Monocyte-Derived Macrophages Aggravate Cardiac Dysfunction After Ischemic Stroke in Mice.

BACKGROUND: Cardiac damage induced by ischemic stroke, such as arrhythmia, cardiac dysfunction, and even cardiac arrest, is referred to as cerebral-cardiac syndrome (CCS). Cardiac macrophages are reported to be closely associated with stroke-induced cardiac damage. However, the role of macrophage subsets in CCS is still unclear due to their heterogeneity. Sympathetic nerves play a significant role in regulating macrophages in cardiovascular disease. However, the role of macrophage subsets and sympathetic nerves in CCS is still unclear. METHODS AND RESULTS: In this study, a middle cerebral artery occlusion mouse model was used to simulate ischemic stroke. ECG and echocardiography were used to assess cardiac function. We used Cx3cr1GFPCcr2RFP mice and NLRP3-deficient mice in combination with Smart-seq2 RNA sequencing to confirm the role of macrophage subsets in CCS. We demonstrated that ischemic stroke-induced cardiac damage is characterized by severe cardiac dysfunction and robust infiltration of monocyte-derived macrophages into the heart. Subsequently, we identified that cardiac monocyte-derived macrophages displayed a proinflammatory profile. We also observed that cardiac dysfunction was rescued in ischemic stroke mice by blocking macrophage infiltration using a CCR2 antagonist and NLRP3-deficient mice. In addition, a cardiac sympathetic nerve retrograde tracer and a sympathectomy method were used to explore the relationship between sympathetic nerves and cardiac macrophages. We found that cardiac sympathetic nerves are significantly activated after ischemic stroke, which contributes to the infiltration of monocyte-derived macrophages and subsequent cardiac dysfunction. CONCLUSIONS: Our findings suggest a potential pathogenesis of CCS involving the cardiac sympathetic nerve-monocyte-derived macrophage axis.

Sex-based differences in short- and longer-term diet-induced metabolic heart disease.

Sex-based differences in the development of obesity-induced cardiometabolic dysfunction are well documented, however, the specific mechanisms are not completely understood. Obesity has been linked to dysregulation of the epitranscriptome, but the role of N6-methyladenosine (m6A) RNA methylation has not been investigated in relation to the sex differences during obesity-induced cardiac dysfunction. In the current study, male and female C57BL/6J mice were subjected to short- and long-term high-fat/high-sucrose (HFHS) diet to induce obesogenic stress. Cardiac echocardiography showed males developed systolic and diastolic dysfunction after 4 mo of diet, but females maintained normal cardiac function despite both sexes being metabolically dysfunctional. Cardiac m6A machinery gene expression was differentially regulated by duration of HFHS diet in male, but not female mice, and left ventricular ejection fraction correlated with RNA machinery gene levels in a sex- and age-dependent manner. RNA-sequencing of cardiac transcriptome revealed that females, but not males may undergo protective cardiac remodeling early in the course of obesogenic stress. Taken together, our study demonstrates for the first time that cardiac RNA methylation machinery genes are regulated early during obesogenic stress in a sex-dependent manner and may play a role in the sex differences observed in cardiometabolic dysfunction.NEW & NOTEWORTHY Sex differences in obesity-associated cardiomyopathy are well documented but incompletely understood. We show for the first time that RNA methylation machinery genes may be regulated in response to obesogenic diet in a sex- and age-dependent manner and levels may correspond to cardiac systolic function. Our cardiac RNA-seq analysis suggests female, but not male mice may be protected from cardiac dysfunction by a protective cardiac remodeling response early during obesogenic stress.

