Mechanisms involved in HFpEF and how they are or may be targeted for therapy
Heart failure with preserved ejection fraction: from mechanisms to therapiesLiterature - Lam CSP et al., - Eur Heart J, 2018 ehy301, https://doi.org/10.1093/eurheartj/ehy301
The ESC Heart Failure Guidelines of 2016 clearly state that heart failure with preserved ejection fraction (HFpEF) is a condition in which ‘no treatment has yet been shown, convincingly, to reduce morbidity and mortality’. As HFpEF is or is becoming the dominant form of HF, it represents a great unmet need. This review aims to link mechanistic insights to potential therapies.
Treating symptoms and precipitating causes in HFpEF: current management
Symptomatic treatment of HFpEF mainly consists of diuretics to reduce congestion, although evidence on this intervention is scarce. In patients who also have atrial fibrillation (AF), the evidence on rate control is limited, and the benefit if rhythm control in this patient group is unclear. Questions remain unanswered as to whether treatment of hypertension is beneficial in patients with established HFpEF. Moreover, appropriate management of coronary artery disease requires consideration. RAAS inhibitors are commonly given to patients with HFpEF, but the evidence that they may yield improved outcomes is thin.
HFpEF: mechanisms to future therapies
This review is based on the concept that HFpEF, like HF with reduced EF (HFrEF), is a hemodynamic 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 propose that ‘the “final common pathway” for development of congestion, i.e. basic hemodynamic mechanisms of increased left ventricular end-diastolic pressure, left atrial hypertension, pulmonary venous congestion, and plasma volume expansion, represents important initial targets for therapy in HFpEF. Six different mechanisms are discussed, along with a translation into potential therapies for HFpEF. First, three hemodynamic mechanisms are considered, followed by three molecular mechanisms.
Left heart congestion/diastolic dysfunction/left atrial hypertension
Patients with “diastolic heart failure” have been shown to have impaired relaxation and diastolic stiffness, and increased left atrial size. The link between left ventricular diastolic dysfunction has been confirmed by several lines of evidence, and collectively the data point in the direction that elevated left ventricular diastolic pressures, with resultant left atrial hypertension, play a pivotal role in the underlying pathophysiology of HFpEF.
Left atrial hypertension has been targeted using a transcatheter interatrial shunt device, which indeed unloaded the left atrium and produced greater reduction in pulmonary capillary wedge pressure compared to the sham-control arm in the REDUCE LAP-HF I trial. A concern with this device is the potential rise in right-sided pressures, which can be detrimental. Clinical outcomes and quality of life with use of the device are currently under investigation.
Pulmonary pressure has been targeted by means of a wireless pulmonary artery pressure recorder (CardioMEMS). The CHAMPION trial tested whether hemodynamically guided HF management with CardioMEMS decreased HF hospitalization. Indeed, a greater reduction in pulmonary pressures was associated with a reduction of 46% in HF hospitalization in 6 months. Consequently, wireless monitoring of pulmonary artery pressure has now received a class IIb-B recommendation in HF in the 2016 ESC HF Guidelines.
Pulmonary vascular disease and right ventricular dysfunction
Pulmonary hypertension (PH) is very common in left ventricular HF, including HFpEF. Increased left ventricular filling pressure in HFpEF leads to pulmonary venous congestion, and consequently PH. Pulmonary arterial pressure (PAP) is a marker of the severity and chronicity of PH. Most HFpEF patients have post-capillary (pulmonary capillary wedge pressure ≤15 mmHg) PH, although pre-capillary (>15 mmhg) also occurs. The combination is also possible, and identification is relevant, as prognosis of those with additional pre-capillary PH is poorer, but patients may respond better to pulmonary vasodilator therapy. Presence and severity of PH correlate with development of RV dysfunction. Taken together, it appears as though pulmonary vascular disease may be an important therapeutic target in HFpEF.
Moreover, altered pulmonary function and lower diffusing capacity contribute to exercise intolerance and mortality in HFpEF. Observations suggest that pulmonary venous remodeling may be the primary target in patients with HF and PH.
Therapy aimed at PH, to reduce RV afterload to improve RV function in HFpEF, has failed to show effectiveness. Conflicting results have been published on the benefits of therapy with the phosphodiesterase (PDE)-5 inhibitor sildenafil. Patients with combined pre- and post-capillary PH (CpcPH) may form a subgroup of HFpEF in whom PDE-5 inhibitor may be beneficial, as an analysis of the COMPERA registry showed improvements in NYHA functional class, 6-minute walking distance and plasma NT-proBNP after 3 and 12 months of therapy (but there was no untreated control group in this analysis). Other medications used in PH without HF have been tested for use in HFpEF with PH, but endothelin antagonists and prostacyclin analogues and soluble guanylate cyclase inhibitors have not been proven to be beneficial.
Plasma volume expansion
In obese patients with HFpEF, increases in pulmonary capillary wedge pressure were found to correlate with plasma volume expansion. This was associated with right heart dilatation and increased total heart volumes, which resulted in increased pericardial restraint and enhanced ventricular interaction, contributing to higher left ventricular filling pressures.
In the CHAMPION trial, greater use of diuretics was seen in the PAP-guided treatment group, and a reduction in HF hospitalizations was seen. The novel class of SGLT2 inhibitors, developed as antidiabetic treatment, may be useful in HFpEF for their osmotic diuretic effects and is currently being tested in HFpEF (regardless of diabetes). Other effects of the SGLT2 inhibitor class include natriuresis and diuresis, beneficial cardiometabolic and renal effects, and potentially improvement of systemic micro-inflammation, which may be particularly attractive for obese HFpEF patients with volume overload and adipose inflammation.
