Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

AIMS: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. METHODS AND RESULTS: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. CONCLUSION: Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01458405.

Update on COVID-19 Myocarditis.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) gained worldwide attention at the end of 2019 when it was identified to cause severe respiratory distress syndrome. While it primarily affects the respiratory system, we now have evidence that it affects multiple organ systems in the human body. Cardiac manifestations may include myocarditis, life threatening arrhythmias, acute coronary syndrome, systolic heart failure, and cardiogenic shock. Myocarditis is increasingly recognized as a complication of Coronavirus-19 (COVID-19) and may result from direct viral injury or from exaggerated host immune response. The diagnosis is established similar to other etiologies, and is based on detailed history, clinical exam, laboratory findings and non-invasive imaging studies. When available, cardiac MRI is the preferred imaging modality. Endomyocardial biopsy may be performed if the diagnosis remains uncertain. Current management is mainly supportive with the potential addition of interventions recommended for severe COVID-19 disease, such as remdesivir, steroids, and convalescent plasma. In the setting of cardiogenic shock and refractory, life-threatening arrhythmias that persist despite medical therapy, advanced mechanical circulatory support devices should be considered. Ultimately, early recognition and aggressive intervention are key factors in reducing morbidity and mortality. Our management strategy is expected to evolve further as we learn more about COVID-19 disease and the associated cardiac complications.

Atrial fibrillation and heart failure: intersecting populations, morbidities, and mortality.

Heart failure (HF) and atrial fibrillation (AF) are the only two cardiovascular disorders that continue to increase in magnitude in the United States. The purpose of this brief overview is to provide a description of these two cardiovascular epidemics of HF and AF as they interact, and to provide additional information regarding the emerging influence of genetics and environment in the development of AF in the HF setting. These two modern epidemics are highly interactive and highly age-dependent. The development of new AF in a patient with either HF with preserved ejection fraction or HF with reduced ejection fraction possesses challenging management issues for practicing physicians. Control of heart rate is always prudent though still not precisely defined. The need to restore normal sinus rhythm is highly patient-dependent and strategies will vary. Elderly patients derive the most benefit from anticoagulation, but are also more prone to falls and bleeding complications. Today, we know much more about AF and HF and how they interact. The extent of AF/HF challenge is now widely recognized. It is inevitable that as people age, they will develop structural and functional changes in the cardiovascular system, some of which will predispose to the development of HF and AF. Not every case of HF or AF is preventable. Nevertheless, it is only throughout careful observations and further studies that we will be able to better manage these two Goliaths.

Effect of Angiotensin-converting enzyme inhibitors and Angiotensin receptor antagonists in atherosclerosis prevention.

Atherosclerosis is a highly complex biological process that has become the scourge of modern civilization. Endothelial dysfunction is the first step in the development of atherosclerosis. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the development of endothelial dysfunction and atherosclerosis. Several studies have shown that in vitro blockade of the RAAS is associated with improvement in markers of endothelial dysfunction and inflammation. Many clinical trials have demonstrated a clear benefit of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) manifested by a reduction of cardiovascular events. These findings suggest that ACEIs and ARBs can play an important role in prevention of atherosclerosis and in the delay of its progression. In this review we focus on the importance of RAAS blockade to prevent or delay progression of atherosclerosis and its impact on reduction of cardiovascular events.

ß-blockers in stage B: a precursor of heart failure.

ß-blockers are an important treatment of heart failure (HF) and are useful in reducing the progression of the syndrome. They should be considered for patients with asymptomatic left ventricular (LV) dysfunction. Evidence-based ß-blocker therapy (bisoprolol, carvedilol, or metoprolol succinate) in combination with standard therapy is a mainstay of treatment of all symptomatic patients with LV systolic dysfunction. Patients in stage B also benefit from the early introduction of ß-blockers, but there are no large randomized clinical trials to support this strategy. Whether there is a role for ivabradine in the treatment of HF is not clear.

Hypotension on cardiopulmonary stress test predicts 90 day mortality after LVAD implantation in INTERMACS 3-6 patients.