Prevalence of electrocardiographic alterations in athletes associated with cardiovascular risk parameters / Prevalencia de alteraciones electrocardiográficas en deportistas asociadas a parametros de riesgo cardiovascular

Sport induces cardiac adaptations that are manifested with specific electrocardiographic alterations. This study was carried out in view of the need to identify the relationship between these electrocardiographic alterations with cardiovascular and demographic variables and physical exercise performed. Methodology: a descriptive cross-sectional study in 370 individuals, 211 men and 159 women (36 ± 13 years) that were distributed in three groups: male athletes, female athletes, and non-athlete men and women. Results: 51.08% of the studied subjects presented electrographic alterations, more frequent in athletes. Demographic and cardiovascular variables and the time of physical exercise performed were significantly associated with certain electrocardiographic alterations; the risk of presenting any of the alterations in athletes could be estimated based on the variables set out. Conclusion: There are associations between specific electrocardiographic alterations and cardiovascular, demographic and type of exercise variables that could classify athletes according to cardiovascular risk profiles (AU)

El deporte induce adaptaciones cardiacasque se manifiestan con alteraciones electrocardiográficas.Este estudio se realizóante la necesidad de identificar la relación existente entre estas alteraciones electrocardiográficas con variablescardiovasculares, demográficas y tiempo de ejerciciofísico. Metodología: estudio descriptivotrasversal en 370 individuos, 211 hombres y 159 mujeres (36 ±13 años)que se distribuyeron en tres grupos, hombres deportistas, mujeresdeportistas, yhombres y mujeres no deportistas.Resultados:El 51,08% de los sujetos estudiados presentaron alteraciones electrográficas, siendo más frecuentes en deportistas.Determinadas alteraciones electrocardiográficasen deportistas; se asociaron significativamente a las variables planteadaspudiendo estimar el riesgo de presentar alguna de las alteraciones electrocardiográficas en función de estas variables. Conclusión:Existen asociaciones entrealteraciones electrocardiográficas y variables cardiovasculares, demográficas y tiempo de ejercicio realizado que podrían clasificar a los deportistas según perfiles de riesgo cardiovascular (AU)

Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.

Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.

Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease.

Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.

Cognitive Impairment in Patients With Cardiac Disease: Implications for Clinical Practice.

Cognitive impairment is common in patients with cardiovascular disease. One in 3 patients presenting at cardiology clinics have some degree of cognitive impairment, depending on the cardiac condition, comorbidities, and age. In up to half of these cases cognitive impairment may go unrecognized; however, it may affect self-management and treatment adherence. The high prevalence of cognitive impairment in patients with cardiac disease is likely due to shared risk factors, as well as direct consequences of cardiac dysfunction on the brain. Moreover, cardiac interventions may have beneficial as well as adverse effects on cognitive functioning. In this review, we describe prevalence and risk factors for cognitive impairment in patients with several common cardiac conditions: heart failure, coronary artery disease, and aortic valve stenosis. We discuss the potential effects of guideline-based treatments on cognition and identify open questions and unmet needs. Given the high prevalence of unrecognized cognitive impairment in cardiac patients, we recommend a stepwise approach to improve detection and management of cognitive impairment.

Perioperative Point of Care Ultrasound for Hemodynamic Assessment: A Narrative Review.

While transesophageal echocardiography (TEE) has traditionally been used in perioperative care, there is growing evidence supporting point of care ultrasound (POCUS) for the anesthesiologist in guiding patient care. It is a quick way to non-invasively evaluate hemodynamically unstable patients and ascertain their state of shock, determine volume status, and guide resuscitation in cardiac arrest. In addition, through use of POCUS, the anesthesiologist is able to identify signs of chronic heart disease to provide a more tailored and safer approach to perioperative care.

The well-developed actin cytoskeleton and Cthrc1 expression by actin-binding protein drebrin in myofibroblasts promote cardiac and hepatic fibrosis.

