agents (e.g., biologics such as mRNA-LNP) in non-hepatic solid organs, such as the heart. Most approaches to date employ intracoronary delivery systems in which there is rapid transit of the biologic and widespread extra-cardiac expression with minimal expression in cardiomyocytes. Accordingly, there remains a need for highly efficient, minimally invasive myocardial delivery methods for therapeutic agents, without broad extracardiac expression. SUMMARY Provided herein are methods of delivering a therapeutic agent to the heart (e.g., to cardiac cells) of a patient (e.g., a human patient) under conditions of cardiac arrest and isolated cardiac circulation. In one aspect, provided herein is a method of delivering a therapeutic agent to cardiac cells in a patient, the method comprising: (a) isolating cardiac circulation from systemic circulation (e.g., percutaneously), (b) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a first composition comprising a cardioplegia solution, thereby inducing cardiac arrest, and (c) introducing into the cardiac circulation (coronary arterial circulation or coronary venous circulation) a second composition comprising a cardioplegia solution and a therapeutic agent, thereby delivering the therapeutic agent to cardiac cells in the patient. Attorney Docket No.: DTJ-006PC In another aspect, provided herein is a method of treating a cardiac condition in a patient, the method comprising: (a) isolating cardiac circulation from systemic circulation (e.g., percutaneously) in a patient with the cardiac condition, (b) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a first composition comprising a cardioplegia solution, thereby inducing cardiac arrest, and (c) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a second composition comprising a cardioplegia solution and a therapeutic agent, thereby delivering the therapeutic agent to cardiac cells in the patient; wherein the therapeutic agent treats the cardiac condition. In some embodiments, cardiac circulation is isolated from the systemic circulation with a cardiopulmonary bypass circuit, with or without occlusion of one or more coronary vessels with a catheter (e.g., endoballoon catheter) or clamp. In some embodiments, the first composition is introduced by infusion into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) through a catheter placed into the lumen of a coronary vessel, such as the aortic root or coronary sinus. In some embodiments, the first composition is administered by infusion into the aortic root after inflating an endoballoon in the ascending aorta. In some embodiments, an endoballoon is inflated in the coronary sinus following cardiac arrest. In some embodiments, cardiac arrest is induced for about 5 minutes to about 30 minutes (e.g., about 15 minutes). In some embodiments, the methods comprise a further step of removing the cardiac arrest, e.g., by deflating endoballoon catheters. In some embodiments, the second composition is administered by anterograde perfusion. In other embodiments, the second composition is administered by retrograde perfusion. In some embodiments, the second composition comprises a cardioplegia solution, blood from the patient, a dye, and a therapeutic agent. In some embodiments, the therapeutic agent is a polypeptide, a nucleic acid, a small molecule, a virus (e.g., an AAV virus comprising a viral genome encoding a therapeutic agent), or a cell. In some embodiments, the therapeutic agent is a nucleic acid, and the nucleic acid is a vector. In some embodiments, the therapeutic agent is Attorney Docket No.: DTJ-006PC driven by a cardiac-specific promoter, ubiquitous promoter, or constitutive promoter in the vector. In some embodiments, the therapeutic agent is a polynucleotide comprising a nucleotide sequence which encodes a polypeptide or RNA. In some embodiments, the therapeutic agent is an angiogenic protein, a growth factor, a signaling protein, an antibody, an enzyme, a base editor, a gene editing agent, a gene modification agent, a transcriptional activator, a transcriptional repressor, a recombinase, a nuclease, a DNA-binding protein, a Cas9 nuclease, a Cre recombinase, a CRISPR / Cas molecule, a nickase, a TALE transcriptional activator, a transcriptional regulator, a siRNA, a shRNA, a dsRNA, a piRNA, a lncRNA, a tmRNA, a tRNA, a sgRNA, a snRNA, a snoRNA, or a miRNA. In some embodiments, the therapeutic agent is VEGF. In some embodiments, the therapeutic agent is encapsulated in an exosome or a lipid nanoparticle (LNP). In some embodiments, the therapeutic agent is a mRNA-LNP. The mRNA-LNP is present in the second composition in a dose of, e.g., about 0.01 mg to 1 mg (e.g., for a patient weighing about 60-120 kg). In some embodiments, the therapeutic agent is a mRNA-LNP. The mRNA-LNP is present in the second composition in a dose of, e.g., about 0.0001 mg / kg to about 0.011 mg / kg. In some embodiments, the second composition is administered by infusion over a period of about 30 seconds to about 2 minutes. In some embodiments, the second composition is recirculated into the isolated coronary arterial circulation. In some embodiments, dwell time of the second composition is about 5 minutes to about 30 minutes (e.g., about 15 minutes). In some embodiments, transmural, pan-cardiac expression of the therapeutic agent is observed after about 9 hours from introduction into the isolated coronary arterial circulation. In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, or at least 90%) of cardiomyocytes express the therapeutic agent when the therapeutic agent is administered at a dose of 0.1 mg or less, for example, when the dwell time is at least 15 minutes (e.g., 15-30 minutes). In some embodiments, the therapeutic agent is expressed preferentially in the heart. In some embodiments, the therapeutic agent is expressed preferentially in the myocardium. In Attorney Docket No.: DTJ-006PC some embodiments, the therapeutic agent is expressed in cardiac endothelial cells and / or interstitial cells. In some embodiments, the patient with a cardiac condition has acquired heart disease, abnormal heart contractility, acute coronary syndrome, angina pectoris, aortic regurgitation, aortic stenosis, arrhythmia, atherosclerosis, autoimmune endocarditis, blood flow disorder, cardiac arrhythmias, cardiac ischemia, cardiomyopathy, cardiomyopathy stemming from rare genetic disorders, congestive heart failure, congenital heart disease, coronary artery disease, endocarditis, heart cancer, heart failure, heart valve disease, hereditary heart disorder, hypersensitivity myocarditis, idiopathic cardiomyopathy, infective myocarditis, ischemia, mitral valve regurgitation, muscular dystrophy, myocardial infarction, myocardial ischemia, non- ischemic cardiomyopathy, pulmonary hypertension, symptomatic arrhythmia, transplant rejection, valvular heart disease, or vascular disease. In another aspect, provided herein is a perfusion composition comprising a cardioplegia solution, blood from a patient, dye, and a therapeutic agent. In yet another aspect, provided herein is a kit comprising the perfusion composition and instructions for use. Other features and advantages of the instant disclosure will be apparent from the following detailed description and examples, which should not be construed as limiting. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic of a representative cardiopulmonary bypass circuit suitable for use to isolate the coronary arterial circulation in the methods disclosed herein. FIG. 2 is a representative image of immunohistochemistry showing lack of detectable nLacZ signal in the heart of control pigs, in which no biologic (mRNA-LNP) was administered. Red: nLacZ; Blue: DAPI (nuclei), Green: f-actin phalloidin. FIG. 3 is a representative image of immunohistochemistry showing global nuclear LacZ cardiac expression across the heart muscle from the inner-most layer (“endo” – endocardium), the middle layer (“mid”), and the outer layer (“epi” – epicardium) of the lateral ventricle (LV) following the administration of a 1mg nLACZ-LNP dose and collection at 36hr post- transfection. Red: nLacZ; Blue: DAPI (nuclei), Green: f-actin phalloidin. Attorney Docket No.: DTJ-006PC FIG. 4 is a representative image showing the lack of acute cardiac inflammation 36 hours after the administration of 1 mg mRNA-LNP. FIG. 5 is a representative image of immunohistochemistry showing minimal or no nLacZ expression in the liver tissue following administration of 1mg mRNA-LNP. Red: nLacZ; Blue: DAPI (nuclei), Green: f-actin phalloidin. FIG. 6 is a representative image of immunohistochemistry showing global nuclear LacZ cardiac expression across the heart muscle from the inner-most layer (“endo” – endocardium), the middle layer (“mid”), and the outer layer (“epi” – epicardium) of the lateral ventricle (LV) following the administration of a 0.1 mg nLACZ-LNP dose and collection at 36 hours post- transfection. Red: nLacZ; Blue: DAPI (nuclei), Green: f-actin phalloidin. FIG. 7 is a representative image showing the lack of acute cardiac inflammation 36 hours after the administration of 0.1 mg mRNA-LNP. FIG. 8 is a representative image of immunohistochemistry showing minimal or no nLacZ expression in the liver tissue following administration of 0.1 mg mRNA-LNP. Red: nLacZ; Blue: DAPI (nuclei), Green: f-actin phalloidin. FIG. 9 is a series of graphs showing the cell specific quantification of the percentage of cells staining positive for the nLacZ reporter in the (A) Left Ventricle (LV), (B) Right Ventricle (RV), and (C) liver in a pig with the administration of both 1 mg (blue) and 0.1 mg (orange) biologic with a 15 minute dwell time. The animals were sacrificed at 36 hours after administering the mRNA-LNP. DETAILED DESCRIPTION The present invention provides novel methods for delivering therapeutic agents (e.g., mRNA-LNP) to the heart of a patient under cardioplegia and cardiac isolation from systemic circulation in a fully percutaneous system. This system allows for the separation of fluid flows while maximizing transduction specifically to the heart. As described in the following Examples, the methods disclosed herein achieve several key therapeutic endpoints which have not been achieved by previous methods. First, the methods provide highly efficient global cardiomyocyte expression in transmural distribution. This global cardiac expression enables expression in the nuclei of cardiomyocytes, with broad applications, including gene editing requiring intranuclear transport, and with a preferentially Attorney Docket No.: DTJ-006PC cardiac-restricted pattern of expression. Expression of the therapeutic agent in the liver is minimal, thus avoiding the need to engineer cardiotropic delivery vehicles. Moreover, low doses of therapeutic agent (e.g., 0.1 mg or less of mRNA-LNP) are sufficient to achieve pan-cardiac expression across a broad range of cardiac cell types, including cardiomyocytes, interstitial cells, and endothelial cells, thereby limiting side effects and off-target effects, with only a short period (e.g., 15 minutes or less) of transient cardiac arrest, further contributing to safety of the methods. The methods can be carried out with percutaneous clinically-approved catheters in a clinically tractable manner. I. Definitions In order that the present description may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The use of “or” or “and” means “and / or” unless stated otherwise. The term “about” as used herein when referring to a measurable value such as an amount, a temporal duration and the like, is encompasses variations of up to ± 10% from the specified value. As used herein, “delivery” refers to the act or manner of delivering a therapeutic agent to a target (e.g., a target organ such as the heart or a target cell such as a cardiac cell (e.g., cardiomyocyte)). As used herein, “isolating cardiac circulation” or “isolated cardiac circulation” refers to isolation of the cardiac circulation from systemic circulation to maximize perfusion of cardiac tissue with a therapeutic agent and minimize exposure of extra-cardiac tissue to the therapeutic agent, for example, via a cardiopulmonary bypass circuit optionally in combination with antegrade occlusion of selected coronary vessels (e.g., occlusion via balloon catheters) allowing perfusion of other, selected coronary vessels (e.g., ballon occlusion of the RCA allowing perfusion of the LMCA), alternatively or in combination with occlusion of the coronary veins to scavenge the perfusate. In isolated cardiac circulation, the therapeutic agent has a longer dwell Attorney Docket No.: DTJ-006PC time in the heart than in extra-cardiac tissue. “Substantially isolating cardiac circulation” or “substantially isolated cardiac circulation” is not intended to refer to absolute isolation of the cardiac circulation from the systemic circulation, but that a majority (e.g., major portion or substantially all of) of the cardiac circulation is isolated from the systemic circulation. As used herein, “cardioplegia solution” refers to an agent which arrests the heart diluted in crystalloid to various concentrations depending on the blood-to-cardioplegia solution delivery ratio. In one embodiment, is the cardioplegia solution comprises potassium. In another embodiment, the cardioplegia solution comprises histidine-tryptophan-ketoglutarate (HTK). As used herein, “cardioplegia” refers to a variable blood / cardioplegia solution mix delivered to the heart for myocardial protection. As used herein, “therapeutic agent” refers to any agent that, when administered to a patient, has a therapeutic, diagnostic, and / or prophylactic effect and / or elicits a desired biological and / or pharmacological effect. Exemplary therapeutic agents include, but are not limited to, small molecule compounds, antisense molecules, siRNA molecules, antibodies, enzymes, peptides, organic molecules, inorganic molecules, natural compounds, synthetic compounds, and the like. As used herein, “administering,” “introducing,” and “delivering,” as well as their variations (e.g., “administered,” “introduced,” “delivered”), are used interchangeably. Therapeutic agents, as used herein, exclude devices (e.g., delivery devices) such as stents and catheters. As used herein, “nucleic acid” and “polynucleotide,” which are used interchangeably, are intended to include DNA molecules and RNA molecules. A nucleic acid molecule may be single-stranded or double-stranded, and may be cDNA. There is no intended distinction in length between the term “nucleic acid” and “polynucleotide.” As used herein, “RNA” or “RNA molecule” or “ribonucleic acid molecule” refers to a polymer of ribonucleotides; the term “DNA” or “DNA molecule” or “deoxyribonucleic acid molecule” refers to a polymer of deoxyribonucleotides. DNA and RNA can be single-stranded (i.e., ssRNA or ssDNA, respectively) or multi-stranded (e.g., double stranded, i.e., dsRNA and dsDNA, respectively). DNA and RNA can be synthesized naturally, e.g., by DNA replication and transcription of DNA, respectively; or be chemically synthesized. The term “mRNA” or “messenger RNA” refers to a single stranded RNA that encodes the amino acid sequence of one or more polypeptides. Attorney Docket No.: DTJ-006PC As used herein, “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid,” which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Certain vectors can direct the expression of genes to which they are operatively linked (e.g., recombinant expression vectors, or simply, expression vectors). As used herein, “promoter” refers to a nucleic acid site to which a polymerase enzyme binds to initiate transcription (DNA to RNA) or reverse transcription (RNA to DNA). As used herein, “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to a chain comprising at least two consecutively linked amino acid residues, with no upper limit on the length of the chain. One or more amino acid residues in the polypeptide may contain a modification such as, but not limited to, glycosylation, phosphorylation or disulfide bond formation. As used herein, “gene editing agent” refers to an agent capable of inserting, deleting, or replacing nucleotide(s) in the genome of a living