Role of circadian clock system in the mitochondrial trans-sulfuration pathway and tissue remodeling.

Previous studies from our laboratory revealed that the gaseous molecule hydrogen sulfide (H2S), a metabolic product of epigenetics, involves trans-sulfuration pathway for ensuring metabolism and clearance of homocysteine (Hcy) from body, thereby mitigating the skeletal muscle's pathological remodeling. Although the master circadian clock regulator that is known as brain and muscle aryl hydrocarbon receptor nuclear translocator like protein 1 (i.e., BMAL 1) is associated with S-adenosylhomocysteine hydrolase (SAHH) and Hcy metabolism but how trans-sulfuration pathway is influenced by the circadian clock remains unexplored. We hypothesize that alterations in the functioning of circadian clock during sleep and wake cycle affect skeletal muscle's biology. To test this hypothesis, we measured serum matrix metalloproteinase (MMP) activities using gelatin gels for analyzing the MMP-2 and MMP-9. Further, employing casein gels, we also studied MMP-13 that is known to be influenced by the growth arrest and DNA damage-45 (GADD45) protein during sleep and wake cycle. The wild type and cystathionine ß synthase-deficient (CBS-/+) mice strains were treated with H2S and subjected to measurement of trans-sulfuration factors from skeletal muscle tissues. The results suggested highly robust activation of MMPs in the wake mice versus sleep mice, which appears somewhat akin to the "1-carbon metabolic dysregulation", which takes place during remodeling of extracellular matrix during muscular dystrophy. Interestingly, the levels of trans-sulfuration factors such as CBS, cystathionine γ lyase (CSE), methyl tetrahydrofolate reductase (MTHFR), phosphatidylethanolamine N-methyltransferase (PEMT), and Hcy-protein bound paraoxonase 1 (PON1) were attenuated in CBS-/+ mice. However, treatment with H2S mitigated the attenuation of the trans-sulfuration pathway. In addition, levels of mitochondrial peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC 1-α) and mitofusin-2 (MFN-2) were significantly improved by H2S intervention. Our findings suggest participation of the circadian clock in trans-sulfuration pathway that affects skeletal muscle remodeling and mitochondrial regeneration.

Sleep Apnea and Heart Failure-Current State-of-The-Art.

Sleep-disordered breathing (SDB), including obstructive and central sleep apnea, significantly exacerbates heart failure (HF) through adverse cardiovascular mechanisms. This review aims to synthesize existing literature to clarify the relationship between SDB and HF, focusing on the pathophysiological mechanisms, diagnostic challenges, and the effectiveness of treatment modalities like continuous positive airway pressure (CPAP) and adaptive servo-ventilation ASV. We analyzed peer-reviewed articles from 2003 to 2024 sourced from PubMed, EMBASE, Scopus, and Web of Science databases. The prevalence of SDB in HF patients is high, often underdiagnosed, and underappreciated. Management strategies, including CPAP and ASV, have been shown to mitigate symptoms and improve cardiac function. However, despite the availability of effective treatments, significant challenges in screening and diagnosis persist, affecting patient management and outcomes. DB significantly impacts HF prognosis. Enhanced screening strategies and broader utilization of therapeutic interventions like CPAP and ASV are essential to improve the management and outcomes of HF patients with concomitant SDB. Future research should focus on refining diagnostic and treatment protocols to optimize care for HF patients with SDB.

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2023 European Society of Cardiology Congress.

