Heart failure with preserved ejection fraction: uncertainties and dilemmas

Many uncertainties surround the syndrome of heart failure with preserved ejection fraction (HFpEF), which was the topic reviewed in an Expert Meeting at the University of Ferrara. This concluded that the absence of clear diagnostic clinical criteria was the major barrier to progress. There was general agreement that symptoms or signs of heart failure, normal LVEF despite an elevated plasma concentration of natriuretic peptides, and signs of abnormal LV relaxation, LV filling, LV hypertrophy, or left atrial enlargement, or diastolic dysfunction supported the diagnosis. However, HFpEF, like all heart failure syndromes, is heterogeneous in aetiology and pathophysiology, rather than being a single disease. HFpEF may account for about half of all patients with heart failure. The classical risk factors for developing HFpEF include age and co‐morbidities, notably hypertension, atrial fibrillation, and the metabolic syndrome. When complicated by increasing congestion requiring hospital admission, the prognosis is poor; 30% or more of patients will die within 1 year (nearly two‐thirds die from cardiovascular causes). Patients with chronic stable symptoms have a much better prognosis. Despite many clinical trials, there is no solid evidence that any treatment alters the natural history of HFpEF. Several treatments have shown promising early results and are now being tested in substantial randomized clinical trials. Further basic research is required to better characterize the disease and accelerate progress. Our review highlights the many difficulties encountered in performing randomized clinical trials in HFpEF, often due to difficulties in characterizing HFpEF itself.     

Obesity and heart failure with preserved ejection fraction: A growing problem

Heart Failure with Preserved Ejection Fraction (HFpEF) is increasing in prevalence due to the aging of the United States population as well as the current obesity epidemic. While obesity is very common in patients with HFpEF, obesity may represent a specific phenotype of HFpEF characterized by unique hemodynamics and structural abnormalities. Obesity induces a systemic inflammatory response that may contribute to myocardial fibrosis and endothelial dysfunction. The most obese patients continue to be excluded from HFpEF clinical trials, and thus ongoing research is needed to determine the role of pharmacologic and interventional approaches in this growing population.     

Heart failure with preserved ejection fraction

Progressive aging of the population and prolongation of life expectancy have led to the rising prevalence of heart failure (HF). Despite the improvements in medical therapy, the mortality rate of this condition has remained unacceptably high, becoming the primary cause of death in the elderly population. Almost half of patients with signs and symptoms of HF are found to have a nearly normal ejection fraction, which delineates a distinct clinical syndrome, known as HF with preserved ejection fraction (HF-PEF). While early research focused on the importance of diastolic dysfunction, more recent studies reported the pathophysiological complexity of the disease with multiple cardiovascular abnormalities contributing to its development and progression. HF-PEF is a challenging major health problem with yet no solution as there is no evidence-based treatment which improves clinical outcomes. This review summarizes the state of current knowledge on diagnosis, prognosis and treatment of HF-PEF, with particular insights on the pathological characteristics in the elderly population.     

Lead aVR is a predictor for mortality in heart failure with preserved ejection fraction

BackgroundNormally, lead augmented vector right (aVR) has a negative T wave polarity (TaVR) in the electrocardiography (ECG). Positive TaVR and ST segment deviation in lead aVR (STaVR) have negative effects on mortality in heart failure with reduced ejection fraction patients.AimOur aim was to investigate the relationship between lead aVR changes and mortality in heart failure with preserved ejection fraction (HFpEF) patients.MethodsWe retrospectively examined 249 patients in 2011–2015 years (mean age 70.8 ± 11.9 years and follow-up period 38.3 ± 9.6 months). ECG, echocardiographic, and laboratory findings were recorded and compared in the study. Existence of positive TaVR, STaVR, and quantitative TaVR values were recorded and the absolute numerical values of TaVR and STaVR were recorded from the 12-lead surface ECG (T/STaVR ratio or vice versa).ResultsThe patients were divided into two groups: living (171) and deceased (78). Age, systolic blood pressure, left atrial diameter, QRS duration, positive TaVR frequency, STaVR, absolute value of TaVR, and ratio were significantly higher in the deceased group. Age (OR: 1.106), STaVR (OR: 2.349), TaVR (OR: 1.612), and T/STaVR ratio (OR: 5.156) were determined as independent predictors for mortality.ConclusionsST segment and T wave polarity changes in lead aVR closely associated with mortality in patients with HFpEF.     

Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond

Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high‐voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid‐range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.     

The cost-effectiveness of dapagliflozin in heart failure with preserved or mildly reduced ejection fraction: A European health-economic analysis of the DELIVER trial

Aims

To determine the cost-effectiveness of dapagliflozin, added to usual care, in patients with heart failure (HF) with mildly reduced or preserved ejection fraction for the UK, German and Spanish payers using detailed patient-level data from the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial.

Methods and results

A lifetime Markov state-transition cohort model was developed. Quartiles of the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) defined health states and monthly transition count data informed transition probabilities. Multivariable generalized estimating equations captured the incidence of HF hospitalizations and urgent HF visits, while cardiovascular deaths and all-cause mortality were estimated using adjusted parametric survival models. Health state costs were assigned to KCCQ-TSS quartiles (2021 British pound [GBP]/Euro) and patient-reported outcomes were sourced from DELIVER. Future values of costs and effects were discounted according to country-specific rates. In the UK, dapagliflozin treatment was predicted to increase quality-adjusted life years (QALYs) and life-years by 0.231 and 0.354, respectively, and extend the time spent in the best quartile of KCCQ-TSS by 4.2 months. Comparable outcomes were projected for Germany and Spain. The incremental cost-effectiveness ratios were £7761, €9540 and €5343/QALY in the UK, Germany and Spain, respectively. According to regional willingness-to-pay thresholds, 91%, 89% and 92% of simulations in the UK, Germany and Spain, respectively, were cost-effective following probabilistic sensitivity analyses.