organism. In some embodiments, a genome editing agent is an engineered nuclease that can create site-specific double-strand breaks (DSBs) at desired locations in the genome. Engineered nucleases suitable for genome-editing can be programmed to target any desired sequence in the genome and are also referred to as “programmable nucleases.” Exemplary genome-editing nucleases include, for example, meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN), and the CRISPR / Cas system (e.g., a Cas9 and a guide RNA). Programmable nucleases and methods of using them for genome-editing are well known in the art. As used herein, “vasoactive agent” refers to a natural or synthetic substance that increases vascular permeability and / or enhances the transfer of molecules (e.g., gene delivery vectors) from blood vessels. Examples of vasoactive agents suitable for use in the methods described herein include, for example, nitric oxide donors (e.g., sodium nitroprusside), histamine and derivatives thereof, histamine receptor agonists, vascular permeability factor (VPF), VEGF, and VEGF agonists. As used herein, “expression” refers to (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript; (3) translation of an RNA Attorney Docket No.: DTJ-006PC into a polypeptide or protein; (4) folding of a polypeptide or protein; and / or (5) post-translational modification of a polypeptide or protein. As used herein, "percutaneous" or “percutaneously” refers to a medical procedure in which inner organs (e.g., the heart) are accessed by a puncture of the skin, rather than by an “open” approach where inner organs or tissue are exposed. The percutaneous approach is common in vascular procedures and involves giving a needle catheter or cannula access to a blood vessel, followed by inserting a wire through the lumen (path) of the needle. As used herein, “anterograde perfusion” refers to injection of an agent into a patient’s vascular system in the direction of normal blood flow. As used herein, “retrograde perfusion” refers to injection of an agent into a patient’s vascular system in the direction that opposes normal blood flow. As used herein, “dwell time” refers to the length of time a composition (e.g., a composition comprising a therapeutic agent) remains in the coronary vasculature during cardiac arrest. As used herein, “cardiac cell” refers to any cell of the heart involved in providing a function of the heart, such as a cell of the heart vasculature, a cell present in a cardiac valve, or a cardiac muscle cell. Examples of cardiac cells include cardiomyocytes, epithelial cells, fibroblasts, endothelial cells, cardiac pacemaking cells, interstitial cells, or cells of conducting tissue. As used herein, “preferentially expressed” or “preferential expression” indicates that the targeted cell, tissue, or organ has a higher level of expression of the therapeutic agent than a non- targeted cell, tissue, or organ. As used herein, "introducing" refers to the physical introduction of a composition comprising a cardioplegia solution, and / or a composition comprising a therapeutic agent to a patient. In the context of the present invention, the composition may be introduced by way of a catheter, e.g., a endoballoon catheter, into the isolated cardiac circulation. “Introducing” can also be performed, for example, once, a plurality of times, continuously over a certain period of time, and / or over one or more extended periods. As used herein, “treating,” “treat,” and “treatment” refer to partially or completely alleviating, ameliorating, improving, relieving, reversing, delaying onset of, inhibiting progression of, reducing severity of, and / or reducing incidence of one or more symptoms or Attorney Docket No.: DTJ-006PC features of a cardiac condition. Treatment can be administered to a subject who does not exhibit signs of a cardiac condition, and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the cardiac condition. As used herein, “effective amount” refers to an amount sufficient to achieve or at least partially achieve a desired effect. A "therapeutically effective amount" of a therapeutic agent is any amount of the agent that, when used alone or in combination with another therapeutic agent, promotes regression of a cardiac condition (e.g., cardiac disease) evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. A therapeutically effective amount of a therapeutic agent includes a "prophylactically effective amount,” which is any amount of the therapeutic agent that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or of suffering a recurrence of disease, inhibits the development or recurrence of the disease. The ability of a therapeutic agent to promote disease regression or inhibit the development or recurrence of the disease can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials and in animal model systems (e.g., porcine models) predictive of efficacy in humans. As used herein, “cardiac condition” refers to a medical condition that directly affects the heart or circulatory system. In some embodiments, a cardiac condition causes a decrease in heart function. Cardiac conditions which can be treated using the methods described herein include, but are not limited to, acquired heart disease, abnormal heart contractility, acute coronary syndrome, angina pectoris, aortic regurgitation, aortic stenosis, arrhythmia, atherosclerosis, autoimmune endocarditis, blood flow disorder, cardiac arrhythmias, cardiac ischemia, cardiomyopathy, congestive heart failure, congenital heart disease, coronary artery disease, endocarditis, heart cancer, heart failure, heart valve disease, hypersensitivity myocarditis, idiopathic cardiomyopathy, cardiomyopathy stemming from rare genetic disorders, hereditary heart disorder, infective myocarditis, ischemia, mitral valve regurgitation, muscular dystrophy, myocardial infarction, myocardial ischemia, non-ischemic cardiomyopathy, pericarditis, pulmonary hypertension, symptomatic arrhythmia, transplant rejection, valvular heart disease, or vascular disease. Attorney Docket No.: DTJ-006PC As used herein, “pharmaceutical composition” refers to a composition comprising a therapeutic agent that is suitable for administration to a patient in need thereof and is used to prevent, reduce in intensity, cure, or otherwise treat a cardiac condition. A "pharmaceutically acceptable carrier" refers to any substantially non-toxic carrier useable for formulation and administration of a composition (e.g., pharmaceutically acceptable composition) in which a therapeutic agent will remain stable and bioavailable. As used herein, “patient” includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment. In a preferred embodiment, the patient is a human patient. Various aspects described herein are described in further detail in the following subsections. II. Methods of delivery and treatment Provided herein are methods of delivering a therapeutic agent to the heart (e.g., to cardiac cells) of a patient (e.g., a human patient) under conditions of cardiac arrest and isolated cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation), allowing for highly efficient uptake and expression of a therapeutic agent (e.g., mRNA-LNP). Accordingly, in one aspect, provided herein is a method of delivering a therapeutic agent to cardiac cells in a patient, the method comprising: (a) isolating (e.g., substantially isolating) cardiac circulation (e.g., coronary arterial circulation) from systemic circulation, (b) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a first composition comprising a cardioplegia solution, thereby inducing cardiac arrest, and (c) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a second composition comprising a cardioplegia solution and a therapeutic agent, thereby delivering the therapeutic agent to cardiac cells in the patient. Methods of isolating the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) from systemic circulation are well known in the art and can be applied to the present invention. These include, for example, routine procedures used in cardiac surgery, such as extracorporeal circulation used during coronary artery bypass surgery. An exemplary Attorney Docket No.: DTJ-006PC cardiopulmonary bypass circuit suitable for use in the methods described herein is shown in FIG. 1. In some embodiments, the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) is isolated from systemic circulation percutaneously, e.g., using multiple catheters. In some embodiments, the cardiac circulation is isolated from systemic circulation (e.g., non-percutaneously) using open chest techniques, as are commonly used in cardiac surgery. In both instances, a cardiopulmonary circuit is used to support the pump activity of the heart and oxygenating activity of the lung, thus allowing isolation of the heart by various means. In some embodiments, the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) is isolated from the systemic circulation by occluding one or more coronary vessels. In some embodiments, the one or more coronary vessels are occluded using a catheter, such as an endoballoon catheter. The use of balloon catheters to dilate blood vessels is well known in the art. In some embodiments, balloon catheters also deliver the therapeutic agents, e.g., via an open catheter lumen or channel along the catheter shaft. Methods of positioning balloon catheters in targeted vessels in conjunction with guide catheters are also well known in the art. In some embodiments, a catheter is placed in the right coronary artery. In some embodiments, a catheter is placed in the left coronary artery. In some embodiments, a catheter is placed in the coronary sinus. In some embodiments, the first composition comprising the cardioplegia solution is introduced by infusion into the coronary arterial circulation through a catheter placed into the lumen of a coronary vessel. In some embodiments, the first composition is introduced using an endoballoon catheter. In some embodiments, the first composition is introduced by infusion into the aortic root or the coronary sinus. In some embodiments, the first composition is administered by infusion into the aortic root after inflating an endoballoon in the ascending aorta. In some embodiments, the cardioplegia solution in the first composition comprises potassium chloride. In some embodiments, the cardioplegia solution comprises one or more or all of potassium chloride, lactated Ringers solution, lidocaine hydrochloride, sodium bicarbonate, and / or mannitol. Other cardioplegia solutions known in the art are also suitable for use in the Attorney Docket No.: DTJ-006PC methods described herein (e.g., Plegisol®, Custodiol®, St. Thomas Hospital Solution No. 2 (STH2), DelNido solution). In other embodiments, the cardioplegia solution in the first composition comprises HTK. In some embodiments, the cardioplegia solution in the first composition is used cold (e.g., at 4°C). In some embodiments, the first composition further comprises blood. In some embodiments, the blood is autologous (i.e., blood from the patient to which the agent is delivered). In some embodiments, the blood is allogenic (i.e., blood from a donor who is not the patient to which the agent is delivered). Accordingly, in some embodiments, the first composition comprises a cardioplegia solution and blood. In some embodiments, the first composition is introduced into the coronary arterial circulation by infusion over a period of 3-20 minutes (e.g., about 3 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, 3-20 minutes, 3-15 minutes, 3-10 minutes, 3-5 minutes, 5-20 minutes, 5-15 minutes, 5-10 minutes, 10-20 minutes, 10-15 minutes, or 15-20 minutes). In some embodiments, the first composition is infused over a period of 5-10 minutes. The second composition used in the methods described herein comprises a mixture of a cardioplegia solution and a therapeutic agent. In some embodiments, the second composition further comprises blood. In some embodiments, the blood is autologous. In other embodiments, the blood is allogenic. Accordingly, in some embodiments, the second composition comprises a mixture of cardioplegia solution, a therapeutic agent, and blood. In some embodiments, the second composition further comprises a dye (e.g., contrast agent). Accordingly, in some embodiments, the second composition comprises a mixture of cardioplegia solution, blood, a therapeutic agent, and a dye. In some embodiments, the second composition further comprises one or more additional therapeutic agents. For example, in some embodiments, the second composition further comprises a vasoactive agent (e.g., nitric oxide donors, histamine and derivatives thereof, histamine receptor agonists, VPF, VEGF, and VEGF agonists). In some embodiments, the second composition further comprises one or more molecules (e.g., nucleic acids) that together constitute a therapeutic agent (e.g., one or more nucleic acids encoding a gene editing agent, such as CRISPR-Cas9 system). Attorney Docket No.: DTJ-006PC In some embodiments, the second composition is administered by anterograde perfusion. In other embodiments, the second composition is administered by retrograde perfusion. In some embodiments, the first and second compositions are introduced by infusion through the same coronary vessel. In other embodiments, the first and second compositions are introduced by infusion through different coronary vessels. In some embodiments, the second composition is recirculated into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation). This allows for the increasing the efficiency of perfusion of the heart with the second composition and thus the therapeutic agent and reducing extra-cardiac expression of the agent. Methods for recirculation and scavenging are well known and can be applied into the setup for isolating the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) from systemic circulation in the methods described herein. Exemplary methods for recirculation and scavenging include, for example, the recirculation system used for the closed loop recirculatory system described in Kaye et al., J Am Coll Cardiol 2007;50:253-60, the contents of which are herein incorporated by reference in their entirety. In some embodiments, cardiac arrest is induced for about 5 minutes to about 240 minutes, for example, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 120 minutes, about 140 minutes, about 160 minutes, about 180 minutes, about 200 minutes, about 220 minutes, about 240 minutes, 5-240 minutes, 5-210 minutes, 5-180 minutes, 5-150 minutes, 5-120 minutes, 5-90 minutes, 5-60 minutes, 5-45 minutes, 5-30 minutes, 5-15 minutes, 5-10 minutes, 10-240 minutes, 10-210 minutes, 10-180 minutes, 10-150 minutes, 10-120 minutes, 10-90 minutes, 10-60 minutes, 10-50 minutes, 10-40 minutes, 10-30 minutes, 10-20 minutes, 20-240 minutes, 20-210 minutes, 20-180 minutes, 20- 150 minutes, 20-120 minutes, 20-90 minutes, 20-60 minutes, 20-50 minutes, 20-40 minutes, 20- 30 minutes, 30-240 minutes, 30-210 minutes, 30-180 minutes, 30-150 minutes, 30-120 minutes, 30-90 minutes, 30-60 minutes, 30-50 minutes, 30-40 minutes, 40-240 minutes, 40-210 minutes, 40-180 minutes, 40-150 minutes, 40-120 minutes, 40-90 minutes, 40-60 minutes, 40-50 minutes, 60-240 minutes, 60-210 minutes, 60-180 minutes, 60-150 minutes, 60-120 minutes, 60-90 minutes, 80-240 minutes, 80-210 minutes, 80-180 minutes, 80-150 minutes, 80-120 minutes, 100-240 minutes, 100-210 minutes, 100-180 minutes, 100-150 minutes, 100-120 minutes, 120- Attorney Docket No.: DTJ-006PC 240 minutes, 120-210 minutes, 120-180 minutes, 120-150 minutes, 150-240 minutes, 150-210 minutes, 150-180 minutes, 180-240 minutes, or 180-210 minutes. The second composition may be introduced into the coronary arterial circulation by infusion for a period of about 15 seconds to about 180 seconds, for example, about 15 seconds, about 20 seconds, about 30 seconds, about 40 seconds, about 50 seconds, about 60 seconds, about 70 seconds, about 80 seconds, about 90 seconds, about 100 seconds, about 110 seconds, about 120 seconds, about 140 seconds, about 160 seconds, about 180 seconds, 30-180 seconds, 30-160 seconds, 30-140 seconds, 30-120 seconds, 