PURPOSE OF REVIEW: To summarize selected late-breaking science on cardiovascular (CV) disease prevention presented at the 2023 European Society of Cardiology (ESC) congress. RECENT FINDINGS: The NATURE-PARADOX was a naturally randomized trial that used genetic data from the UK Biobank registry to create "cumulative exposure to low-density lipoprotein-cholesterol (LDL-C)" biomarker and evaluate its association with major CV events regardless of plasma LDL-C levels or age. Safety and efficacy data of inclisiran, a PCSK9-interfering mRNA (PCSK9i) administered subcutaneously twice annually, were presented. Data on two new PCSK9is were presented, recaticimab, an oral drug, and lerodalcibep, a subcutaneous drug with a slightly different architecture than currently available PSCK9is. A phase 1 trial on muvalaplin, an oral lipoprotein (a) inhibitor, was presented. An atherosclerotic CV disease (ASCVD) risk prediction algorithm for the Asian population using SCORE2 data was presented. Long-term follow-up of patients enrolled in the CLEAR outcomes trial showed sustained and more significant ASCVD risk reduction with bempedoic acid in high-risk patients. The late-breaking clinical science at the 2023 congress of the ESC extends the known safety and efficacy data of a PCSK9i with the introduction of new drugs in this class. Using cumulative exposure to LDL-C rather than a single value will help clinicians tailor the LDL-C reduction strategy to individual risk and is an important step towards personalized medicine.

Pharmacotherapy in Ventricular Arrhythmias.

BACKGROUND: Ventricular ectopy is observed in most of the population ranging from isolated premature ventricular contractions to rapid hemodynamically unstable ventricular tachyarrhythmias like ventricular tachycardia and ventricular fibrillation. Multiple mechanisms exist for ventricular arrhythmias such as triggered activity, reentry, and automaticity. Scar-based reentry forms the basis of most malignant VA that can lead to sudden cardiac death. Many antiarrhythmic drugs have been utilized for the suppression of ventricular arrhythmia. They are commonly classified using the Vaughan Williams Singh classification which distinguishes them based on the predominant action on different phases of the cardiac action potential. Class Ic agents are widely used in premature ventricular contraction suppression but are contraindicated in patients with prior myocardial infarction or ischemic scar and heart failure. ß-Blockers continue to be a mainstay in the treatment of most symptomatic VA and are well tolerated, relatively safe, and have additional benefits in symptomatic coronary heart disease and left ventricular systolic dysfunction. Amiodarone continues to be used for the management of most cases of serious VA especially in the acute setting when accompanied by hemodynamic perturbations but has the disadvantage of having a poor toxicity profile for long-term use. SUMMARY: Historically used for long-term ventricular arrhythmia suppression and prevention of sudden cardiac death, antiarrhythmics are now used to reduce implantable defibrillator shocks and symptoms. They still have a role in premature ventricular complex suppression in patients with failed catheter ablation or those who are not candidates for invasive therapy. Newer concepts in cardiac imaging and the use of artificial intelligence may help further delineate sudden cardiac risk and identify patients that may benefit from pharmacological management. KEY MESSAGE: Anti-arrhythmic agents continue to perform an important role in the suppression of ventricular arrhythmias especially channelopathies, polymorphic VT, and idiopathic ventricular fibrillation. Judicious use of these agents while recognizing side effects can help reduce the long-term effects of ventricular arrhythmias on cardiac function.

New Drugs and Therapies in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has now considerably improved. Despite these advances, PAH inevitably remains a progressive disease with significant morbidity and mortality. Thus, there is still an unmet need for the development of new drugs and other interventional therapies for the treatment of PAH. One shortcoming of currently approved vasodilator therapies is that they do not target or reverse the underlying pathogenesis of the disease process itself. A large body of evidence has evolved in the past two decades clarifying the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of PAH. This review focuses on newer targets and drugs that modify these pathways as well as novel interventional therapies in PAH.

Renal Denervation Helps Preserve the Ejection Fraction by Preserving Endocardial-Endothelial Function during Heart Failure.