AIMS: Cardiopulmonary stress test (CPX) is routinely performed when evaluating patient candidacy for left ventricular assist device (LVAD) implantation. The predictive value of hypotensive systolic blood pressure (SBP) response during CPX on clinical outcomes is unknown. This study aims to determine the effect of hypotensive SBP response during to clinical outcomes among patients who underwent LVAD implantation. METHODS AND RESULTS: This was a retrospective single center study enrolling consecutive patients implanted with a continuous flow LVAD between 2011 and 2022. Hypotensive SBP response was defined as peak exercise SBP below the resting value. Multivariable Cox-regression analysis was performed to evaluate the relationship between hypotensive SBP response and all-cause mortality within 30 and 90 days of LVAD implantation. A subgroup analysis was performed for patients implanted with a HeartMate III (HM III) device. Four hundred thirty-two patients underwent LVAD implantation during the pre-defined period and 156 with INTERMACS profiles 3-6 met our inclusion criteria. The median age was 63 years (IQR 54-69), and 52% had ischaemic cardiomyopathy. Hypotensive SBP response was present in 35% of patients and was associated with increased 90 day all-cause mortality (unadjusted HR 9.16, 95% CI 1.98-42; P = 0.0046). Hazard ratio remained significant after adjusting for age, INTERMACS profile, serum creatinine, and total bilirubin. Findings were similar in the HM III subgroup. CONCLUSIONS: Hypotensive SBP response on pre-LVAD CPX is associated with increased perioperative and 90 day mortality after LVAD implantation. Additional studies are needed to determine the mechanism of increased mortality observed.

Heart Failure Care Delivery in the COVID-19 Era: The Patients' Perspective.

Purpose: The SARS-CoV-2 pandemic is changing healthcare delivery around the world with hospital systems experiencing a dramatic decline in patient volumes. Surveying our center's heart failure (HF) clinic population, we aimed to understand our patients' perception of coronavirus disease 2019 (COVID-19) and care delivery preferences. Methods: Patients with chronic HF presenting either in-person or virtually were approached to complete a ten question, anonymous, voluntary survey. Acutely decompensated patients and heart transplant recipients were excluded. Results: 109 patients completed the survey. Average age was 62 ± 14 years, 67% were male, and 59% had HF with reduced ejection fraction (HFrEF). Overall, patients were worried about contracting COVID-19 and believed they were prone to more severe infection given their underlying HF. However, they were not hesitant to initiate healthcare contact for symptoms and preferred in-person appointments over virtual visits. Although the difference did not reach statistical significance, female patients and those with HF with preserved ejection fraction (HFpEF) were more concerned. Conclusions: Patients with HF are concerned about their increased risk of contracting COVID-19. However, they are actively seeking healthcare contact and prefer in-person over virtual visits.

Advanced heart failure and transplant cardiology: a subspecialty is born.

Recently, the American Board of Medical Specialties approved a proposal from the American Board of Internal Medicine for establishing the secondary subspecialty of Advanced Heart Failure and Transplant Cardiology. This step represents culmination of a process that began 4 years ago, through advocacy by the Heart Failure Society of America. It represents an essential step to ensure quality of care by specialists in a field that has grown up de facto amid rapid expansion both of the population of patients with heart failure and of diagnostic and therapeutic options for their management. The vast majority of care for most patients with heart failure will continue to be provided by general internists and cardiologists. Certification in Advanced Heart Failure and Transplant Cardiology will require a high degree of competency in all aspects of heart failure care, including technical proficiencies required to manage patients undergoing heart transplant and device implants. These specialists will play a key role in delivering the highest quality of complex care in the most cost-effective manner. In the years to come, the specialty must adapt to the ongoing rapid expansion of evidence-based knowledge in this field to continue to provide the highest level of care and the best outcomes to patients with heart failure.

Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system. The relationship between soluble ACE2 (sACE2), myocardial function, and clinical outcomes in patients with chronic systolic heart failure is not well established. METHODS AND RESULTS: We measured sACE2 activity in 113 patients with chronic systolic heart failure (left ventricular ejection fraction [LVEF]

Cardiac Calcitropes, Myotropes, and Mitotropes: JACC Review Topic of the Week.