30-100 seconds, 30-80 seconds, 30-60 seconds, 30-40 seconds, 45-180 seconds, 45-160 seconds, 45-140 seconds, 45-120 seconds, 45- 100 seconds, 45-80 seconds, 45-60 seconds, 60-180 seconds, 60-160 seconds, 60-140 seconds, 60-120 seconds, 60-100 seconds, 60-80 seconds, 75-180 seconds, 75-160 seconds, 75-140 seconds, 75-120 seconds, 75-100 seconds, 75-80 seconds, 90-180 seconds, 90-160 seconds, 90- 140 seconds, 90-120 seconds, 90-100 seconds, 100-180 seconds, 100-160 seconds, 100-140 seconds, 100-120 seconds, 120-180 seconds, 120-160 seconds, 120-140 seconds, 140-180 seconds, 140-160 seconds, or 160-180 seconds. In some embodiments, the second composition is infused over a period of about 30 seconds to about 2 minutes. In the methods described herein, the second composition perfuses the heart for a certain length of time, referred to as the dwell time. In some embodiments, the dwell time of the second composition is from about 5 minutes to about 60 minutes, for example, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, 5-60 minutes, 5-45 minutes, 5-30 minutes, 5-15 minutes, 5-10 minutes, 10-60 minutes, 10-45 minutes, 10-30 minutes, 10-15 minutes, 15-60 minutes, 15-45 minutes, 15-30 minutes, 20- 60 minutes, 20-45 minutes, 20-30 minutes, 30-60 minutes, 30-45 minutes, 35-60 minutes, 35-45 minutes, 40-60 minutes, 40-45 minutes, or 50-60 minutes. In some embodiments, the dwell time of the second composition is from about 5 minutes to about 30 minutes. Following perfusion of the heart with the second composition for a certain dwell time, cardiac arrest is reversed. Reversal can occur by flushing the second composition out of the cardiac circulation by infusing a third composition comprising cardioplegia solution and blood into the coronary arterial circulation. In some embodiments, the third composition has a higher temperature than the second composition (e.g., warm cardioplegia solution). The third Attorney Docket No.: DTJ-006PC composition may be infused into the aortic root. In some embodiments, the third composition comprises blood, which can be autologous or allogeneic blood. In some embodiments, endoballoon catheters, if used, are deflated. In some embodiments, additional agents are administered to improve cardiac function and protect against diastolic dysfunction, such as magnesium and / or epinephrine. Once cardiac arrest is reversed, the patient may be weaned off of bypass, vessels are repaired, catheters are removed, wounds are closed, and the patient undergoes standard recovery procedures. In one exemplary embodiment of the methods of delivery described herein, a human patient undergoes general anesthesia and intubation, the conditions / parameters of which can readily be determined by the anesthesiologist and surgeon. Once under anesthesia, heparin is administered, with an activated clotting time of, e.g., >480 seconds. A coronary sinus balloon is used to occlude and scavenge coronary flow is placed percutaneously (e.g., in the left common femoral vein). A superior vena cava (SVC) cannula is placed percutaneously (e.g., in the right jugular vein) and positioned at the SVC-right atrial (RA) junction. An inferior vena cava (IVC) cannula is placed percutaneously (e.g., in the right common femoral vein) and positioned at the IVC-RA junction. An arterial cannula is placed percutaneously (e.g., right common femoral artery) to assure adequate arterial flow. An endoballoon catheter is placed via an arterial approach (e.g., left common femoral artery) percutaneously and advanced into the ascending aorta above the sinotubular junction via either echocardiographic or radiographic imaging. The cannulae are deaired and connected to a cardiopulmonary bypass circuit. Cardiopulmonary bypass is initiated to assure appropriate perfusion and the absence of cardiac ejection. The endoballoon is inflated and cardioplegia solution infused into the aortic root resulting in cardiac arrest. Aortic root, endoballoon, and mean arterial pressures are monitored to assure appropriate occlusion of the ascending aorta. The coronary sinus balloon is then inflated. A mixture of the biologic, cardioplegia solution, and imaging dye is infused through the endoballoon into the aortic root providing perfusion of the coronary system with biologic. After a period of cardiac arrest and biologic dwell time, the coronary sinus catheter is used to scavenge the coronary system and a dose of warm blood is infused into the aortic root still with the endoballoon inflated to wash the coronary system of biologic. This is again scavenged with the coronary sinus balloon. The coronary sinus balloon is then deflated. The endoballoon is subsequently deflated to allow normal coronary perfusion and resumption of cardiac activity. After a period of Attorney Docket No.: DTJ-006PC stabilization, the patient is weaned from CPB and normal cardiac activity without CPB support is confirmed by transesophageal echo. The patient is decannulated and protamine administered. Sterile dressing is placed over the wounds and the patient emerges from anesthesia and is extubated, thereby concluding the procedure. It will be understood that various aspect of the procedure (e.g., materials used, vessels targeted) can be modified as appropriate so long as the cardiac circulation is isolated (e.g., substantially isolated) from the systemic circulation (e.g., use of an equivalent cardioplegia solution, use of clamps in place of balloon catheters for vessel occlusion, infusion in a retrograde manner into the coronary venous circulation). Therapeutic agents (e.g., in the second composition) suitable for use in the methods described herein include, for example, polypeptides, lipoproteins, nucleic acids, nucleic acid analogues, polynucleotides, polynucleotide delivery agents, small molecules, ribozymes, DNAzymes, aptamers, biologics, pharmaceuticals, immunotherapeutic agents, synthetic molecules, hormones, retrotransposons, cytokines, enzymes, viral vectors, gene therapy agents, and combinations and variants thereof. In some embodiments, the therapeutic agent is a cell (e.g., stem cell, CART cell). Therapeutic agents may be nucleic acids or polynucleotides which encode polypeptides that are therapeutic (e.g., a nucleic acid encoding a growth factor such as VEGF). Alternatively, therapeutic agents may be the polypeptides themselves (e.g., a growth factor such as VEGF). In some embodiments, the therapeutic agent is a nucleic acid, which is a vector. The vector may be, for example, a DNA vector (e.g., a DNA plasmid). In some embodiments, expression of the therapeutic agent is driven by a cardiac-specific promoter in the vector, for example, a cardiomyocyte-specific myosin light chain promoter or a cardiomyocyte-specific myosin heavy chain promoter. In other embodiments, expression of the therapeutic agent is driven by a constitutive promoter in the vector, such as a CMV promoter, RSV promoter, and SV40 promoter. In yet other embodiments, expression of the therapeutic agent is driven by a ubiquitous promoter in the vector. Suitable promoters for tissue-specific, constitutive, or ubiquitous expression are well known in the art. In some embodiments, the vector is a viral vector. Attorney Docket No.: DTJ-006PC In some embodiments, the therapeutic agent is a nucleic acid comprising a nucleotide sequence which encodes a polypeptide or an RNA molecule. In some embodiments, the nucleic acid is a locked nucleic acid (LNA). In some embodiments, the therapeutic agent is a synthetic peptide, chimeric protein, genetically engineered protein, mutated protein, or a modified protein. In some embodiments, the therapeutic agent is an angiogenic protein, a growth factor, a signaling protein, an antibody, an enzyme, a base editor, a gene editing agent, or a gene modification agent. In some embodiments, the therapeutic agent is a growth factor (e.g., angiogenic factor) selected from, but not limited to, vascular endothelial growth factor (VEGF) (e.g., VEGF-A, such as VEGF-121, VEGF-145, VEGF-165, VEGF-189, and VEGF-206; VEGF-B, such as VEGF-167, VEGF-186; VEGF-C), fibroblast growth factor (FGF) (e.g., FGF-1, FGF-2, FGF-4, FGF-5, FGF-6), a platelet-derived growth factor (PDGF) (e.g., PDGF-A, PDGF-B), a hypoxia inducible factor (HIF), an angiogenic polypeptide regulator, and an insulin-like growth factor (IGF) (e.g., IGF-1). Sequences encoding these growth factors, as well as their polypeptide sequences, are readily available in the art, e.g., via GENBANK sequence database. In some embodiments, the therapeutic agent is a signaling protein selected from, but not limited to, beta-adrenergic signaling proteins, such as beta-adrenergic receptors, G-protein receptor kinase inhibitors, and adenylyl cyclases. In some embodiments, the therapeutic agent is a base editor selected from, but not limited to, a cytidine base editor and an adenine base editor. See, e.g., Rees and Liu (Nature reviews: Genetics 2018;19:770-88; Komor et al. (Nature 2016;533:420-4); Gaudelli et al. (Nature 2017;511:464-71). In some embodiments, the therapeutic agent is a gene editing agent selected from, but not limited to, a transcriptional activator, a transcriptional repressor, a recombinase, a nuclease, a nucleic acid-binding protein, a nucleic acid binding polynucleotide or oligonucleotide, a DNA- binding protein, a DNA-binding nucleic acid, or a combination thereof. In some embodiments, the therapeutic agent is a gene editing agent selected from, but not limited to, a Cas9 nuclease, a Cre recombinase, a CRISPR / Cas molecule, a nickase, a TALE transcriptional activator, and combinations thereof. Methods of gene editing and, e.g., designing a CRISPR / Cas system for a particular genomic target, are well known in the art. Attorney Docket No.: DTJ-006PC In some embodiments, the therapeutic agent is a gene modification agent selected from, but not limited to, a retrotransposable element and a reverse transcriptase. In some embodiments, the therapeutic agent is a DNA molecule, for example, a complementary DNA (cDNA) molecule. In some embodiments, the cDNA molecule may encode a messenger RNA (mRNA) molecule, which in turn encodes a polypeptide which is therapeutic. In this scenario, each of the cDNA molecule, the mRNA molecule encoded by the cDNA molecule, and the polypeptide encoded by the mRNA molecule fall within the definition of a “therapeutic agent.” In some embodiments, the therapeutic agent is an RNA molecule, for example, an mRNA molecule. Exemplary RNA molecules suitable for use in the methods described herein include, but are not limited to, small interfering RNA (siRNA), a short hairpin RNA (shRNA), a double- stranded RNA (dsRNA), a piwi-interacting RNA (piRNA), a long non-coding RNA (lncRNA), a transfer-messenger (tmRNA), a transfer RNA (tRNA), a guide RNA (gRNA), a short guide RNA (sgRNA), a small nuclear RNA (snRNA), a small nucleolar RNA (snoRNA), or a microRNA (miRNA). In some embodiments, the therapeutic agent is a polynucleotide which decreases the expression of a nucleic acid sequence within a cardiac cell. In other embodiments, the polynucleotide increases the production of a polypeptide within a cardiac cell. In yet other embodiments, more than one nucleic acid or protein is increased and / or decreased by using one or more polynucleotides simultaneously or sequentially. The therapeutic agent may be encapsulated, for example, by an exosome or lipid nanoparticle (LNP). In some embodiments, the LNP comprises one or more or all of an ionizable cationic lipid, a helper phospholipid, cholesterol, and a polyethylene glycol (PEG) lipid. In some embodiments, the therapeutic agent is a mRNA molecule encapsulated by a LNP (i.e., a mRNA-LNP). The amount (dose) of the therapeutic agent in the second composition can be readily determined by a physician based on doses of the therapeutic agent or class of therapeutic agent reported in the art, for example, doses of the therapeutic agent or class of therapeutic agent reported in the art to treat a disease or condition (e.g., a cardiac condition). In some embodiments, the therapeutic agent is a mRNA-LNP, which is present in the second composition at a dose of about 0.01 mg to about 1 mg, for example, 0.01 to 1 mg, 0.01 to Attorney Docket No.: DTJ-006PC 0.5 mg, 0.01 to 0.25 mg, 0.01 to 0.1 mg, 0.01 to 0.05 mg, 0.05 to 1 mg, 0.05 to 0.5 mg, 0.05 to 0.25 mg, 0.05 to 0.1 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.1 to 0.25 mg, 0.25 to 1 mg, 0.25 to 0.5 mg, or 0.5 to 1 mg. In some embodiments, the therapeutic agent is a mRNA-LNP, which is present in the second composition at a per weight dose of about 0.01 mg to about 1 mg, for example, 0.01 to 1 mg, 0.01 to 0.5 mg, 0.01 to 0.25 mg, 0.01 to 0.1 mg, 0.01 to 0.05 mg, 0.05 to 1 mg, 0.05 to 0.5 mg, 0.05 to 0.25 mg, 0.05 to 0.1 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.1 to 0.25 mg, 0.25 to 1 mg, 0.25 to 0.5 mg, or 0.5 to 1 mg, in a patient weighing from about 60 to about 120 kg. In one embodiment, the mRNA-LNP is present in the second composition at a dose of about 0.01 mg to about 1 mg for a patient weighing about 60 kg to about 120 kg (e.g., 60-120 kg, 60-100 kg, 60- 80 kg, 80-120 kg, 80-100 kg, or 100-120 kg). In some embodiments, the therapeutic agent is a mRNA-LNP, which is present in the second composition at a per weight dose of about 0.0001 mg / kg to about 0.011 mg / kg, for example, 0.0001 to 0.011 mg / kg, 0.0005 to 0.011 mg / kg, 0.001 to 0.011 mg / kg, 0.005 to 0.011 mg / kg, 0.0075 to 0.011 mg / kg, 0.0001 to 0.0075 mg / kg, 0.0005 to 0.0075 mg / kg, 0.001 to 0.0075 mg / kg, 0.005 to 0.0075 mg / kg, 0.0001 to 0.005 mg / kg, 0.0005 to 0.005 mg / kg, 0.001 to 0.005 mg / kg, 0.0001 to 0.001 mg / kg, 0.0005 to 0.001 mg / kg, or 0.0001 to 0.0005 mg / kg. In some embodiments, the mRNA of the mRNA-LNP encodes VEGF, or a functional fragment thereof. In some embodiments, the therapeutic agent is a viral vector, for example, an adenovirus, an adeno-associated virus (AAV), a bovine papilloma virus, a herpes simplex virus, a lentivirus, a polyoma virus, a retrovirus, or a vaccinia virus. In some embodiments, the viral genome of the viral vector comprises a nucleotide sequence encoding a therapeutic agent described herein (e.g., a nucleic acid or polypeptide). In some embodiments, the viral vector is replication-deficient. In some embodiments, expression of the therapeutic agent is observed in the heart at about 48 hours or earlier, for example, at about 48 hours, at about 36 hours, at about 24 hours, at about 12 hours, at about 10 hours, at about 9 hours, at about 8 hours, at about 7 hours, at about 6 hours, at about 5 hours, 5-48 hours, 5-36 hours, 5-24 hours, 5-12 hours, 5-10 hours, 5-9 hours, 5- 8 hours, 9-48 hours, 9-36 hours, 9-24 hours, 9-12 hours, 12-48 hours, 12-36 hours, 12-24 hours, 24-48 hours, 24-36 hours, or 36-48 hours, after infusion of the therapeutic agent. Attorney Docket No.: DTJ-006PC In some embodiments, expression of the therapeutic agent is sustained for at least 2 weeks, for example, for at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, at least 2 weeks to 1 year, at least 2 weeks to 6 months, at least 2 weeks to 3 months, at least 1 month to 1 year, at least 1 month to 6 months, at least 1 month to 3 months, at least 3 months to 1 year, at least 3 months to 6 months, or at least 6 months to 1 year, after infusion of the therapeutic agent. The methods described herein can achieve transmural, pan-cardiac expression of the therapeutic agent. In some embodiments, transmural, pan-cardiac expression of the therapeutic agent is observed after about 9 hours, for example, after about 9 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, about 36 hours, about 40 hours, about 44 hours, about 48 hours, 9-48 hours, 9-36 hours, 9-24 hours, 9-12 hours, 12-48 hours, 12-36 hours, 12-24 hours, 24-48 hours, 24-36 hours, or 36-48 hours, from infusion of the therapeutic agent into the coronary arterial circulation. Expression of the therapeutic agent can be determined, for example, with a traceable detectable label using art-recognized methods, e.g., fluorescent reporter probes and bioluminescence imaging, and single photon emission computed tomography / computed tomography