Renal denervation (RDN) protects against hypertension, hypertrophy, and heart failure (HF); however, it is not clear whether RDN preserves ejection fraction (EF) during heart failure (HFpEF). To test this hypothesis, we simulated a chronic congestive cardiopulmonary heart failure (CHF) phenotype by creating an aorta-vena cava fistula (AVF) in the C57BL/6J wild type (WT) mice. Briefly, there are four ways to create an experimental CHF: (1) myocardial infarction (MI), which is basically ligating the coronary artery by instrumenting and injuring the heart; (2) trans-aortic constriction (TAC) method, which mimics the systematic hypertension, but again constricts the aorta on top of the heart and, in fact, exposes the heart; (3) acquired CHF condition, promoted by dietary factors, diabetes, salt, diet, etc., but is multifactorial in nature; and finally, (4) the AVF, which remains the only one wherein AVF is created ~1 cm below the kidneys in which the aorta and vena cava share the common middle-wall. By creating the AVF fistula, the red blood contents enter the vena cava without an injury to the cardiac tissue. This model mimics or simulates the CHF phenotype, for example, during aging wherein with advancing age, the preload volume keeps increasing beyond the level that the aging heart can pump out due to the weakened cardiac myocytes. Furthermore, this procedure also involves the right ventricle to lung to left ventricle flow, thus creating an ideal condition for congestion. The heart in AVF transitions from preserved to reduced EF (i.e., HFpEF to HFrEF). In fact, there are more models of volume overload, such as the pacing-induced and mitral valve regurgitation, but these are also injurious models in nature. Our laboratory is one of the first laboratories to create and study the AVF phenotype in the animals. The RDN was created by treating the cleaned bilateral renal artery. After 6 weeks, blood, heart, and renal samples were analyzed for exosome, cardiac regeneration markers, and the renal cortex proteinases. Cardiac function was analyzed by echocardiogram (ECHO) procedure. The fibrosis was analyzed with a trichrome staining method. The results suggested that there was a robust increase in the exosomes' level in AVF blood, suggesting a compensatory systemic response during AVF-CHF. During AVF, there was no change in the cardiac eNOS, Wnt1, or ß-catenin; however, during RDN, there were robust increases in the levels of eNOS, Wnt1, and ß-catenin compared to the sham group. As expected in HFpEF, there was perivascular fibrosis, hypertrophy, and pEF. Interestingly, increased levels of eNOS suggested that despite fibrosis, the NO generation was higher and that it most likely contributed to pEF during HF. The RDN intervention revealed an increase in renal cortical caspase 8 and a decrease in caspase 9. Since caspase 8 is protective and caspase 9 is apoptotic, we suggest that RDN protects against the renal stress and apoptosis. It should be noted that others have demonstrated a role of vascular endothelium in preserving the ejection by cell therapy intervention. In the light of foregoing evidence, our findings also suggest that RDN is cardioprotective during HFpEF via preservation of the eNOS and accompanied endocardial-endothelial function.

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2022 European Society of Cardiology Congress.

PURPOSE OF REVIEW: Focused review of select studies presented at the 2022 European Society of Cardiology Congress. RECENT FINDINGS: Included studies assessed the effects of aspirin and omega-3 fatty acid supplements on heart failure (ASCEND study); the impact of icosapent ethyl on ST-elevation MI incidence (REDUCE-IT); air temperature's effect on cardiovascular mortality (EXHAUSTION project); LVEF outcomes after troponin-guided neurohormonal blockade for the prevention of anthracycline toxicity; efficacy of routine stress testing after high-risk PCI (POST-PCI trial); influenza vaccine among patients with acute coronary syndromes (VIP-ACS trial); empagliflozin in patients with acute myocardial infarction (EMMY); effects of comprehensive imaging-based cardiovascular screening on death and cardiovascular events (DANCANVAS); safety of long-term evolocumab in patients with established atherosclerotic cardiovascular disease (FOURIER-OLE); and use of a cardiovascular polypill as a global strategy to improve secondary prevention (SECURE). Research presented at the 2022 ESC Congress highlighted many novel applications of preventative and treatment strategies in cardiology, including the effects of environmental risk factors on the incidence of cardiovascular disease.