Conclusion

Dapagliflozin, added to usual care, is very likely cost-effective for HF with mildly reduced or preserved ejection fraction in several European countries.     

Integration of exercise evaluation into the algorithm for evaluation of patients with suspected heart failure with preserved ejection fraction

Approximately half of all patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFPEF) and the prevalence of this form of HF is increasing. Although dyspnoea on exertion and diminished functional capacity is the key symptom of patients with HFPEF, current diagnostic criteria focus on resting indices of ventricular function. Specifically, current proposed criteria for the diagnosis of HFPEF, include clinical signs of HF; normal left ventricular systolic function; and evidence of abnormal diastolic performance and/or altered natriuretic peptides. By contrast, recent studies demonstrate that the key pathophysiologic features of HFPEF may not be evident at rest, and can only be detected during exertion. This review addresses the potential role of exercise testing using invasive haemodynamic or echocardiographic assessment in patients with suspected HFPEF in which current diagnostic criteria are not met.     

Heart failure with preserved ejection fraction: Classification based upon phenotype is essential for diagnosis and treatment

Heart failure (HF) is classified based upon the left ventricular ejection fraction (LVEF). Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disorder with increasing prevalence in the elderly that remains incompletely understood and inadequately treated as no therapy has shown favorable effects. In this review, we summarize the current theories regarding HFpEF pathogenesis, propose a phenotype-based classification of HFpEF, discuss prevention strategies, explain why clinical trials on HFpEF treatment have failed, and make suggestions for the future.     

Role of global longitudinal strain in assessment of left ventricular systolic function in patients with heart failure with preserved ejection fraction

Objectives

To detect systolic dysfunction in heart failure with preserved ejection fraction (HFpEF) patients by using global longitudinal strain (GLS).

Medication dosing for heart failure with reduced ejection fraction — opportunities and challenges

Multiple drug classes have shown incremental benefits in heart failure with reduced ejection fraction. Most of these trials were designed to achieve specific doses of the investigational agent. Clinical practice guidelines recommend using the same target dosing of therapies, as tolerated. However, with the increasing number of available therapies, clinicians face the challenge of simultaneously using several drugs, achieving target doses, and managing side effects that are often overlapping. Blood pressure, renal function, hyperkalaemia, and other factors may impede achieving target doses of all medications, leaving clinicians with dilemmas as to how to sequence and dose these various classes of drugs. The guideline‐directed eligibility for certain drugs and devices requires stability on maximally tolerated doses of background therapies. However, significant variability exists in dosing achieved in clinical practice. We discuss the existing background data regarding the doses of heart failure medications in clinical trials and in practice, and provide recommendations on how to navigate this complex therapeutic decision‐making.     

Therapeutic interventions for heart failure with preserved ejection fraction:A summary of current evidence

Heart failure with preserved ejection fraction(HFPEF)is common and represents a major challenge in cardiovascular medicine.Most of the current treatment of HFPEF is based on morbidity benefits and symptom reduction.Various pharmacological interventions available for heart failure with reduced ejection fraction have not been supported by clinical studies for HFPEF.Addressing the specific aetiology and aggressive risk factor modification remain the mainstay in the treatment of HFPEF.We present a brief overview of the currently recommended therapeutic options with available evidence.     

Predictive value of serum galectin-3 levels in patients with acute heart failure with preserved ejection fraction

Aims

This study was conducted to determine whether galectin-3 (Gal3), a β-galactoside-binding lectin, has usefulness to predict outcomes in patients with heart failure (HF) and preserved left ventricular ejection fraction (LVEF).

Methods and results

We measured Gal3, urea, creatinine and natriuretic peptides on admission in 419 selected patients with HF and LVEF over 45%. The primary endpoint was all-cause mortality and/or readmission at one-year follow-up. Multivariable Cox proportional hazards models were generated for Gal3 and classical risk factors. We also evaluated the reclassification of patients on the basis of the different score category after adding Gal3 levels.A total of 219 patients had combined adverse events, and 129 patients died during the follow-up. Kaplan–Meir survival curve showed significantly increased primary endpoint and all-cause mortality according to quartiles of Gal3 (log rank, P < 0.001). Serum Gal3 levels above median (13.8 ng/ml) was a significant predictor of primary endpoint risk after adjustment for age, estimated glomerular filtration rate, anemia, diabetes, serum sodium, brain natriuretic peptide levels, NYHA class and urea, respectively (hazard ratio 1.43, 95% CI 1.07–1.91 P = 0.015). The reclassification index increased significantly after addition of Gal3 (9.5%, P < 0.001) and the integrated discrimination index was 0.022, (P = 0.001). The clinical prediction model with Gal3 increased the c-statistic from 0.711 to 0.731 (difference of 0.020, P = 0.001).

Conclusions

Serum Gal3 is a strong and independent predictor of unfavorable outcomes in patients with HF and preserved LVEF. We also demonstrated the improvement of adding the new biomarker to the model.     

Epidemiology and clinical course of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFPEF) is increasingly recognized as a major public health problem worldwide. Significant advances have been made in our understanding of the epidemiology of HFPEF over the past two decades, with the publication of numerous population‐based epidemiological studies, large heart failure registries, and randomized clinical trials. These recent studies have provided detailed characterization of larger numbers of patients with HFPEF than ever before. This review summarizes the state of current knowledge with regards to the disease burden, patient characteristics, clinical course, and outcomes of HFPEF. Despite the wealth of available data, substantive gaps in knowledge were identified. These gaps represent opportunities for further research in HFPEF, a syndrome that is clearly a rising societal burden and that is associated with substantial morbidity and mortality.