imaging strategies described in Boutagy et al., Circ Cardiovasc Imaging 2019;12:e009063, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the therapeutic agent is a mRNA-LNP, and at least 50%, for example, at least 60 %, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of cardiomyocytes in the heart express the therapeutic agent when the therapeutic agent is administered at a dose of 1 mg or less (e.g., 0.9 mg or less, 0.8 mg or less, 0.7 mg or less, 0.6 mg or less, 0.5 mg or less, 0.4 mg or less, 0.3 mg or less, 0.2 mg or less, 0.1 mg or less, 0.09 mg or less, 0.08 mg or less, 0.07 mg or less, 0.06 mg or less, 0.05 mg or less, 0.04 mg or less, 0.03 mg or less, 0.02 mg or less, 0.01 mg or less, 0.01 to 1 mg, 0.01-0.5 mg, 0.01-0.1 mg, 0.01-0.05 mg, 0.05-1 mg, 0.05-0.5 mg, 0.05-0.1 mg, 0.1-1 mg, 0.1-0.5 mg, or 0.5-1 mg (e.g., for a patient weighing from 60 kg to about 120 kg, e.g., 60-120 kg, 60-100 kg, 60-80 kg, 80-120 kg, 80-100 kg, or 100-120 kg), or a dose of about 0.011 mg / kg or less (e.g., 0.011 mg / kg or less, 0.0075 mg / kg or less, 0.005 mg / kg or less, 0.001 mg / kg or less, 0.0005 mg / kg or less, 0.0001 mg / kg or less, 0.0001 to 0.011 mg / kg, 0.0005 to 0.011 mg / kg, 0.001 to 0.011 mg / kg, 0.005 to 0.011 mg / kg, 0.0075 to 0.011 mg / kg, 0.0001 to Attorney Docket No.: DTJ-006PC 0.0075 mg / kg, 0.0005 to 0.0075 mg / kg, 0.001 to 0.0075 mg / kg, 0.005 to 0.0075 mg / kg, 0.0001 to 0.005 mg / kg, 0.0005 to 0.005 mg / kg, 0.001 to 0.005 mg / kg, 0.0001 to 0.001 mg / kg, 0.0005 to 0.001 mg / kg, or 0.0001 to 0.0005 mg / kg), for example, when the dwell time of the therapeutic agent is at least 10 minutes, at least 15 minutes, for example, at least 20 minutes, at least 25 minutes, at least 30 minutes, 10-30 minutes, 15-30 minutes, 20-30 minutes 25-30 minutes, 10-25 minutes, 15-25 minutes, 20-25 minutes, 20-30 minutes, 25-30 minutes. In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, or 100%) of cardiomyocytes in the heart express the therapeutic agent when the therapeutic agent is administered at a dose of 0.1 mg or less (e.g., for a patient weighing from about 60 kg to about 120 kg), or about 0.001 mg / kg or less, for example, when the dwell time of the therapeutic agent is at least 15 minutes (e.g., 15-30 minutes). In some embodiments, the therapeutic agent is preferentially expressed in the heart relative to other organs. In some embodiments, the therapeutic agent is preferentially expressed in the heart relative to the liver. In some embodiments, the therapeutic agent is preferentially expressed in the myocardium. Preferential expression of the therapeutic agent can be determined using, for example, animal models (porcine models) as described in the Examples. Other methods for determining preferential expression in the heart of a patient relative to other organs (e.g., liver) include, for example, using a traceable detectable label, as described supra. In some embodiments, the therapeutic agent is expressed in one or more or all of cardiomyocytes, endothelial cells, epithelial cells, interstitial cells, cardiac pacemaking cells, and / or cells of conducting tissue. In some embodiments, the therapeutic agent is a nucleic acid which is introduced into the patient by somatic gene transfer and is not introduced into the germ line. In some embodiments, the therapeutic agent is not expressed in germ cells, e.g., is not detectable in germ cells when using a traceable detectable label. In some embodiments, the expression of the therapeutic agent in the heart results in the increased survival of cardiac cells, increase in cardiac myocardial contractility, increase in angiogenesis, increase in ejection fraction, prevention or decrease the continued degradation of cardiac tissue, or prevention or decrease of cardiac remodeling, e.g., relative to a reference, e.g., before infusion of the therapeutic agent (e.g., relative to before infusion of the second composition or before the patient undergoes the methods described herein) or a non-treated Attorney Docket No.: DTJ-006PC patient. Administering a therapeutic agent to the heart using the methods described herein may result in improvements or an increase in a cardiac function (e.g., angiogenesis, cardiac cell survival, cardiac myocardial contractility, ejection fraction) by, e.g., 5-100%, 5-80%, 5-60%, 5- 40%, 5-20%, 10-100%, 10-80%, 10-60%, 10-40%, 10-20%, 20-100%, 20-80%, 20-60%, 20- 40%, 40-100%, 40-80%, 40-60%, 60-100%, 60-80%, 80-100%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, or more, for example, relative to a reference, e.g., before the therapeutic agent is administered or a non-treated patient. In general, “increase” as used herein means an increase by a statistically significant amount, e.g., relative to a reference (e.g., baseline level or a non-treated patient). Conversely, “decreased” as used herein means a decrease by a statistically significant amount, e.g., relative to a reference (e.g., baseline level or a non-treated patient). Accordingly, in some embodiments, the therapeutic agent administered using the methods described herein decreases the continued degradation of cardiac tissue or cardiac remodeling by, e.g., 5-100%, 5- 80%, 5-60%, 5-40%, 5-20%, 10-100%, 10-80%, 10-60%, 10-40%, 10-20%, 20-100%, 20-80%, 20-60%, 20-40%, 40-100%, 40-80%, 40-60%, 60-100%, 60-80%, 80-100%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, relative to a reference (e.g., baseline level such as before administration of the therapeutic agent or a non-treated patient). The methods of delivering a therapeutic agent to the heart described herein can be applied to the treatment of patients who suffer from a cardiac condition, or are at risk of a cardiac condition (e.g., a human subject with a predisposition, e.g., a genetic predisposition, to a cardiac condition). Accordingly, in another aspect, provided herein is a method of treating a cardiac condition in a patient (or a patient at risk of a cardiac condition), the method comprising: (a) isolating (e.g., substantially isolating) cardiac circulation from systemic circulation (e.g., percutaneously) in the patient, (b) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a first composition comprising a cardioplegia solution, thereby inducing cardiac arrest, and Attorney Docket No.: DTJ-006PC (c) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a second composition comprising a cardioplegia solution and a therapeutic agent, thereby delivering the therapeutic agent to cardiac cells in the patient; wherein the therapeutic agent treats the cardiac condition or reduces the risk of a developing a cardiac condition. In some embodiments, the cardiac condition is a disease or a disorder characterized by insufficient cardiac function. Accordingly, in another aspect, provided herein is a method of enhancing cardiac function in a human subject (e.g., a human patient with a cardiac condition or at risk of developing a cardiac condition), the method comprising: (a) isolating (e.g., substantially isolating) cardiac circulation from systemic circulation percutaneously in the human subject, (b) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a first composition comprising a cardioplegia solution, thereby inducing cardiac arrest, and (c) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a second composition comprising a cardioplegia solution and a therapeutic agent, thereby delivering the therapeutic agent to cardiac cells in the subject; wherein the therapeutic agent enhances the cardiac function of the subject. Exemplary cardiac conditions which can be treated using the methods described herein include, but are not limited to, acquired heart disease, abnormal heart contractility, acute coronary syndrome, angina pectoris, aortic regurgitation, aortic stenosis, arrhythmia, atherosclerosis, autoimmune endocarditis, blood flow disorder, cardiac arrhythmias, cardiac ischemia, cardiomyopathy, cardiomyopathy stemming from rare genetic disorders, congestive heart failure, congenital heart disease, coronary artery disease, endocarditis, heart attack, heart cancer, heart failure, heart valve disease, hereditary heart disorder, hypersensitivity myocarditis, idiopathic cardiomyopathy, infective myocarditis, ischemia, mitral valve regurgitation, muscular dystrophy, myocardial infarction, myocardial ischemia, non-ischemic cardiomyopathy, pulmonary hypertension, stroke, symptomatic arrhythmia, transplant rejection, valvular heart disease, or vascular disease. Therapeutic agents that can be used in gene therapy for cardiac conditions which are suitable for use in the methods described herein are well known in the art (see, e.g., Wolfram and Attorney Docket No.: DTJ-006PC Donahue, JAHA 2013;2:e000119; Korpela et al., J Intern Med 2021;230:567-82). Exemplary therapeutic agents include, but are not limited to, growth factors such as VEGF, FGF, PDGF, HIF-1α, and HGF for therapeutic angiogenesis; transgenes which regulate intracellular calcium, such as SERCA2a (which when reduced in heart failure affects systolic and diastolic cardiac function by abnormal calcium regulation (see, e.g., Kawase et al., J Am Coll Cardiol 2008;51:1112-9), S100A1 (which levels are depleted in failing cardiomyocytes (see, e.g., Pleger et al., Sci Transl Med 2011;3:92ra64), parvalbumin, phosphatase-1 inhibitor 1 (which levels are reduced in heart failure (see, e.g., Wittköpper et al., Cardiovasc Res 2011;91:392-401)), small ubiquitin-related modifier (SUMO)-1 (levels of which are reduced in heart failure (see, e.g., Tilemann et al., Sci Transl Med 2013;5:211ra159)); regulators of the β-adrenergic system, such as β-adrenergic receptor kinase c-terminal peptide (which improves cardiac function and delays the progression of heart failure (Raake et al., Eur Heart J 2013;34:1437-47)); regulators of cAMP production, such as adenylyl cyclase 6 (levels of which decline in failing cardiomyocytes in heart failure) (Lai et al., Circulation 2004;110:330-6)); chemokines such as stromal cell- derived factor-1 (Chung et al., Eur Heart J 2015;36:2228-38); and microRNAs such as miRNA- 199a (levels of which are reduced in hypoxia (Gabisonia et al., Nature 2019;569:418-22; Kuang GMQ et al., Circ Res 2005;23:1-7)). In some embodiments, the therapeutic agent is a gene listed in any one of Tables 2-6 of U.S. Patent No. 10,086,043, the contents of which are herein incorporated by reference in their entirety. In some embodiments, the patient has arrhythmia. Exemplary therapeutic agents which can be effective for treating arrhythmia include, but are not limited to, KCNH2-G628S, SCN4a, connexin 32, connexin 40, connexin 43, SERCA2a, adenylyl cyclase 1, adenylyl cyclase 6, and Kir2.1 (see, e.g., Wolfram and Donahue, supra). In some embodiments, the patient has a hereditary heart disorder, and the therapeutic agent is a gene-editing agent (e.g., CRISPR / Cas system) which corrects a gene mutation or disrupts disease-carrying mutations. Such applications are described, for example, in Liu et al. (Circulation Research 2022;130:1827-50). For example, the CRISPR / Cas9 gene editing system can be used to specifically target mutant alleles in diseases caused by dominant negative mutations in a gene, restore loss-of-function mutations in, e.g., autosomal recessive or X-linked recessive diseases, and precisely correct point mutations by base editing. For example, in one embodiment, the patient has an autosomal dominant form of Wolff-Parkinson-White syndrome, Attorney Docket No.: DTJ-006PC caused by a missense H530R mutation in the PRKAG2 gene, and CRISPR / Cas9 gene editing is used to target the mutant allele of the PRKAG2 gene (see, e.g., Xie et al., Cell Res 2016;265:1099-111). In another embodiment, the patient has ischemia-reperfusion injury from a heart attack or stroke, and CRISPR / Cas9 gene editing is used to target CaMKIIδ (Lebek et al., Science 2023;379:179-85). In some embodiments, treating the patient using the methods described herein reduces one or more symptoms of a cardiac condition (e.g., heart failure). A therapeutically significant reduction of a symptom is, e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% or more in a measured parameter as compared to a reference, e.g., baseline (before administration of therapeutic agent), a control, or non-treated patient. The therapeutic effect on such symptoms can be evaluated by assessing, for example, calcium metabolism (peak or resting intracellular calcium concentration), cardiac metabolism, electrocardiogram (ECG or EKG), heart contractility, heart rate, survival, and ventricular function (e.g., LVEDP, LVSP, ESPVR). The therapeutic effect can be assessed before, during, or after the treatment. In some embodiments, measurable parameters include clinically detectable markers of disease, such as depressed or elevated levels of a biological marker (e.g., aspartate aminotransferase, creatine phosphokinase, or lactate dehydrogenase). In some embodiments, the measurable parameters are clinically accepted scales (e.g., of symptoms or markers). In some embodiments, improvements in a cardiac condition or symptoms of a cardiac condition are determined through art-recognized methods, such as echocardiogram, electrocardiogram, Doppler ultrasound, angiogram, chest X-ray, exercise stress test, nuclear cardiac stress test, and nuclear medicine imaging. Nuclear medicine imaging, for example, allows for the analysis of the effects of the treatment by visualizing the structure and function of the heart. The ability of a therapeutic agent to treat a cardiac condition can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials or in animal model systems (e.g., porcine models) predictive of efficacy in humans. such as animal models of ischemia-reperfusion injury. III. Perfusion compositions Attorney Docket No.: DTJ-006PC Also provided herein are perfusion compositions suitable for use in the methods described herein. In some embodiments, the perfusion composition comprises a cardioplegic solution and a therapeutic agent. In some embodiments, the perfusion composition further comprises blood, wherein the blood is autologous or allogeneic blood. In some embodiments, the perfusion composition further comprises a dye (e.g., a contrast agent). In some embodiments, the perfusion composition comprises a cardioplegia solution, blood, and a therapeutic agent. In some embodiments, the perfusion composition comprises a cardioplegia solution, blood, a dye, and a therapeutic agent. In some embodiments, the perfusion composition further comprises a carrier, e.g., a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable excipients are well known in the art and include, for example, fillers, diluents, excipients, encapsulating materials, and solvents. Suitable pharmaceutically acceptable are described, for example, in Remington’s Pharmaceutical Sciences (by E.W. Martin). IV. Kits Also provided herein are kits comprising the perfusion compositions or compositions comprising a therapeutic agent (e.g., the second composition in the methods described herein). Accordingly, in some embodiments, the kit comprises the perfusion compositions described herein and instructions for use. In some embodiments, the kit further comprises a delivery system or one or more devices to administer the perfusion composition into one or more coronary vessels. In some embodiments, the one or more devices comprise one or more catheters, such as balloon catheters. In some embodiments, the kit further comprises a vasoactive agent (e.g., a vasculature permeability agent). V. Exemplary Embodiments 1. A method of delivering a therapeutic agent to cardiac cells in a patient, the method comprising: (a) isolating (e.g., substantially isolating) cardiac circulation from systemic circulation percutaneously, Attorney Docket No.: DTJ-006PC (b) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a first composition comprising a cardioplegia solution, thereby inducing cardiac arrest, and (c) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a second composition comprising a cardioplegia solution and a therapeutic agent, thereby delivering the therapeutic agent to cardiac cells in the patient. 