Fibrosis is mainly triggered by inflammation in various tissues, such as heart and liver tissues, and eventually leads to their subsequent dysfunction. Fibrosis is characterized by the excessive accumulation of extracellular matrix proteins (e.g., collagens) produced by myofibroblasts. The well-developed actin cytoskeleton of myofibroblasts, one of the main features differentiating them from resident fibroblasts in tissues under inflammatory conditions, contributes to maintaining their ability to produce excessive extracellular matrix proteins. However, the molecular mechanisms via which the actin cytoskeleton promotes the production of fibrosis-related genes in myofibroblasts remain unclear. In this study, we found, via single-cell analysis, that developmentally regulated brain protein (drebrin), an actin-binding protein, was specifically expressed in cardiac myofibroblasts with a well-developed actin cytoskeleton in fibrotic hearts. Moreover, our immunocytochemistry analysis revealed that drebrin promoted actin cytoskeleton formation and myocardin-related transcription factor-serum response factor signaling. Comprehensive single-cell analysis and RNA-Seq revealed that the expression of collagen triple helix repeat containing 1 (Cthrc1), a fibrosis-promoting secreted protein, was regulated by drebrin in cardiac myofibroblasts via myocardin-related transcription factor-serum response factor signaling. Furthermore, we observed the profibrotic effects of drebrin exerted via actin cytoskeleton formation and the Cthrc1 expression regulation by drebrin in liver myofibroblasts (hepatic stellate cells). Importantly, RNA-Seq demonstrated that drebrin expression levels increased in human fibrotic heart and liver tissues. In summary, our results indicated that the well-developed actin cytoskeleton and Cthrc1 expression due to drebrin in myofibroblasts promoted cardiac and hepatic fibrosis, suggesting that drebrin is a therapeutic target molecule for fibrosis.

The ebb and flow of cardiac lymphatics: a tidal wave of new discoveries.

The heart is imbued with a vast lymphatic network that is responsible for fluid homeostasis and immune cell trafficking. Disturbances in the forces that regulate microvascular fluid movement can result in myocardial edema, which has profibrotic and proinflammatory consequences and contributes to cardiovascular dysfunction. This review explores the complex relationship between cardiac lymphatics, myocardial edema, and cardiac disease. It covers the revised paradigm of microvascular forces and fluid movement around the capillary as well as the arsenal of preclinical tools and animal models used to model myocardial edema and cardiac disease. Clinical studies of myocardial edema and their prognostic significance are examined in parallel to the recent elegant animal studies discerning the pathophysiological role and therapeutic potential of cardiac lymphatics in different cardiovascular disease models. This review highlights the outstanding questions of interest to both basic scientists and clinicians regarding the roles of cardiac lymphatics in health and disease.

Repercusiones cardíacas en pacientes con pectus excavatum: puesta al día. Segunda parte / Cardiac repercussions in patients with pectus excavatum: update. Part two / Repercussões cardíacas em pacientes com pectus excavatum: atualização. Parte dois

El pectus excavatum (PEX) es una deformación de la pared torácica que obedece a una alteración de los cartílagos costales con el consiguiente hundimiento del esternón. Históricamente, se clasificaba como un defecto únicamente estético o cosmético, sin embargo, en los últimos años se han desarrollado nuevos métodos de estudio para la valoración de las repercusiones de esta patología. Existe cada vez más bibliografía que demuestra importantes repercusiones funcionales. Se realizó una puesta al día de las repercusiones cardíacas de la patología y un análisis de los artículos más relevantes de los últimos años. La evidencia actual permite afirmar que existe una afectación cardíaca por compresión esternal en la mayoría de los pacientes con PEX. Las afectaciones incluyen alteraciones anatomofuncionales (trastornos del ritmo, disminución del llenado ventricular), del volumen sistólico, aumento de la presión de la aurícula derecha, valvulopatías, compresión del ventrículo derecho, derrame pericárdico, entre otras. Todo lo cual permite concluir que el PEX puede presentar importantes alteraciones cardíacas que deben ser tenidas en cuenta a la hora de valorar los pacientes con esta patología.

Pectus excavatum (PEX) is a deformation of the chest wall caused by an alteration of the costal cartilages with the consequent collapse of the sternum. Historically, it had been classified as a solely aesthetic or cosmetic defect, however, in recent years new study methods have been developed to assess the repercussions of this pathology, with increasing bibliography showing important functional consequences. We updated the cardiac pathological repercussions and analyzed the most relevant articles of recent years. The current evidence suggests that there is cardiac involvement due to sternal compression in most patients with PEX. These affectations include anatomical functional alterations: rhythm disorders, decreased ventricular filling, decreased stroke volume, increased right atrial pressure, valve disease, right ventricular compression, pericardial effusion, among others. All of which enables us to conclude that PEX can present important cardiac alterations that must be taken into account when assessing patients with this pathology.

