The management of heart failure: a brief look into the future

Heart failure (HF) is a major cause of death, hospitalization, morbidity, and cost, with a global prevalence of more than 65 million persons. In Western countries, HF is the most common diagnosis for hospitalization in persons ≥ 65 years. With the development of new therapies which extend the survival of patients with HF and with the ageing of the general population, this prevalence is likely to continue to grow. Thus, HF remains a serious worldwide problem. Fortunately, it is being addressed in preclinical and early clinical studies that are reviewed briefly in this article. Genetic studies have shown that DNA is damaged in mice with HF induced by aortic constriction and an insulin-like growth factor binding cytokine is released by senescent vascular endothelial cells. A vaccine-based molecule against this cytokine ameliorated the cardiac dysfunction, raising the possibility in the future that the development of HF might be reduced by a vaccine in patients at high risk.1 Transthyretin amyloidosis is now recognized more frequently than heretofore to be a cause of a cardiomyopathy that is often fatal. In a Phase 1 study using CRISPR-Cas9 gene editing, a single infusion of an investigative drug resulted in striking reductions in serum transthyretin amyloid, suggesting that this serious myopathy may be controlled2; a Phase 3 trial is currently underway. The expression of another gene (BINi) is often reduced in patients with HF, and a trial in patients with chronic HF administered this gene using an adeno-associated viral vector is likely. The circulating messenger (m) RNAs of other genes has been combined to create genetic risk scores which are likely to be of benefit in patient management.3 Although the genetics of HF with preserved ejection fraction (HFpEF) are still obscure, the combination of five mRNAs may identify patients at high risk of developing this condition has been described. This could alter clinical management and improve clinical outcome. Metabolomic profiling: It has been observed that the proteome is a strong predictor of mortality in patients with HF, regardless of left ventricular ejection fraction.4 Increased plasma ketone concentrations are associated with enhanced cardiac output and reduced pulmonary arterial wedge pressure. The mechanism of these important actions may be related to providing additional ‘fuel’ to the failing heart and/or reduction of systemic vascular resistance. Indeed, ketogenesis appears to play an important role in the salutary effects of SGLT2 inhibitors,5–7 and orally administered ketones may prove to be beneficial in the management of patients with HF. With new assays, thousands of plasma proteins can now be measured accurately and rapidly. Using machine learning, a small fraction of these are predictors of early mortality which will personalize the care and outcome of patients with HF. Obesity is a chronic disorder that increases the likelihood of the development of HFpEF. Approximately one-third of patients hospitalized for HFpEF in the USA present with central obesity. It is likely that oral glucagon-like protein agonists (GLP-1), probably combined with other potent anti-obesity medications, will play an important role in the prevention and management of HFpEF. Cell therapy for HF has undergone multiple preclinical and early Phases 1 and 2 trials; the former have shown that the injected cells have only a brief life in the myocardium and that any benefit observed may be of pleiotropic origin.8 Among the various cell types that have been studied, autologous pluripotent stem cells and bone marrow-derived mesenchymal stromal cells appear to be the most promising. Although a single delivery of these cells may provide modest benefit, preclinical studies have demonstrated that deliveries repeated at intervals enhanced this benefit. This observation may not be practical clinically if the cell delivery must be made into the heart.8 It has also been suggested that intact cells may not be necessary to get these effects. Cell products such as specific mRNAs and microRNAs may be angiogenic and/or anti-apoptotic. If that proves to be the case, it could have a profoundly beneficial effect in the future management of HF. Devices: Cardiology became a distinct specialty at the end of the 19th and the beginning of the 20th centuries by the development of three non-invasive devices: the measurement of arterial pressure, electrocardiography, and cardiac size (by roentgenography). Subsequently, cardiac catheterization, pacemakers, prosthetic heart valves, and heart-lung machines are among the devices that have greatly enhanced the specialty. Attention is now focused on the development of new devices designed to augment the action of drugs in the prevention and the reduction of the severity of HF. They fall into two categories—implanted and wearable.9 Three implanted devices have been approved by the US Food and Drug Administration for the management of chronic HF. The CardioMEMS system of implantable monitors provides continuous pulmonary artery pressure remotely. This can guide pharmacologic therapy and thereby enhance survival and HF hospitalization in patients with HF and reduced ejection fraction (HFrEF).10 Cardiac contractility modulators (CCM) consist of an implanted power source that delivers non-excitatory biphasic electrical impulses to the inter-ventricular septum during the brief refractory period following ventricular contraction,11 These stimuli enhance myocardial contractility by increasing intracellular calcium concentration and/or modifying myocardial gene expression and thereby improve HF patients’ functional capacity and maximal O2 consumption (VO2) and the quality of life in patients with HFrEF. The third approved device in chronic HF is barostimulation in which electrical stimulation of the carotid sinuses increases parasympathetic activation and reduces sympathetic activation, thereby also enhancing ventricular function.12 Intermittent occlusion of the superior vena cava by a balloon mounted on a catheter may be of benefit in patients with acutely decompensated HF.13 Stimulation of the vagus and phrenic nerves and/or of the diaphragm is currently being studied and may prove to be effective in patients with advanced HFrEF. In preclinical studies, a novel transaortic pulsatile pump placed in the descending aorta has undergone encouraging results to unload ventricular function in pigs in cardiogenic shock. While these devices may be effective, they occasionally cause infection or malfunction and are quite costly. However, it is likely that their continued improvement will reduce the threshold for their application in patients with HFrEF, whose symptoms cannot be controlled by medical therapy. It is likely that non-invasive monitoring and telehealth will play increasingly important roles in patients with HF, especially in rural areas. In addition to the information provided by electrocardiography and remote measurement of arterial oxygen saturation, of physical activity (and plasma concentration of glucose in patients with T2D) will be employed more frequently and will be helpful in the determination of the need for adjustment of therapy, of personal visit to a health care facility, or of hospitalization.14 Two additional approaches could have enormously salutary effects in reducing the frequency and severity of HF. The first, for asymptomatic or mildly symptomatic persons, consists simply of much stricter application of established guidelines for primordial and primary care.15 The second, for patients with advanced HF and a serious prognosis, is xenotransplantation of a genetically modified porcine heart, since availability of human donor hearts is inadequate. This approach requires further efforts designed for inhibiting rejection. Between these two ends of the spectrum of HF, the many advances summarized above are likely to improve the future management of patients with this important condition. E.B. reports grant support through his institution from AstraZeneca, Daiichi Sankyo, Merck, and Novartis and consulting fees from Bristol Myers Squibb, Boehringer Ingelheim/Lilly, Cardurion, Edgewise, IMMEDIATE, and Verve.