2. A method of treating a cardiac condition, the method comprising: (a) isolating (e.g., substantially isolating) cardiac circulation from systemic circulation percutaneously in a human patient with the cardiac condition, (b) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a first composition comprising a cardioplegia solution, thereby inducing cardiac arrest, and (c) introducing into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) a second composition comprising a cardioplegia solution and a therapeutic agent, thereby delivering the therapeutic agent to cardiac cells in the patient; wherein the therapeutic agent treats the cardiac condition or enhances cardiac function. 3. The method of embodiment 1 or 2, wherein the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) is isolated from the systemic circulation with a cardiopulmonary bypass circuit. 4. The method of any one of embodiments 1-3, wherein the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) is isolated from the systemic circulation by occluding one or more coronary vessels. 5. The method of embodiment 4, wherein the one or more coronary vessels are occluded using an endoballoon catheter. 6. The method of any one of embodiments 1-5, wherein a catheter is placed in the right coronary artery, right carotid artery, and / or the left common carotid artery. Attorney Docket No.: DTJ-006PC 7. The method of any one of embodiments 1-6, wherein an endoballoon catheter is placed in the right carotid artery. 8. The method of any one of embodiments 1-7, wherein a cardiac plug sheath is placed in the left carotid artery. 9. The method of any one of embodiments 1- 8, wherein a catheter is placed in the inferior vena cava and / or the superior vena cava. 10. The method of any one of embodiments 1- 9, wherein the first composition is introduced by infusion into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) through a catheter placed into the lumen of a coronary vessel. 11. The method of any one of embodiments 1-10, wherein the first composition is introduced by infusion into the aortic root or the coronary sinus. 12. The method of embodiment 11, wherein the first composition is administered by infusion into the aortic root after inflating an endoballoon in the ascending aorta. 13. The method of any one of embodiments 1-12, wherein the first composition comprises potassium chloride or HTK. 14. The method of embodiment 13, wherein the first composition further comprises one or more, or all of, lactated Ringers solution, lidocaine hydrochloride, sodium bicarbonate, and mannitol. 15. The method of any one of embodiments 1-14, wherein the first composition comprises potassium chloride, lactated Ringers solution, lidocaine hydrochloride, sodium bicarbonate, and mannitol. Attorney Docket No.: DTJ-006PC 16. The method of any one of embodiments 1-15, wherein the first composition further comprises blood from the patient. 17. The method of any one of embodiments 1-16, wherein the first composition is administered by infusion over a period of 3-20 minutes (e.g., about 3 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, 3-20 minutes, 3-15 minutes, 3-10 minutes, 3-5 minutes, 5-20 minutes, 5-15 minutes, 5-10 minutes, 10-20 minutes, 10-15 minutes, or 15-20 minutes). 18. The method of any one of embodiments 1-17, wherein the first composition is administered by infusion over a period of 5-10 minutes. 19. The method of any one of embodiments 4-18, wherein a balloon is inflated in the coronary sinus following cardiac arrest. 20. The method of any one of embodiments 1-19, wherein the second composition is administered to the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation) after cardiac arrest occurs. 21. The method of any one of embodiments 1-20, wherein the second composition is administered by anterograde perfusion. 22. The method of any one of embodiments 1-20, wherein the second composition is administered by retrograde perfusion. 23. The method of any one of embodiments 1-22, wherein the second composition further comprises blood from the patient. 24. The method of any one of embodiments 1-23, wherein the second composition further comprises a dye. Attorney Docket No.: DTJ-006PC 25. The method of any one of embodiments 1-24, wherein the second composition comprises a cardioplegia solution, blood from the patient, a dye, and a therapeutic agent. 26. The method of any one of embodiments 1-25, wherein the second composition further comprises a vasoactive agent. 27. The method of any one of embodiments 1-26, wherein the first and second compositions are administered through the same coronary vessel. 28. The method of any one of embodiments 1-26, wherein the first and second compositions are administered through different coronary vessels. 29. The method of any one of embodiments 1-28, wherein the second composition is recirculated into the cardiac circulation. 30. The method of any one of embodiments 1-29, wherein cardiac arrest is induced for about 5 minutes to about 240 minutes (e.g., about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 120 minutes, about 140 minutes, about 160 minutes, about 180 minutes, about 200 minutes, about 220 minutes, about 240 minutes, 5-240 minutes, 5-210 minutes, 5-180 minutes, 5-150 minutes, 5-120 minutes, 5-90 minutes, 5-60 minutes, 5-45 minutes, 5-30 minutes, 5-15 minutes, 5-10 minutes, 10-240 minutes, 10-210 minutes, 10-180 minutes, 10-150 minutes, 10-120 minutes, 10-90 minutes, 10-60 minutes, 10-50 minutes, 10-40 minutes, 10-30 minutes, 10-20 minutes, 20-240 minutes, 20-210 minutes, 20-180 minutes, 20-150 minutes, 20-120 minutes, 20-90 minutes, 20-60 minutes, 20-50 minutes, 20-40 minutes, 20-30 minutes, 30-240 minutes, 30-210 minutes, 30-180 minutes, 30-150 minutes, 30- 120 minutes, 30-90 minutes, 30-60 minutes, 30-50 minutes, 30-40 minutes, 40-240 minutes, 40- 210 minutes, 40-180 minutes, 40-150 minutes, 40-120 minutes, 40-90 minutes, 40-60 minutes, 40-50 minutes, 60-240 minutes, 60-210 minutes, 60-180 minutes, 60-150 minutes, 60-120 minutes, 60-90 minutes, 80-240 minutes, 80-210 minutes, 80-180 minutes, 80-150 minutes, 80- 120 minutes, 100-240 minutes, 100-210 minutes, 100-180 minutes, 100-150 minutes, 100-120 Attorney Docket No.: DTJ-006PC minutes, 120-240 minutes, 120-210 minutes, 120-180 minutes, 120-150 minutes, 150-240 minutes, 150-210 minutes, 150-180 minutes, 180-240 minutes, or 180-210 minutes). 31. The method of any one of embodiments 1-30, wherein the second composition is administered by infusion over a period of about 15 seconds to about 180 seconds (e.g., about 15 seconds, about 20 seconds, about 30 seconds, about 40 seconds, about 50 seconds, about 60 seconds, about 70 seconds, about 80 seconds, about 90 seconds, about 100 seconds, about 110 seconds, about 120 seconds, about 140 seconds, about 160 seconds, about 180 seconds, 30-180 seconds, 30-160 seconds, 30-140 seconds, 30-120 seconds, 30-100 seconds, 30-80 seconds, 30- 60 seconds, 30-40 seconds, 45-180 seconds, 45-160 seconds, 45-140 seconds, 45-120 seconds, 45-100 seconds, 45-80 seconds, 45-60 seconds, 60-180 seconds, 60-160 seconds, 60-140 seconds, 60-120 seconds, 60-100 seconds, 60-80 seconds, 75-180 seconds, 75-160 seconds, 75- 140 seconds, 75-120 seconds, 75-100 seconds, 75-80 seconds, 90-180 seconds, 90-160 seconds, 90-140 seconds, 90-120 seconds, 90-100 seconds, 100-180 seconds, 100-160 seconds, 100-140 seconds, 100-120 seconds, 120-180 seconds, 120-160 seconds, 120-140 seconds, 140-180 seconds, 140-160 seconds, or 160-180 seconds). 32. The method of embodiment 31, wherein the second composition is administered by infusion over a period of about 30 seconds to about 2 minutes. 33. The method of any one of embodiments 1-32, wherein dwell time of the second composition is from about 5 minutes to about 60 minutes (e.g., about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, 5-60 minutes, 5-45 minutes, 5-30 minutes, 5-15 minutes, 5-10 minutes, 10-60 minutes, 10-45 minutes, 10-30 minutes, 10-15 minutes, 15-60 minutes, 15-45 minutes, 15-30 minutes, 20-60 minutes, 20-45 minutes, 20-30 minutes, 30-60 minutes, 30-45 minutes, 35-60 minutes, 35-45 minutes, 40-60 minutes, 40-45 minutes, or 50-60 minutes). 34. The method of embodiment 33, wherein dwell time of the second composition is from about 5 minutes to about 30 minutes. Attorney Docket No.: DTJ-006PC 35. The method of any one of embodiments 1-34, further comprising a step of removing the cardiac arrest. 36. The method of embodiment 35, wherein the second composition is flushed out of the cardiac circulation by infusing a third composition comprising cardioplegia solution and blood into the cardiac circulation (e.g., coronary arterial circulation or coronary venous circulation), wherein the third composition has a higher temperature than the second composition. 37. The method of embodiment 36, wherein the third composition is infused into the aortic root. 38. The method of any one of embodiments 5-37, wherein the endoballoon catheters, if present, are deflated. 39. The method of any one of embodiments 36-38, wherein the third composition further comprises blood from the patient. 40. The method of any one of embodiments 1-39, wherein the therapeutic agent is a polypeptide, a protein, a nucleic acid, a small molecule, a biologic, a pharmaceutical, a hormone, a retrotransposon, a cytokine, an enzyme, a viral vector, a gene therapy agent, or a cell. 41. The method of embodiment 40, wherein the therapeutic agent is a nucleic acid, and the nucleic acid is a vector. 42. The method of embodiment 40 or 41, wherein the nucleic acid is a polynucleotide molecule comprising a nucleotide sequence which encodes a polypeptide, protein, or an RNA molecule. 43. The method of any one of embodiments 1-42, wherein the therapeutic agent is an angiogenic protein, a growth factor, a signaling protein, an antibody, an enzyme, a base editor, a gene modification agent, or a gene-editing agent. Attorney Docket No.: DTJ-006PC 44. The method of embodiment 43, wherein the gene editing agent is a transcriptional activator, a transcriptional repressor, a recombinase, a nuclease, a DNA-binding protein, a nucleic acid, or combinations thereof. 45. The method of embodiment 43 or 44, wherein the gene editing agent is a Cas9 nuclease, a Cre recombinase, a CRISPR / Cas molecule, a nickase, a TALE transcriptional activator, a transcriptional regulator, or combinations thereof. 46. The method of any one of embodiments 1-43, wherein the therapeutic agent is VEGF. 47. The method of embodiment 40 or 41, wherein the nucleic acid is a DNA molecule. 48. The method of embodiment 47, wherein the DNA molecule is a complementary DNA (cDNA) molecule. 49. The method of any one of embodiments 40 and 42-46, wherein the nucleic acid is an RNA molecule. 50. The method of embodiment 49, wherein the RNA molecule is a messenger RNA (mRNA) molecule. 51. The method of embodiment 50, wherein the therapeutic agent is a small interfering RNA (siRNA), a short hairpin RNA (shRNA), a double-stranded RNA (dsRNA), a piwi-interacting RNA (piRNA), a long non-coding RNA (lncRNA), a transfer-messenger (tmRNA), a transfer RNA (tRNA), a guide RNA (gRNA), a short guide RNA (sgRNA), a small nuclear RNA (snRNA), a small nucleolar RNA (snoRNA), or a microRNA (miRNA). 52. The method of any one of embodiments 40-51, wherein expression of the therapeutic agent is driven by a cardiac-specific promoter in the vector. Attorney Docket No.: DTJ-006PC 53. The method of embodiment 40-51, wherein expression of the therapeutic agent is driven by a constitutive promoter in the vector. 54. The method of embodiment 40-51, wherein expression of the therapeutic agent is driven by a ubiquitous promoter in the vector. 55. The method of any one of embodiments 1-54, wherein the therapeutic agent is encoded by a nucleic acid. 56. The method of any one of embodiments 1-55, wherein the therapeutic agent is encapsulated in an exosome. 57. The method of any one of embodiments 1-55, wherein the therapeutic agent is encapsulated in a lipid nanoparticle (LNP). 58. The method of embodiment 57, wherein the LNP comprises an ionizable lipid, cholesterol, a phospholipid, a helper lipid, a polyethylene glycol lipids, or combinations thereof. 59. The method of embodiment 57 or 58, wherein the therapeutic agent is an mRNA, and the mRNA is encapsulated in the LNP (mRNA-LNP). 60. The method of embodiment 59, wherein the mRNA-LNP is present in the second composition at a dose of about 0.01 mg to about 1 mg (e.g., 0.01 to 1 mg, 0.01 to 0.5 mg, 0.01 to 0.25 mg, 0.01 to 0.1 mg, 0.01 to 0.05 mg, 0.05 to 1 mg, 0.05 to 0.5 mg, 0.05 to 0.25 mg, 0.05 to 0.1 mg, 0.1 to 1 mg, 0.1 to 0.5 mg, 0.1 to 0.25 mg, 0.25 to 1 mg, 0.25 to 0.5 mg, or 0.5 to 1 mg). 61. The method of embodiment 59, wherein the mRNA-LNP is present in the second composition at a dose of about 0.0001 mg / kg to about 0.011 mg / kg (e.g., 0.0001 to 0.011 mg / kg, 0.0005 to 0.011 mg / kg, 0.001 to 0.011 mg / kg, 0.005 to 0.011 mg / kg, 0.0075 to 0.011 mg / kg, 0.0001 to 0.0075 mg / kg, 0.0005 to 0.0075 mg / kg, 0.001 to 0.0075 mg / kg, 0.005 to 0.0075 Attorney Docket No.: DTJ-006PC mg / kg, 0.0001 to 0.005 mg / kg, 0.0005 to 0.005 mg / kg, 0.001 to 0.005 mg / kg, 0.0001 to 0.001 mg / kg, 0.0005 to 0.001 mg / kg, or 0.0001 to 0.0005 mg / kg). 62. The method of embodiment 40, wherein the viral vector is an adenovirus, an adeno- associated virus (AAV), a bovine papilloma virus, a herpes simplex virus, a lentivirus, a polyoma virus, a retrovirus, or a vaccinia virus. 63. The method of embodiment 62, wherein the virus is replication-deficient. 64. The method of any one of embodiments 40, 62, or 63, wherein the viral vector comprises a nucleotide sequence encoding the therapeutic agent described in any one of embodiments 40-51. 65. The method of any one of embodiments 1-64, wherein expression of the therapeutic agent in the heart results in the survival of cardiac cells, increase in cardiac myocardial contractility, increase in angiogenesis, prevention or decrease of cardiac remodeling, prevention or decrease of continual degradation of cardiac structure, e.g., relative to before infusion of the second composition. 66. The method of any one of embodiments 1-65, wherein expression of the therapeutic agent in the heart is observed at about 48 hours or earlier (e.g., at about 48 hours, at about 36 hours, at about 24 hours, at about 12 hours, at about 10 hours, at about 9 hours, at about 8 hours, at about 7 hours, at about 6 hours, at about 5 hours, 5-48 hours, 5-36 hours, 5-24 hours, 5-12 hours, 5-10 hours, 5-9 hours, 5-8 hours, 9-48 hours, 9-36 hours, 9-24 hours, 9-12 hours, 12-48 hours, 12-36 hours, 12-24 hours, 24-48 hours, 24-36 hours, or 36-48 hours) after infusion of the second composition. 67. The method of any one of embodiments 1-66, wherein expression of the therapeutic agent is sustained for at least 2 weeks (e.g., at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, 2 weeks to 1 year, 2 weeks to 6 months, 2 weeks to 3 months, 1 month to 1 year, 1 month to 6 months, 1 month to 3 months, 3 months to 1 year, 3 months to 6 months, 6 months to 1 year, or 1 year or longer). Attorney Docket No.: DTJ-006PC 68. The method of any one of embodiments 1-67, wherein transmural, pan-cardiac expression of the therapeutic agent is observed after about 9 hours (e.g., about 9 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, about 36 hours, about 40 hours, about 44 hours, about 48 hours, 9-48 hours, 9-36 hours, 9-24 hours, 9-12 hours, 12-48 hours, 12-36 hours, 12-24 hours, 24-48 hours, 24-36 hours, or 36-48 hours) from introduction into the isolated coronary arterial circulation. 