Pectus excavatum (PEX) é uma deformação da parede torácica decorrente de uma alteração das cartilagens costais com consequente colapso do esterno. Historicamente, foi classificado como um defeito exclusivamente estético ou cosmético, porém, nos últimos anos, novos métodos de estudo foram desenvolvidos para avaliar as repercussões dessa patologia, com crescente bibliografia mostrando importantes repercussões funcionais. Foi realizada uma atualização das repercussões cardíacas da patologia e análise dos artigos mais relevantes dos últimos anos. As evidências atuais permitem afirmar que há acometimento cardíaco por compressão esternal na maioria dos pacientes com PEX. As afecções incluem alterações anatomofuncionais: distúrbios do ritmo, diminuição do enchimento ventricular, diminuição do volume sistólico, aumento da pressão atrial direita, doença valvular, compressão do ventrículo direito, derrame pericárdico, entre outras. Tudo isso permite concluir que o PEX pode apresentar alterações cardíacas importantes que devem ser levadas em consideração na avaliação de pacientes com essa patologia.

Deep Time Growing Neural Network vs Convolutional Neural Network for Intelligent Phonocardiography.

This paper explores the capabilities of a sophisticated deep learning method, named Deep Time Growing Neural Network (DTGNN), and compares its possibilities against a generally well-known method, Convolutional Neural network (CNN). The comparison is performed by using time series of the heart sound signal, so-called Phonocardiography (PCG). The classification objective is to discriminate between healthy and patients with cardiac diseases by applying a deep machine learning method to PCGs. This approach which is called intelligent phonocardiography has received interest from the researchers toward the development of a smart stethoscope for decentralized diagnosis of heart disease. It is found that DTGNN associates further flexibility to the approach which enables the classifier to learn subtle contents of PCG, and meanwhile better copes with the complexities intrinsically that exist in the medical applications such as the imbalance training. The structural risk of the two methods is compared using the A-Test method.

De-novo development of fragmented QRS during a six-month follow-up period in patients with COVID-19 disease and its cardiac effects.

OBJECTIVE: The aim of this study is to examine the probability of de-novo fQRS in patients with mild COVID-19 disease, as an indicator of cardiac injury. METHODS: Data of 256 patients with normal admission electrocardiography and no comorbidities between 1.12.2020-31.12.2021, were examined retrospectively 6-month after mild COVID-19 disease. Patients were divided into two groups: fQRS+ group (n = 102) and non-fQRS group (n = 154). Relation between fQRS and other electrocardiography, echocardiographic and laboratory findings were investigated. RESULTS: No significant difference was found between the groups among age and gender. Troponin-I and creatine kinase myocardial band values (retrospectively 9.10 ± 1.76 vs 0.74 ± 1.43, 34.05 ± 82.20 vs. 14.68 ± 4.42), COVID-19 IgG levels (45.78 ± 14.82 vs. 36.49 ± 17.68), diastolic dysfunction (39.21% vs. 15.07%), EF value (58.02 ± 1.95 vs. 64.27 ± 3.07), dyspnea (41.17% vs. 6.84%), post-COVID-19 tachycardia syndrome (19.6% vs. 2.74) were more frequent in fQRS+ group compared to non-fQRS group. The EF value was lower in the presence of fQRS in the high lateral leads (57.12 ± 1.99, 58.47 ± 1.79, p:0.018). There was a positive correlation between IgG value and endsystolic diameter, septum thickness and left atrium diameter. In multivariate analysis de-novo fQRS, dyspnea, high troponin and IgG values, diastolic dysfunction, low EF value and left atrial diameter were determined as independent risk factors for post-COVID-19 tachycardia syndrome in follow-up. CONCLUSION: In COVID-19 disease de-novo fQRS, dyspnea, high IgG and troponin value, left atrial diameter, lower EF value, diastolic dysfunction were associated with post-COVID-19 tachycardia syndrome. The de-novo fQRS in SARS-COV-2 may be a predictor of future more important adverse cardiovascular outcomes and this should alert clinicians.

Cardiac Manifestations of Systemic Lupus Erythematous: An Overview of the Incidence, Risk Factors, Diagnostic Criteria, Pathophysiology and Treatment Options.

