Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction
A Multiorgan Roadmap

Shah SJ, Kitzman DW, Borlaug BA, et al.
Circulation. 2016;134:73-90
 Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of all HF cases, and does not respond to neurohumoral inhibition. This might be the consequence of:

• the different systemic and myocardial signalling in HFpEF compared with HF with reduced ejection fraction (HFrEF)
• the heterogeneity of the HFpEF phenotypes

In this review, the HFpEF-specific systemic and myocardial signalling is described, the various HFpEF phenotypes are summarised, and appropriate therapeutic strategies are discussed.

Systemic and Myocardial Signalling

Most HFpEF patients are elderly, of female gender, and have multiple comorbidities (frequently obesity, hypertension, diabetes, renal dysfunction, sleep apnoea) that are associated with chronic systemic inflammation. Systemic inflammation may affect myocardial remodelling and dysfunction in HFpEF patients, through an extra-myocardial signalling cascade, which begins with coronary microvascular endothelial dysfunction, and develops to myocardial infiltration, fibrosis, and hypertrophy. This extra-myocardial origin of HFpEF differs from the intra-myocardial origin of HFrEF, in which remodelling is driven by cardiomyocyte cell death due to ischemia, infection, or
toxicity.

Phenotypic Framework

Clinically, HFpEF is a complex syndrome that can be triggered by several comorbidities and inflammatory mediators, and is characterised by both extra-cardiac and cardiac signs and symptoms. Due to the diversity of the HFpEF syndrome, a one-size-fits-all treatment strategy cannot be successful, thus an effort should be made to personalise therapies for HFpEF patients. For this purpose, a stepwise approach is presented, which combines predisposition phenotypes with clinical presentation phenotypes, with the objective to guide clinical care and future research.

Phenotypic Treatment Strategy

Diuretics

The use of diuretics to decrease left ventricular filling pressures is very important for the management of HFpEF patients. There are data showing that in seemingly compensated HFpEF patients, diastolic left ventricular pressure is still increased. During transition to decompensation, the haemodynamic monitoring of the progressively increasing diastolic left ventricular pressures over weeks allows for early up-titration of diuretics, which improves outcomes.

Caloric Restriction

Weight loss should be considered in any treatment strategy for HFpEF patients. According to recent clinical data, a 20-week caloric restriction diet is feasible and safe, and leads to significant improvements of symptoms, peak oxygen consumption, and quality-of-life scores.

Statins

The presence of systemic inflammation supports the use of statins in HFpEF. Statins improve endothelial function independently of low-density lipoprotein lowering.

Inorganic Nitrite/Nitrate

Organic nitric oxide (NO) donors may be useful in HFpEF for the restoration of the myocardial NO content and the elevated arterial load. However, according to recent data, organic nitrate isosorbide mononitrate did not improve submaximal exercise capacity. In contrast to organic nitrates, the inorganic nitrate-nitrite pathway represents an alternative way to restore NO signalling in HFpEF, since they have been shown to reduce arterial stiffness in healthy volunteers, and improve systemic vasodilation during exercise in patients with HFpEF.

Sacubitril and Other Protein Kinase G (PKG)-Stimulating Drugs

Many HFpEF patients have ventricular hypertrophy with interstitial fibrosis and diastolic chamber stiffening. Therefore, it is thought that the blockade of key activators of this process and the stimulation of intrinsic suppressors of these changes might be of benefit for these patients. An interesting example is the PKG stimulation that has potent anti-fibrotic and anti-hypertrophic effects in cultured myocytes and fibroblasts, and exhibits a protective effect in several experimental cardiac disease models including pressure-overload hypertrophy.

Spironolactone and E-Matrix Modification

The homeostasis of collagen plays a major role in diastolic dysfunction. HFpEF is more often associated with interstitial, reactive fibrosis and HFrEF with focal, replacement fibrosis. In HFpEF, collagen synthesis is increased and collagen degradation is decreased resulting in a net increase in collagen content. Three agents that affect the extracellular matrix have been tested in HFpEF:

• spironolactone in the TOPCAT study did not reduce the composite primary endpoint in the overall population
• valsartan/sacubitril in the PARAMOUNT study led to a significant decrease in N-terminal pro-BNP and left atrial volume in HFpEF patients
• torasemide improved diastolic left ventricular dysfunction in patients with hypertensive heart disease.

Arterial Hypertension

Large studies testing neurohumoral inhibition in HFpEF patients, led to conflicting results in respect to clinical outcomes, thus, it is not clear whether there is an additional benefit from the use of ACEIs and ARBs in these patients. However, there are data supporting that ACEIs and ARBs are safe, well tolerated, and improve symptoms and quality of life, which may be a worthwhile treatment goal.

Renal Dysfunction

HFpEF in the presence of renal dysfunction is a distinct HFpEF phenotype associated with more left ventricular hypertrophy, a larger left ventricular systolic functional deficit, impaired left atrial mechanics, right ventricular dysfunction, and poor prognosis. The poor prognosis is associated with excessive reactive pulmonary hypertension and right ventricular dysfunction, which, in turn contribute to renal dysfunction in HFpEF. Therefore, intense diuresis, combined with ultrafiltration if appropriate, is crucial for HFpEF patients with renal dysfunction.

Coronary Artery Disease

HFpEF in the presence of coronary artery disease is another distinct HFpEF phenotype with a larger left ventricular systolic functional deficit, poor prognosis, and a high incidence of sudden death. While ACEIs are recommended for the prevention of recurrent cardiovascular events in these patients, observational data suggest that complete revascularisation is associated with a better prognosis.

Chronotropic Incompetence

The decreased cardiac output reserve in HFpEF is related to a decreased stroke volume augmentation, and with chronotropic incompetence, which has been associated with endothelial dysfunction and systemic inflammation. The direct relationship between heart rate response to activity and aerobic capacity led to the hypothesis that rate-adaptive atrial pacing can improve exercise capacity in patients with HFpEF, and this is currently tested in a clinical trial.

Pulmonary Hypertension

Pulmonary hypertension and right ventricular dysfunction are frequently present in HFpEF, and lead to increased morbidity and mortality. Recent clinical data show that pulmonary vascular function in HFpEF patients can be significantly improved with dobutamine. Other trials are testing the use of pulmonary vasodilators in HFpEF patients that target cGMP, endothelin, and NO.

Skeletal Muscle Weakness

HFpEF patients have abnormalities in skeletal muscle mass, composition, capillary density, and oxidative metabolism. Exercise training significantly improves peak Vo2 in HFpEF patients by improving skeletal muscle mitochondrial mass or function.

Atrial Fibrillation

Any effort should be made to restore sinus rhythm with cardioversion in HFpEF patients with atrial fibrillation. Catheter ablation in these patients has limited long-term success. If cardioversion is unsuccessful, rate control and permanent anticoagulation are recommended, as well as exercise training and weight loss.

Conclusions

HFpEF patients are frequently of advanced age and have multiple comorbidities that lead to chronic systemic inflammation, which, in turn, triggers an extra-myocardial signalling cascade. The extra-myocardial origin of HFpEF differs from the intra-myocardial origin of HFrEF, in which remodelling is driven by cardiomyocyte cell death because of ischemia, infection, or toxicity. This might explain why HFpEF does not respond to neurohumoral inhibition. Clinically, HFpEF is a complex syndrome characterised by both extra-cardiac and cardiac signs and symptoms that cannot be successfully managed with a one-size-fits-all treatment strategy and needs a personalised approach.

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