69. The method of any one of embodiments 1-68, wherein at least 70% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) of cardiomyocytes express the therapeutic agent when the therapeutic agent is administered at a dose of 1 mg or less (e.g., 0.9 mg or less, 0.8 mg or less, 0.7 mg or less, 0.6 mg or less, 0.5 mg or less, 0.4 mg or less, 0.3 mg or less, 0.2 mg or less, 0.1 mg or less, 0.09 mg or less, 0.08 mg or less, 0.07 mg or less, 0.06 mg or less, 0.05 mg or less, 0.04 mg or less, 0.03 mg or less, 0.02 mg or less, 0.01 mg or less, 0.01-1 mg, 0.01-0.5 mg, 0.01-0.1 mg, 0.01-0.05 mg, 0.05-1mg, 0.05-0.5 mg, 0.05-0.1 mg, 0.1-1mg, 0.1-0.5 mg, or 0.5-1 mg), e.g., for a patient weight about 60-120 kg. 70. The method of embodiment 69, wherein at least 70% (e.g., at least 80% or at least 90%) of cardiomyocytes express the therapeutic agent when the therapeutic agent is administered at a dose of 0.1 mg or less, e.g., for a patient weighing about 60-120 kg. 71. The method of any one of embodiments 1-68, wherein at least 70% (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) of cardiomyocytes express the therapeutic agent when the therapeutic agent is administered at a dose of about 0.001 mg / kg or less (e.g., 0.001 mg / kg or less, 0.0005 mg / kg or less, 0.0001 mg / kg or less, 0.0001 to 0.001 mg / kg, 0.0005 to 0.001 mg / kg, or 0.00075 to 0.001 mg / kg). 72. The method of any one of embodiments 69-71, wherein dwell time of the therapeutic agent is at least 15 minutes (e.g., 15-30 minutes). Attorney Docket No.: DTJ-006PC 73. The method of any one of embodiments 1-72, wherein the therapeutic agent is expressed preferentially in the heart. 74. The method of any one of embodiments 1-73, wherein the therapeutic agent is expressed preferentially in the myocardium. 75. The method of any one of embodiments 1-74, wherein the therapeutic agent is expressed in one or more or all of vascular endothelial cells, cardiomyocytes, epithelial cells, fibroblasts, endothelial cells, cardiac pacemaking cells, interstitial cells, or cells of conducting tissue of the heart. 76. The method of any one of embodiments 1-75, wherein the therapeutic agent is not expressed (e.g., not detectable by, e.g., a traceable detectable marker) in germ cells. 77. The method of any one of embodiments 2-76, wherein the cardiac condition is a disease or disorder characterized by insufficient cardiac function. 78. The method of any one of embodiments 2-77, wherein the cardiac condition is acquired heart disease, abnormal heart contractility, acute coronary syndrome, angina pectoris, aortic regurgitation, aortic stenosis, arrhythmia, atherosclerosis, autoimmune endocarditis, blood flow disorder, cardiac arrhythmias, cardiac ischemia, cardiomyopathy, cardiomyopathy stemming from rare genetic disorders, congestive heart failure, congenital heart disease, coronary artery disease, endocarditis, heart attack, heart cancer, heart failure, heart valve disease, hereditary heart disease, hypersensitivity myocarditis, idiopathic cardiomyopathy, infective myocarditis, ischemia, mitral valve regurgitation, muscular dystrophy, myocardial infarction, myocardial ischemia, non-ischemic cardiomyopathy, pulmonary hypertension, stroke, symptomatic arrhythmia, transplant rejection, valvular heart disease, or vascular disease. 79. A perfusion composition comprising a cardioplegic solution and a therapeutic agent. Attorney Docket No.: DTJ-006PC 80. The perfusion composition of embodiment 79, further comprising blood from a patient to which the composition is to be administered. 81. The perfusion composition of embodiment 79 or 80, further comprising a dye. 82. The perfusion composition of any one of embodiments 79-81, wherein the therapeutic agent is as described in any one of embodiments 42-51. 83. A kit comprising the perfusion composition of any one of embodiments 79-82 and instructions for use. 84. The kit of embodiment 83, wherein the kit further comprises one or more devices for introducing the composition into one or more coronary vessels. 85. The kit of embodiment 84, wherein the one or more devices comprises a one or more catheters (e.g., a balloon catheter). VI. EXAMPLES Methods 1) Cardiopulmonary bypass / percutaneous isolation of cardiac circulation from systemic circulation a. Anesthesia and medication Pigs (approximately 80 kg each) were sedated with a mixture of tiletamine and zolazepam (equal parts), 3 mg / kg (TZED 100 mg / mL) via intramuscular (IM) administration of body weight and glycopyrrolate (0.02 mg / kg IM). After achieving sedation, general anesthesia was maintained using isoflurane inhalation and IV administration of a small bolus of propofol (0.5 mg / kg) to facilitate endotracheal intubation. General anesthesia was continued by inhalant isoflurane in a concentration of 2% vol during the length of the procedure (discontinued for some time during cardiopulmonary bypass (CPB) as inhalant was then delivered from the perfusion machine). During the procedure, amiodarone in constant rate of infusion (CRI) was Attorney Docket No.: DTJ-006PC administered IV at a rate of 0.5 mg / kg / h. Separately, ringer acetate with lidocaine (0.2 mg / mL) and metoprolol (5 mcg / mL) was administered as CRI at a rate of 1 mg / kg / h of lidocaine and 25 mcg / kg / h of metoprolol. These drugs were infused over the course of the procedure, but amiodarone was discontinued during the step of wound closure. b. Cannulation To determine individual variations in coronary vascularity as well as the suitability of coronary sinus catheterization, coronary arteries and veins were first imaged with CT by antegrade injections of contrast agent (Omnipaque). Arterial cannulation: Right coronary artery catheterization was achieved from the right femoral artery using a 16F Edwards Femflex catheter. A 16Fr sheath for endoballoon was placed in the right carotid artery. A 9F sheath was placed in the left common carotid artery via the femoral arterial cannula. Venous cannulation: Inferior vena cava (IVC) catheterization was achieved from the left femoral vein using a 19F Medtronic multistage femoral venous cannula. Superior vena cava (SVC) catheterization was achieved from the right internal jugular vein using a 19F Medtronic Biomedicus short basket venous cannula. Endoballoon delivery system: An Edwards IntraClude intra-aortic occlusion device was placed in the right common carotid artery. A cardiac plug sheath was placed in the left carotid artery and the circuit was connected. c. Bypass procedure Initiation of flow was commenced after autologous blood priming of the line. Full flow was achieved when the heart was fully drained and mean arterial pressures were sufficient (>45 mmHg). The pump flow was 3 to 4 LPM and line pressure was 160-220 mmHg. Gas flow to the oxygenator was 1 LPM, 100% FiO2, and 2% isoflurane. For cardioplegia delivery, an endoballoon was inflated in the ascending aorta using CT verification to a balloon pressure >300 mmHg. 1L of cardioplegia solution (lactated Ringer’s 306.5 mL, lidocaine hydrochloride 250 mg, sodium bicarbonate 11 mEq, potassium chloride 48 mEq, mannitol 31,260 mg; 4 parts blood to 1 part cardioplegia solution, e.g., 1L = 800 mL whole blood + 200 mL cardioplegia) was delivered to the aortic root using the endoballoon delivery Attorney Docket No.: DTJ-006PC system to arrest the heart (over the course of 5-10 mins). Once finalized, the coronary sinus balloon was inflated. The mRNA-LNP for delivery was prepared as a mixture containing cardioplegia + whole blood solution, dye, and mRNA-LNP, and infused over the course of 30 seconds to 2 minutes. The mRNA payload for the experiments described herein was nuclear β-galactosidase (nLacZ). The LNP in this instance is composed of an ionizable cationic lipid, helper phospholipid, cholesterol, and polyethylene glycol (PEG) lipid. The characteristics of the LNP display inherent hypoimmune properties. A schematic of an exemplary CBP circuit suitable for use in the methods described herein is shown in FIG. 1. d. Restarting heart and coming off bypass After approximately 15 minutes of mRNA-LNP dwell time, and as QRS complexes appeared more regularly, the coronary sinus balloon was deflated and a 50 mL “hot shot” was infused. The “hot shot” is a warm cardioplegia / blood solution administered to the aortic root prior to the end of bypass to flush the coronary circulation of cold cardioplegia (and the mRNA- LNP) and in doing so enhance the metabolic state of the heart). Once the endoballoon was deflated, the heart began beating with reperfusion of coronary arteries. Electric activity was monitored, and bypass was gradually reduced and ejection restored. Once vitals were stable, the animals were weaned off the bypass. 1 g of magnesium was administered to decrease the chances of postoperative arrhythmias and to improve cardiac function. Epinephrine was also administered at a constant rate of infusion at 0.01 mg / min / kg to protect against diastolic dysfunction post-bypass. Vessels were repaired, indwelling catheters were removed, and wounds were closed. 2) Sample collection Prior to euthanasia animals were deeply sedated by infusion of tiletamine / zolazepam mixture (2-3mg / kg) via indwelling venous line. Then a bolus of heparin was administered and the drugs allowed to circulate for a minimum of at least five minutes. A bolus of euthanasia solution containing pentobarbital and phenothiazine was then infused. Asystole was confirmed via auscultation or ECG and the animal was transported to necroscopy. Attorney Docket No.: DTJ-006PC For necropsy, the thoracic cavity was opened and the heart explanted. The heart was formalin perfused prior to further dissection and tissue collection. During heart perfusion, other samples were collected. Once perfusion was completed, the heart was dissected starting from precise structures such as the aorta, coronary artery, or valves, followed by right and left ventricle sampling. Following tissue harvest, samples were washed in PBS and placed in 5mL collection tubes where they were suspended in a 4:1 mix of 15% sucrose:formalin fixative prior to being frozen and embedded for histological analysis. The 15% solution was prepared by dissolving 75 g sucrose in 500 mL PBS. 3) Immunohistology Sample Process and Embedding Samples selected for staining were transferred to 70% ethanol prior to processing. Each tissue of reasonable size was loaded into an individual histology cassette where samples were processed using a Leica-ASP-300 Tissue Processor. Frist, samples were incubated in increasing concentrations of ethanol reagent for intervals of 15-30 mins at RT. The samples were then incubated and cleared in xylene and paraffin embedded. Additional samples not selected for immediate staining were directly embedded to OCT compound following the histology routine. Such samples were then frozen at -80C for long-term storage. Tissue Sectioning Each formalin-fixed, paraffin-embedded (FFPE) block was sectioned with a thickness of 5 micrometers. Sections were loaded to a histology glass slide from the water bath. Slides were heated at 60°C for 1 hour in an oven before performing the staining protocol in a Leica Autostainer XL. H&E Stain Sections were cleared in xylene to deparaffinize and slowly rehydrated by incubation in decreasing concentration of ethanol followed by rinsing in water. Slides were then stained using Harris Hematoxylin for nuclear staining, followed by a water rinse and a 1% acidic ethanol incubation to define nuclei appearance. Following another water rinse, the slides were stained in Attorney Docket No.: DTJ-006PC eosin for cytoplasmic staining and again rinsed in water. The slides were then dehydrated in increasing concentrations of ethanol, cleared in xylene, mounted with a coverslip, and left to dry. IHC-IF Stain Following tissue sectioning, tissue sections were deparaffinized and rehydrated by incubations in decreasing concentrations of ethanol. Antigen retrieval was then performed by incubating in citrate buffer. Next, tissue slides were rinsed and blocked using a blocking buffer consisting of 2.5% Normal Horse Serum. The tissue sections were then incubated with Rabbit anti-β-Galactosidase antibody for 1 hr. The slides were washed three times using TBST after which the sections were stained with a Goat anti-Rb IgG amplifier antibody. Tissues were again washed three times with TBST and then incubated with Horse anti-goat IgG HRP Polymer antibody. Following a further TBST wash, a fluorophore incubation step with Opal 620 Flurophore Reagent was performed. Following a TBST wash, 2.5% Normal Goat Serum was used for blocking. Next, phalloidin detection was performed using Phalloidin-GFP solution. Tissue sections were washed again with TBST and then a nuclear stain was applied using Hoechst 33342. Following a final rinse in TBST and distilled water, coverslips were applied with Vibrance Antifade for mounting and left to dry. Whole-Slide Image Acquisition All H&E and IHC-IF stained slides were scanned using an Akoya Phenolmager Fusion with a resolution of 0.5um / pixel (20x). For IHC-IF, exposure times were optimized for 3 fluorescence filters (DAPI (2.85ms), Opal 520 (410ms), and Opal 620 (60ms), and remained consistent across all whole-slide images. Each image was generated as a qptiff file, which could be opened directly in Akoya Phenochart software for viewing and quantification analysis. Quantification A field of each microscopic image was chosen to identify approximately 100 cells. Cells were counted twice; once to identify the number of cells (blue DAPI), and a second count for nLACZ expression (red). This was repeated for three separate fields for each cell type and the counts were averaged. Attorney Docket No.: DTJ-006PC Example 1: Delivery of mRNA-LNP to cardiac cells by all-percutaneous cardiopulmonary bypass and cardiac arrest (1 mg biologic, 15 minute dwell time) In this Example, expression of a nLacZ reporter and its biodistribution following antegrade perfusion of the cardioplegia / biologic (mRNA-LNP, 1 mg) solution was measured at 36 hours post-infusion. A CPB circuit was established as described in the Methods section. The cardioplegia / biologic solution was infused into a pig (94 kg), with a dwell time of 15 minutes for the mRNA-LNP (1 mg). One pig, used as a control, was not infused with the biologic, but samples were processed in the same manner as with the experimental pig. The pigs were sacrificed 36 hours later and expression of the nLacZ reporter was determined. As expected, the heart of the control pig showed no detectable LacZ signal (FIG. 2). In the experimental pig, transmural, pan-cardiac expression of the nuclear nLacZ reporter was observed throughout the entire myocardium (FIG. 3). There was no acute cardiac inflammation after 36 hours of mRNA-LNP administration (FIG. 4) and limited nLacZ reporter expression was detected in the liver (FIG. 5). Percent delivery by organ is shown in FIG. 9, demonstrating that nearly all cardiac cells assessed (cardiomyocytes, interstitial cells, endothelial cells) expressed the reporter. Similar results in terms of expression pattern and level, and percent of cells expressing the reporter, were observed in a pig sacrificed at 9 hours (1 mg biologic, 15 minute dwell time) instead of 36 hours. Example 2. Delivery of mRNA-LNP to cardiac cells by all-percutaneous cardiopulmonary bypass and cardiac arrest (0.1 mg biologic, 15 minute dwell time) In this Example, expression of a nLacZ reporter and its biodistribution following antegrade perfusion of the cardioplegia / biologic (mRNA-LNP, 0.1 mg) solution was measured at 36 hours post-infusion. A CPB circuit was established as described in the Methods section. The cardioplegia / biologic solution was infused into a pig (88 kg), with a dwell time of 15 minutes for the mRNA-LNP (0.1 mg). The pig was sacrificed 36 hours later and expression of the nLacZ reporter was determined. Similar to Example 1 above, transmural, pan-cardiac expression of the nLacZ reporter was observed throughout the entire myocardium with a 10-fold reduction in biologic dose Attorney Docket No.: DTJ-006PC relative to the experiments in Example 1 (0.1 mg vs. 1 mg mRNA-LNP) (FIG. 6). No acute cardiac inflammation was observed after 36 hours of mRNA-LNP administration (FIG. 7), and reporter expression in the liver was minimal (FIG. 8). Percent delivery by organ is shown in FIG. 9, demonstrating that most of the cardiac cells assessed (cardiomyocytes, interstitial cells, endothelial cells) expressed the reporter, similar to the 1 mg dose of mRNA-LNP described in Example 1. VII. Equivalents and Scope The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to certain embodiments, it is apparent that further embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