Molecular Pathways in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension is a multifactorial, chronic disease process that leads to pulmonary arterial endothelial dysfunction and smooth muscular hypertrophy, resulting in impaired pliability and hemodynamics of the pulmonary vascular system, and consequent right ventricular dysfunction. Existing treatments target limited pathways with only modest improvement in disease morbidity, and little or no improvement in mortality. Ongoing research has focused on the molecular basis of pulmonary arterial hypertension and is going to be important in the discovery of new treatments and genetic pathways involved. This review focuses on the molecular pathogenesis of pulmonary arterial hypertension.

COVID-19 Mimics Pulmonary Dysfunction in Muscular Dystrophy as a Post-Acute Syndrome in Patients.

Although progressive wasting and weakness of respiratory muscles are the prominent hallmarks of Duchenne muscular dystrophy (DMD) and long-COVID (also referred as the post-acute sequelae of COVID-19 syndrome); however, the underlying mechanism(s) leading to respiratory failure in both conditions remain unclear. We put together the latest relevant literature to further understand the plausible mechanism(s) behind diaphragm malfunctioning in COVID-19 and DMD conditions. Previously, we have shown the role of matrix metalloproteinase-9 (MMP9) in skeletal muscle fibrosis via a substantial increase in the levels of tumor necrosis factor-α (TNF-α) employing a DMD mouse model that was crossed-bred with MMP9-knockout (MMP9-KO or MMP9-/-) strain. Interestingly, recent observations from clinical studies show a robust increase in neopterin (NPT) levels during COVID-19 which is often observed in patients having DMD. What seems to be common in both (DMD and COVID-19) is the involvement of neopterin (NPT). We know that NPT is generated by activated white blood cells (WBCs) especially the M1 macrophages in response to inducible nitric oxide synthase (iNOS), tetrahydrobiopterin (BH4), and tetrahydrofolate (FH4) pathways, i.e., folate one-carbon metabolism (FOCM) in conjunction with epigenetics underpinning as an immune surveillance protection. Studies from our laboratory, and others researching DMD and the genetically engineered humanized (hACE2) mice that were administered with the spike protein (SP) of SARS-CoV-2 revealed an increase in the levels of NPT, TNF-α, HDAC, IL-1ß, CD147, and MMP9 in the lung tissue of the animals that were subsequently accompanied by fibrosis of the diaphragm depicting a decreased oscillation phenotype. Therefore, it is of interest to understand how regulatory processes such as epigenetics involvement affect DNMT, HDAC, MTHFS, and iNOS that help generate NPT in the long-COVID patients.

Unmet Need for Further LDL-C Lowering in India despite Statin Therapy: Lipid Association of India Recommendations for the Use of Bempedoic Acid.

Lipid-lowering therapy plays a crucial role in reducing adverse cardiovascular (CV) events in patients with established atherosclerotic cardiovascular disease (ASCVD) and familial hypercholesterolemia. Lifestyle interventions along with high-intensity statin therapy are the first-line management strategy followed by ezetimibe. Only about 20-30% of patients who are on maximally tolerated statins reach recommended low-density lipoprotein cholesterol (LDL-C) goals. Several factors contribute to the problem, including adherence issues, prescription of less than high-intensity statin therapy, and de-escalation of statin dosages, but in patients with very high baseline LDL-C levels, including those with familial hypercholesterolemia and those who are intolerant to statins, it is critical to expand our arsenal of LDL-C-lowering medications. Moreover, in the extreme risk group of patients with an LDL-C goal of ≤30 mg/dL according to the Lipid Association of India (LAI) risk stratification algorithm, there is a significant residual risk requiring the addition of non-statin drugs to achieve LAI recommended targets. This makes bempedoic acid a welcome addition to the existing non-statin therapies such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors. A low frequency of muscle-related side effects, minimal drug interactions, a significant reduction in high-sensitivity C-reactive protein (hsCRP), and a lower incidence of new-onset or worsening diabetes make it a useful adjunct for LDL-C lowering. However, the CV outcomes trial results are still pending. In this LAI consensus document, we discuss the pharmacology, indications, contraindications, advantages, and evidence-based recommendations for the use of bempedoic acid in clinical practice.