Systemic microvascular inflammation
In HFpEF, comorbidities are thought to lead to microvascular inflammation. Inflammatory activation in chronic HF leads to proinflammatory and profibrotic processes, which culminate in ventricular remodeling, dysfunction and HF. Microvascular ischemia, concentric left ventricular remodeling, and fibrosis further contribute to diastolic dysfunction. The role for chronic systemic inflammation in HFpEF is supported by various lines of evidence, but a causal link in the development remains to be proven.
Promising results have been obtained with anti-inflammatory strategies in animal models of HFpEF. In humans, treatment with the IL-1 receptor antagonist anakinra was associated with increased peak VO2, which correlated with lower C-reactive protein and improvement in ventilatory efficiency. In the D-HART2 trial, however, anakinra failed to improve peak oxygen consumption and the minute ventilation/carbon dioxide production slope, although C-reactive protein and NT-proBNP levels were reduced, and improvements were seen in exercise time and quality of life (QoL).
Therapies targeting the NO-cGMP pathway have not been conclusive either. Negative results with isosorbide mononitrate in the NEAT-hFpEF trial may be explained by pharmacological (pseudo)tolerance, and also, organic nitrates have been paradoxically shown to cause endothelial dysfunction. Inorganic nitrates are important in vivo sources of NO if hypoxia and acidosis occur. Indeed, some studies have shown beneficial results with inorganic nitrite/nitrate therapy on exercise capacity, although recent results indicated that four weeks of inhaled nitrate therapy had no effect on daily activity levels, NT-proBNP or QoL Various studies are ongoing to further evaluate targeting of this pathway.
Vericiguat targets sGC to stimulate cGMP. While it did not alter the primary endpoint of NT-proBNP and left atrial volume, patients seemed to experience improvements in health-related QoL, physical limitations, NYHA class and signs and symptoms of congestion.
cGMP can also be enhanced by targeting guanylate cyclase via stimulation with natriuretic peptides. Sacubitril/valsartan not only blocks the renin-angiotensin system, but also augments the endogenous vasoactive peptide system. In PARAMOUNT, sacubitril/valsartan reduced NT-proBNP at 12 weeks and improved left atrial function an NYHA class at 36 weeks. The PARAGON-HF trial is ongoing, to assess morbidity and mortality with sacubitril/valsartan in patients with HFpEF.
The role of impaired myocardial energetics in development and progression of HFpEF is gaining interest. Direct evidence for the postulated mechanisms in HFpEF is limited, as most of the data are derived from HFrEF studies. Indirect data are available that show that mitochondrial content, oxidative capacity and fusion in skeletal muscle were aberrant in older HFpEF patients. It is to date unclear whether similar abnormalities exist in the myocardium in HFpEF.
Several therapies that target cardiometabolic functional abnormalities for the treatment of HFpEF are currently being investigated, including:
- Partial adenosine A1-agonists: capadenoson and neladenoson, as preclinical studies suggest that they may improve myocardial energy metabolism and utilization, and calcium homeostasis.
- Carnitine palmitoyltransferase-1 inhibitors: etomoxir and perhexiline, for their involvement in mitochondrial uptake of fatty acids and the switch from fatty acid to glucose oxidation.
- Fatty acid b-oxidation inhibitor: trimetazidine, as it directly inhibits fatty acid b-oxidation.
- Mitochondrial enhancer: elamipretide, as it binds to cardiolipin, which increases the efficiency of mitochondrial respiration under conditions of oxidative stress, thereby normalizing mitochondrial function.
- Intravenous iron: ferric carboxymaltose, because inron deficiency is common in HFrEF and HFpEF patients and it directly impairs mitochondrial function.
Cellular (titin)/extracellular (fibrosis, amyloid) structural abnormalities
Cardiomyocytes in HFpEF patients show increased stiffness, and the composition of the extracellular matrix changes and it expands. Due to crosstalk between cardiomyocytes and the non-myocytic compartment of the heart, aberrations in one compartment are often accompanied by changes in the other.
The elastic sarcomeric titin protein regulates most of the myocardial passive tension, and thus of cardiomyocyte-derived stiffness. Differences in titin phosphorylation associated with stiffness between patients and controls, have been described.
PDE-5 inhibitors can inhibit breakdown of cGMP, and thereby increase titin phosphorylation by PKG. While this concept worked in animal models, human trials have yielded mixed results. Other strategies worth exploring further may involve PDE-9 or genetic strategies to modulate titin stiffness.
TGF-β is central to fibrosis. Pifenidone inhibits TGF-β, and a trial to test its effect on cardiac fibrosis is underway (PIROUETTE). Moreover, galectin-3 is upregulated in HFpEF and its inhibition may reduce fibrosis. Other antifibrotic agents are also being studied, but it should be noted that translation from experimental studies to clinical applications is difficult, considering the highly complex dynamics in the process of fibrosis.
While awaiting results of trials evaluating novel therapies, clinical focus should be directed at effective treatment of congestion, elimination of precipitating factors (e.g. uncontrolled blood pressure or atrial fibrillation), optimal management of inflammation inciting comorbidities, and identification of at-risk patients for preventive cardiovascular risk strategies.