Summary Heart failure is a global problem with an estimated prevalence of 38 million patients worldwide, a number that is increasing with the ageing of the population. It is the most common diagnosis ...in patients aged 65 years or older admitted to hospital and in high-income nations. Despite some progress, the prognosis of heart failure is worse than that of most cancers. Because of the seriousness of the condition, a declaration of war on five fronts has been proposed for heart failure. Efforts are underway to treat heart failure by enhancing myofilament sensitivity to Ca2+ ; transfer of the gene for SERCA2a, the protein that pumps calcium into the sarcoplasmic reticulum of the cardiomyocyte, seems promising in a phase 2 trial. Several other abnormal calcium-handling proteins in the failing heart are candidates for gene therapy; many short, non-coding RNAs—ie, microRNAs (miRNAs)—block gene expression and protein translation. These molecules are crucial to calcium cycling and ventricular hypertrophy. The actions of miRNAs can be blocked by a new class of drugs, antagomirs, some of which have been shown to improve cardiac function in animal models of heart failure; cell therapy, with autologous bone marrow derived mononuclear cells, or autogenous mesenchymal cells, which can be administered as cryopreserved off the shelf products, seem to be promising in both preclinical and early clinical heart failure trials; and long-term ventricular assistance devices are now used increasingly as a destination therapy in patients with advanced heart failure. In selected patients, left ventricular assistance can lead to myocardial recovery and explantation of the device. The approaches to the treatment of heart failure described, when used alone or in combination, could become important weapons in the war against heart failure.
Abstract The PARADIGM-HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial demonstrated that a new angiotensin receptor ...antagonist-neprilysin inhibitor was superior to an angiotensin-converting enzyme inhibitor in reducing mortality in patients with heart failure and reduced ejection fraction. This paper traces the research path that culminated in the development of this drug. The first phase, elucidation of the renin-angiotensin-aldosterone system, began with Tigerstedt’s discovery of renin, followed by isolation of angiotensin, isolation of angiotensin-converting enzyme, and synthesis of its inhibitors and of angiotensin receptor blockers. Phase 2 began with de Bold’s discovery of atrial natriuretic peptide, followed by isolation of the enzyme that degrades it (neprilysin) and its inhibitors. Phase 3 consists of blocking both the renin-angiotensin-aldosterone and atrial natriuretic peptide–degrading systems simultaneously. A molecular complex, LCZ696, developed by scientists at Novartis, combines an angiotensin receptor blocker with a neprilysin inhibitor, is well tolerated, and represents an important step in the management of heart failure and reduced ejection fraction.
In this review of heart disease, Nabel and Braunwald focus on two themes — coronary artery disease and myocardial infarction — and explain how our understanding has evolved over the past two ...centuries. The authors consider therapies that have led to improved survival.
The remarkable facts, that the paroxysm, or indeed the disease itself, is excited more especially upon walking up hill, and after a meal; that thus excited, it is accompanied with a sensation, which threatens instant death if the motion is persisted in; and, that on stopping, the distress immediately abates, or altogether subsides; have . . . formed a constituent part of the character of Angina Pectoris.
1
“Remarks on Angina Pectoris” by John Warren, M.D., appeared in 1812 as the first article in the first issue of
The New England Journal of Medicine and Surgery
.
1
Warren's description of angina pectoris . . .
Patients with type 2 diabetes mellitus have an increased risk for the development of cardiac and other vascular events, heart failure (HF), and decline in renal function. After several large ...cardiovascular outcome trials with mostly neutral results, 2 studies of the sodium–glucose co-transporter 2 inhibitors (SGLT2is), empagliflozin and canagliflozin, reported favorable effects on the primary endpoint, a composite of myocardial infarction, stroke, and cardiovascular death. In addition, reductions of hospitalizations for HF were observed; in the case of empagliflozin, reductions in both cardiovascular mortality and total mortality occurred. These findings prompted several analyses to elucidate the mechanisms of action of SGLT2is and have initiated several large clinical trials in patients with HF without type 2 diabetes mellitus. This review summarizes known and possible mechanisms that contribute to these salutary effects of SGLT2is. Also discussed is the interplay between cardiac and renal function, as well as safety issues associated with this class of drugs.