Systemic lupus erythematosus (SLE) is a complex connective tissue disease that can potentially affect every organ of the human body. In some cases, SLE may present with diverse cardiac manifestations including pericarditis, myocarditis, valvular disease, atherosclerosis, thrombosis, and arrhythmias. Heart disease in SLE is associated with increased morbidity and mortality. It is unclear whether traditional treatments for coronary artery disease significantly impact mortality in this population. Current therapeutic agents for SLE include glucocorticoids, hydroxychloroquine, mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide, and B cell-directed therapies. This article will provide a comprehensive review and update on this important disease state.

Role of the vascular endothelial sodium channel activation in the genesis of pathologically increased cardiovascular stiffness.

Cardiovascular (CV) stiffening represents a complex series of events evolving from pathological changes in individual cells of the vasculature and heart which leads to overt tissue fibrosis. While vascular stiffening occurs naturally with ageing it is accelerated in states of insulin (INS) resistance, such as obesity and type 2 diabetes. CV stiffening is clinically manifested as increased arterial pulse wave velocity and myocardial fibrosis-induced diastolic dysfunction. A key question that remains is how are these events mechanistically linked. In this regard, heightened activation of vascular mineralocorticoid receptors (MR) and hyperinsulinaemia occur in obesity and INS resistance states. Further, a downstream mediator of MR and INS receptor activation, the endothelial cell Na+ channel (EnNaC), has recently been identified as a key molecular determinant of endothelial dysfunction and CV fibrosis and stiffening. Increased activity of the EnNaC results in a number of negative consequences including stiffening of the cortical actin cytoskeleton in endothelial cells, impaired endothelial NO release, increased oxidative stress-meditated NO destruction, increased vascular permeability, and stimulation of an inflammatory environment. Such endothelial alterations impact vascular function and stiffening through regulation of vascular tone and stimulation of tissue remodelling including fibrosis. In the case of the heart, obesity and INS resistance are associated with coronary vascular endothelial stiffening and associated reductions in bioavailable NO leading to heart failure with preserved systolic function (HFpEF). After a brief discussion on mechanisms leading to vascular stiffness per se, this review then focuses on recent findings regarding the role of INS and aldosterone to enhance EnNaC activity and associated CV stiffness in obesity/INS resistance states. Finally, we discuss how coronary artery-mediated EnNaC activation may lead to cardiac fibrosis and HFpEF, a condition that is especially pronounced in obese and diabetic females.

Coronary microcirculation damage in anthracycline cardiotoxicity.

AIMS: The aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment. METHODS AND RESULTS: Large-white male pigs (n=40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure [0.45 mg/kg intracoronary (IC) doxorubicin per injection] and follow-up: control (no doxorubicin); single injection and sacrifice either at 48 h (ExPr. 1) or 2 weeks (ExPr. 2); 3 injections 2 weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; five injections 2 weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (three bi-weekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibres even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime. CONCLUSION: Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.

Physiological and pathological roles of protein kinase A in the heart.

Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters, and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind ß-adrenergic receptors to stimulate cAMP-dependent PKA activation in cardiomyocytes. Elevated PKA activity enhances Ca2+ cycling and increases cardiac muscle contractility. Dynamic control of PKA is essential for cardiac homeostasis, as dysregulation of PKA signalling is associated with a broad range of heart diseases. Specifically, abnormal PKA activation or inactivation contributes to the pathogenesis of myocardial ischaemia, hypertrophy, heart failure, as well as diabetic, takotsubo, or anthracycline cardiomyopathies. PKA may also determine sex-dependent differences in contractile function and heart disease predisposition. Here, we describe the recent advances regarding the roles of PKA in cardiac physiology and pathology, highlighting previous study limitations and future research directions. Moreover, we discuss the therapeutic strategies and molecular mechanisms associated with cardiac PKA biology. In summary, PKA could serve as a promising drug target for cardioprotection. Depending on disease types and mechanisms, therapeutic intervention may require either inhibition or activation of PKA. Therefore, specific PKA inhibitors or activators may represent valuable drug candidates for the treatment of heart diseases.