Attorney Docket No.: DTJ-006PC We claim:

1. A method of delivering a therapeutic agent to cardiac cells in a patient, the method comprising: (a) isolating cardiac circulation from systemic circulation percutaneously, (b) introducing into coronary arterial circulation a first composition comprising a cardioplegia solution, thereby inducing cardiac arrest, and (c) introducing into the coronary arterial circulation a second composition comprising a cardioplegia solution and a therapeutic agent, thereby delivering the therapeutic agent to cardiac cells in the patient.

2. A method of treating a cardiac condition in a patient, the method comprising: (a) isolating cardiac circulation from systemic circulation percutaneously in a patient with the cardiac condition, (b) introducing into coronary arterial circulation a first composition comprising a cardioplegia solution, thereby inducing cardiac arrest, and (c) introducing into the coronary arterial circulation a second composition comprising a cardioplegia solution and a therapeutic agent, thereby delivering the therapeutic agent to cardiac cells in the patient; wherein the therapeutic agent treats the cardiac condition.

3. The method of claim 1 or 2, wherein the cardiac circulation is isolated from the systemic circulation with a cardiopulmonary bypass circuit.

4. The method of any one of claims 1-3, wherein the cardiac circulation is isolated from the systemic circulation by occluding one or more coronary vessels.

5. The method of claim 4, wherein the one or more coronary vessels are occluded using an endoballoon catheter.Attorney Docket No.: DTJ-006PC 6. The method of any one of claims 1-5, wherein the first composition is introduced by infusion into the coronary arterial circulation through a catheter placed into the lumen of a coronary vessel.