The term "inotrope" is familiar and intimately connected with pharmaceuticals clinically used for treatment of low cardiac output with cardiogenic shock. Traditional inotropic agents exert their effect by modulating calcium signaling in the myocardium. Their use is associated with poor long-term outcomes. Newer molecules in development intend to break from calcium mediation and the associated detrimental long-term effects by targeting distinct mechanisms of action to improve cardiac performance. Thus, "inotropy" does not sufficiently describe the range of potential novel pharmaceutical products. To enhance communication around and evaluation of current, emerging, and potential therapies, this review proposes a novel nuanced and holistic framework to categorize pharmacological agents that improve myocardial performance based on 3 myocardial mechanisms: calcitropes, which alter intracellular calcium concentrations; myotropes, which affect the molecular motor and scaffolding; and mitotropes, which influence energetics. Novel chemical entities can easily be incorporated into this structure, distinguishing themselves based on their mechanisms and clinical outcomes.

Prognostic evaluation of ambulatory patients with advanced heart failure.

Previous heart failure (HF) risk models have included clinical and noninvasive variables and have been derived largely from clinical trial databases or decompensated HF registries. The importance of hemodynamic assessment is less established, particularly in ambulatory patients with advanced HF. In this study, 513 consecutive ambulatory patients (mean age 54+/-11 years, mean left ventricular ejection fraction 20+/-9%) with symptomatic HF who underwent diagnostic right-sided cardiac catheterization as part of outpatient assessment from 2000 to 2005 were reviewed. After a total of 1,696 patient-years of follow-up, 139 (27%) patients had died and 116 (23%) had undergone cardiac transplantation. The 1- and 2-year overall survival rates (defined as freedom from death or cardiac transplantation) were 77% and 67%, respectively. Overall, 65% of patients had elevated intracardiac filling pressures, and 40% had cardiac indexes<2.2 L/min/m2. In multivariate analysis, mean pulmonary arterial pressure, cardiac index, and the severity of mitral regurgitation were the 3 strongest predictors of all-cause mortality and cardiac transplantation. Renal dysfunction was also an independent predictor of all-cause mortality. When a clinical model for Cox multivariate analysis of all-cause mortality was compared with a model that also included cardiac index and mean pulmonary arterial pressure, the chi-square score increased from 45 to 69 (p<0.0001). In conclusion, in ambulatory patients with advanced HF, hemodynamic and renal function assessments remain strong independent predictors of all-cause mortality.

Gender differences in patients admitted with advanced decompensated heart failure.

Broad population studies of patients with stable ambulatory heart failure have associated female gender with better age-adjusted survival. This study investigated whether there are gender-specific differences in clinical presentation, response to intensive medical therapy, and outcomes in patients admitted with advanced (cardiac index <2.4 L/min/m(2)) decompensated heart failure (ADHF). We reviewed 278 consecutive patients (age 54 +/- 12 years, cardiac index 1.7 +/- 0.4 L/kg/m(2), pulmonary capillary wedge pressure 26 +/- 9 mm Hg, serum creatinine 1.4 +/- 0.8 mg/dl) with ADHF treated with intensive medical therapy guided by pulmonary artery catheter in a dedicated heart failure intensive care unit from 2000 to 2006. Compared with men (n = 226), women (n = 52) had similar baseline characteristics with the exception of a higher prevalence of nonischemic cause. No differences in medical therapy on admission, during intensive medical therapy, or at discharge were observed. Intensive medical therapy was associated with significant hemodynamic improvement independent of gender. All-cause mortality and heart failure rehospitalization rates were similar between genders. However, adjusted for cause, women with ischemic cardiomyopathy had higher all-cause mortality rates (50% vs 37%, hazard ratio 1.95, 95% confidence interval 0.98 to 3.90, p = 0.05) and those with nonischemic cardiomyopathy had lower all-cause mortality rates (19% vs 40%, hazard ratio 0.40, 95% confidence interval 0.17 to 0.96, p = 0.01) than men. In conclusion, women presenting with ADHF had baseline characteristics and response to therapy similar to men. Overall outcomes were similar between men and women, although subgroup analysis suggested better survival for women with a nonischemic cause.