Display omitted
Despite major improvements in the treatment of virtually all cardiac disorders, heart failure (HF) is an exception, in that its prevalence is rising, and only small prolongations in survival are ...occurring. An increasing fraction, especially older women with diabetes, obesity, and atrial fibrillation exhibit HF with preserved systolic function. Several pathogenetic mechanisms appear to be operative in HF. These include increased hemodynamic overload, ischemia-related dysfunction, ventricular remodeling, excessive neurohumoral stimulation, abnormal myocyte calcium cycling, excessive or inadequate proliferation of the extracellular matrix, accelerated apoptosis, and genetic mutations. Biomarkers released as a consequence of myocardial stretch, imbalance between formation and breakdown of extracellular matrix, inflammation, and renal failure are useful in the identification of the pathogenetic mechanism and, when used in combination, may become helpful in estimating prognosis and selecting appropriate therapy. Promising new therapies that are now undergoing intensive investigation include an angiotensin receptor neprilysin inhibitor, a naturally-occurring vasodilator peptide, a myofilament sensitizer and several drugs that enhance Ca++ uptake by the sarcoplasmic reticulum. Cell therapy, using autologous bone marrow and cardiac progenitor cells, appears to be promising, as does gene therapy. Chronic left ventricular assistance with continuous flow pumps is being applied more frequently and successfully as destination therapy, as a bridge to transplantation, and even as a bridge to recovery and explantation. While many of these therapies will improve the care of patients with HF, significant reductions in prevalence will require vigorous, multifaceted, preventive approaches.
When coronary arteriography was developed in the early 1960s, the very high risk associated with obstructive left main coronary artery disease became evident; this risk was related to the large ...volume of myocardium supplied by this vessel. Among patients receiving the medical therapy available at the time, the 5-year mortality approached 60%, and the survivors usually had severe symptoms, including angina, heart failure, or both.
1
Several years later, after coronary-artery bypass grafting (CABG) became available, two multicenter, randomized trials that compared medical treatment with surgical treatment showed that surgical treatment was strikingly superior.
2
,
3
Since then, there has been general . . .
The nonischemic cardiomyopathies are a diverse group of cardiac disorders that frequently cause heart failure and death and are now recognized with increasing frequency. There has been substantial ...progress in the clinical recognition and understanding of the natural history of these conditions. Well-established and new techniques of cardiac imaging are also helpful in this regard. Basic scientists are elucidating the pathogenesis and pathobiology of individual cardiomyopathies. In this compendium, some of the most important advances in this field are reviewed. Scientific opportunities to enhance further collaborative research to accelerate progress are identified.
It has been known for more than a century that coronary-artery thrombosis is the most common precipitant of acute myocardial infarction and that atherosclerotic plaques in the coronary arteries are ...often responsible for angina pectoris. When anticoagulants and antiplatelet agents became available, clinical investigators rushed to study their efficacy and safety in patients with coronary artery disease. Attention was focused on two large populations — patients with acute coronary syndromes and those with stable ischemic disease, many of whom had previously had an acute event. Hundreds of trials, registries, and systematic analyses on the benefits and risks of individual and . . .
Patients with acute decompensated heart failure were randomly assigned to receive sacubitril–valsartan or enalapril. At 8 weeks, the sacubitril–valsartan group had a greater reduction in the ...N-terminal pro–B-type natriuretic peptide concentration than the enalapril group.
Gliflozins — sodium–glucose cotransporter 2 inhibitors — lower blood glucose and glycated hemoglobin in patients with type 2 diabetes without causing hypoglycemia. The agents also improve cardiac ...function in patients who have heart failure with or without type 2 diabetes and improve renal function, with few adverse effects.
PDF