Usefulness of machine learning in COVID-19 for the detection and prognosis of cardiovascular complications.

Since January 2020, coronavirus disease 2019 (COVID-19) has rapidly become a global concern, and its cardiovascular manifestations have highlighted the need for fast, sensitive and specific tools for early identification and risk stratification. Machine learning is a software solution with the ability to analyze large amounts of data and make predictions without prior programming. When faced with new problems with unique challenges as evident in the COVID-19 pandemic, machine learning can offer solutions that are not apparent on the surface by sifting quickly through massive quantities of data and making associations that may have been missed. Artificial intelligence is a broad term that encompasses different tools, including various types of machine learning and deep learning. Here, we review several cardiovascular applications of machine learning and artificial intelligence and their potential applications to cardiovascular diagnosis, prognosis, and therapy in COVID-19 infection.

Clinical evaluation of infiltrative cardiomyopathies resulting in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction is a very common clinical problem. Its prevalence is increasing with aging of the population. A diverse group of risk factors and etiologies comprise the HFpEF syndrome. No specific therapies have been shown to improve survival for the vast majority of HFpEF cases. Restrictive cardiomyopathies account for a significant portion of HFpEF patients and are characterized by diastolic dysfunction due to infiltration of the myocardium or ventricular hypertrophy. Many of these restrictive diseases occur in the context of myocardial infiltration by other substances such as amyloid, iron or glycogen or endomyocardial fibrosis. These infiltrative diseases usually have important clues in the clinical picture and on cardiac imaging that may allow differentiation from the usual HFpEF phenotype (that is commonly seen in the older, hypertensive patient). Noninvasive diagnosis has replaced endomyocardial biopsy for most instances in the workup of these conditions. Early recognition is important to institute specific therapies and to improve prognosis. In this review, we describe 4 major infiltrative cardiomyopathies (Cardiac Amyloidosis, Sarcoidosis, Hemochromatosis and Fabry disease), and their key imaging features.

Takotsubo cardiomyopathy in a man with no trigger and multiple cardioembolic complications-A rare constellation.

Takotsubo Cardiomyopathy (TC) is an uncommon, transient, reversible cardiomyopathy, with a classic pattern of wall-motion abnormalities, usually seen in women after an emotional stressor. Despite its increased recognition, there remain gaps in the exact mechanisms, predisposing factors, and predictors of recovery; this is particularly true for males where the condition occurs far less frequently than in females. TC typically resolves within weeks, and the prognosis is favorable compared to acute coronary syndromes. Nonetheless, about 1% of cases may be complicated by left ventricular (LV) thrombus and embolism. Herein we describe an atypical case of a man with no obvious trigger, who developed TC with left ventricular thrombus and multiple embolic complications, but subsequently showed complete and full resolution. Multimodality imaging including echocardiography, cardiac CT and cardiac MRI was instrumental in this diagnostic dilemma, as well as useful in guiding treatment options and informing prognosis.

Stress test to STEMI: Utility of coronary CTA in the diagnosis and management of anomalous right coronary artery from the left coronary cusp.

A 42-year-old woman presented to the emergency department with chest pain. Acute coronary syndrome was ruled out. During dobutamine stress echocardiography (DSE), she developed chest pain and inferior ST elevation. Emergent coronary angiography revealed no culprit lesions but did show an anomalous right coronary artery (RCA). Coronary CT angiography (CCTA) confirmed an anomalous RCA arising from the left coronary cusp with a slit-like ostium and interarterial course (ARCA-LCC-IA). Herein, we review the extant literature on ARCA-LCC-IA, its clinical presentation, the vital role of CTA and MRI in its diagnosis, as well as challenges and controversies surrounding management.