Heart failure with preserved ejection fraction: unravelling an enigma.

The management of chronic heart failure has made impressive progress over the last decades. However, progress was mainly restricted to patients with reduced ejection fraction (HFrEF) and more recently those with midrange ejection fraction (HFmrEF), while heart failure with preserved ejection fraction or HFpEF remains an enigma in spite of a considerable morbitiy and mortality. Indeed, inhibitors of the renin–angiotensin–aldosterone system and betablockers have revolutionized the management of HFrEF, but provide little or no benefit in HFpEF. Obviously, we have not fully understood the causes of HFpEF, a topic that Carolyn S.P. Lam and colleagues from the National Heart Centre Singapore try to address in their review ‘Heart failure with preserved ejection fraction: from mechanisms to therapies’. A key concept in this review is that HFpEF is a haemodynamic condition wherein the heart fails to keep up with the circulatory demands of the body or does so at the expense of raised left ventricular filling pressures. The authors therefore propose that the final common pathway for development of congestion, i.e. basic haemodynamic mechanisms of increased left ventricular end-diastolic pressure, left atrial hypertension, pulmonary venous congestion, and plasma volume expansion, represent important initial targets for therapy in HFpEF. Accordingly, they group this review into six mechanisms translating into potential therapies for HFpEF: beginning with three haemodynamic mechanisms (i.e left atrial hypertension, pulmonary hypertension, and plasma volume expansion), and working backwards to three potential molecular mechanisms (i.e. systemic microvascular inflammation, cardiometabolic functional abnormalities, and genetic abnormalities in the contractile apparatus, extracellular fibrosis, and structural abnormalities. Advances in precision medicine are likely to have transformative effects on the way that heart failure is managed in the years to come, as further outlined in a review entitled ‘Transitioning from usual care to biomarker-based personalized and precision medicine in heart failure: call for action’ by Antoni BayésGenı́s and colleagues from the Hospital Universitari Germans Trias i Pujol in Badalona, Spain. The authors note that circulating biomarkers measured with highly sensitive, specific, and reproducible assays will have increasingly important roles in heart failure for the patient-level risk assessment and therapeutic targeting. However, many questions remain unanswered, ranging from the intricacies of clinical use and adequacy of reference cut-off values, to the cellular and molecular mechanisms of biomarker production and release from the healthy and the failing heart or possibly extra-cardiac organs, to the critically important therapeutic implications. While data currently focus on the use of biomarkers to identify heart failure, stratify its risk, and possibly generically guide therapy with drugs developed for diseases other than heart failure, the authors believe the future must bring a much more individualized and focused treatment strategy, including use of complex phenotype/genotype analyses as well as the use of precision therapies targeting deleterious mediator pathways in heart failure. A broad research agenda that spans the spectrum of basic and translational studies, through to substudies of clinical trials investigating novel therapies and their effect among groups defined according to biomarker values, will be needed to position companion biomarkers fully in heart failure precision medicine. Some forms of HFpEF are beginning to be understood in terms of their mechanisms. Indeed, cardiac transthyretin (ATTR) amyloidosis is an increasingly recognized, progressive, and fatal cardiomyopathy where specific therapies are being developed. In their article entitled ‘A new staging system for cardiac transthyretin amyloidosis’, Julian David Gillmore and colleagues from the University College London Medical School in the UK sought to establish and validate a new prognostic staging system applicable to patients both with the wild type and with a hereditary variant. A total of 869 patients with cardiac transthyretin amyloidosis (553 with the wild type and 316 with a hereditary variant) were stratified into three