7. The method of any one of claims 1-6, wherein the first composition is introduced by infusion into the aortic root or the coronary sinus.

8. The method of claim 7, wherein the first composition is administered by infusion into the aortic root after inflating an endoballoon in the ascending aorta.

9. The method of any one of claims 1-8, wherein an endoballoon is inflated in the coronary sinus following cardiac arrest.

10. The method of any one of claims 1-9, wherein the second composition is administered by anterograde perfusion.

11. The method of any one of claims 1-9, wherein the second composition is administered by retrograde perfusion.

12. The method of any one of claims 1-11, wherein the second composition comprises a cardioplegia solution, blood from the patient, a dye, and a therapeutic agent.

13. The method of any one of claims 1-12, wherein the second composition is recirculated into the isolated coronary arterial circulation.

14. The method of any one of claims 1-13, wherein cardiac arrest is induced for about 5 minutes to about 30 minutes (e.g., about 15 minutes).

15. The method of any one of claims 1-14, wherein the second composition is administered by infusion over a period of about 30 seconds to about 2 minutes.Attorney Docket No.: DTJ-006PC 16. The method of any one of claims 1-15, wherein dwell time of the second composition is about 5 minutes to about 30 minutes (e.g., about 15 minutes).

17. The method of any one of claims 1-16, further comprising a step of removing the cardiac arrest.

18. The method of any one of claims 1-17, wherein the therapeutic agent is a polypeptide, a nucleic acid, a small molecule, a virus, or a cell.

19. The method of any one of claims 1-18, wherein the therapeutic agent is a nucleic acid, and the nucleic acid is a vector.

20. The method of any one of claims 1-19, wherein the therapeutic agent is a polynucleotide comprising a nucleotide sequence which encodes a polypeptide or RNA.

21. The method of any one of claims 1-20, wherein the therapeutic agent is an mRNA.

22. The method of any one of claims 1-21, wherein the therapeutic agent is an angiogenic protein, a growth factor, a signaling protein, an antibody, an enzyme, a base editor, a gene- editing agent, a transcriptional activator, a transcriptional repressor, a recombinase, a nuclease, a DNA-binding protein, a Cas9 nuclease, a Cre recombinase, a CRISPR / Cas molecule, a nickase, a TALE transcriptional activator, a transcriptional regulator, a siRNA, a shRNA, a dsRNA, a piRNA, a lncRNA, a tmRNA, a tRNA, a sgRNA, a snRNA, a snoRNA, or a miRNA.

23. The method of any one of claims 1-22, wherein the therapeutic agent is vascular endothelial growth factor (VEGF).

24. The method of any one of claims 19-23, wherein expression of the therapeutic agent is driven by a cardiac-specific promoter in the vector.Attorney Docket No.: DTJ-006PC 25. The method of any one of claims 19-23, wherein expression of the polypeptide, protein, or nucleic acid is driven by a constitutive promoter in the vector.

26. The method of any one of claims 1- 25, wherein the therapeutic agent is encapsulated in an exosome.

27. The method of any one of claims 1- 25, wherein the therapeutic agent is encapsulated in a lipid nanoparticle (LNP) or a virus.

28. The method of claim 27, wherein the virus comprises a viral genome which encodes the therapeutic agent.

29. The method of claim 28, wherein the virus is an adeno-associated virus (AAV).

30. The method of claim 27, wherein the therapeutic agent is an mRNA, and the mRNA is encapsulated in the LNP (mRNA-LNP).

31. The method of claim 30, wherein the mRNA-LNP is present in the second composition at a dose of about 0.01 mg to about 1 mg.

32. The method of claim 30 or 31, wherein the mRNA-LNP is present in the second composition at a dose of about 0.0001 mg / kg to about 0.011 mg / kg.

33. The method of any one of claims 1-32, wherein transmural, pan-cardiac expression of the therapeutic agent is observed after about 9 hours from introduction into the isolated coronary arterial circulation.

34. The method of any one of claims 1-33, wherein at least 50% (e.g., at least 60%, at least 70%, at least 80%, or at least 90%) of cardiomyocytes express the therapeutic agent when the therapeutic agent is administered at a dose of 0.1 mg or less.Attorney Docket No.: DTJ-006PC 35. The method of any one of claims 1-34, wherein at least 50% (e.g., at least 60%, at least 70%, at least 80%, or at least 90%) of cardiomyocytes express the therapeutic agent when the therapeutic agent is administered at a dose of 0.001 mg / kg or less.

36. The method of any one of claims 1-35, wherein dwell time of the therapeutic agent is at least 15 minutes (e.g., 15-30 minutes).

37. The method of any one of claims 1-36, wherein the therapeutic agent is expressed preferentially in the heart.

38. The method of any one of claims 1-37, wherein the therapeutic agent is expressed preferentially in the myocardium.

39. The method of any one of claims 1-38, wherein the therapeutic agent is expressed in one or more of vascular endothelial cells, cardiomyocytes, epithelial cells, fibroblasts, endothelial cells, cardiac pacemaking cells, interstitial cells, and cells of conducting tissue of the heart..

40. The method of any one of claims 2-39, wherein the cardiac condition is acquired heart disease, abnormal heart contractility, acute coronary syndrome, angina pectoris, aortic regurgitation, aortic stenosis, arrhythmia, atherosclerosis, autoimmune endocarditis, blood flow disorder, cardiac arrhythmias, cardiac ischemia, cardiomyopathy, cardiomyopathy stemming from rare genetic disorders, congestive heart failure, congenital heart disease, coronary artery disease, endocarditis, heart cancer, heart failure, heart valve disease, hereditary heart disorder, hypersensitivity myocarditis, idiopathic cardiomyopathy, infective myocarditis, ischemia, mitral valve regurgitation, muscular dystrophy, myocardial infarction, myocardial ischemia, non- ischemic cardiomyopathy, pulmonary hypertension, symptomatic arrhythmia, transplant rejection, valvular heart disease, or vascular disease.

41. A perfusion composition comprising a cardioplegic solution, blood from a patient, dye, and a therapeutic agent.Attorney Docket No.: DTJ-006PC 42. A kit comprising the perfusion composition of claim 41 and instructions for use.

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