Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction
Abstract
Heart failure (HF) with preserved ejection fraction (EF; HFpEF) accounts for 50% of HF cases, and its prevalence relative to HF with reduced EF continues to rise. In contrast to HF with reduced EF, large trials testing neurohumoral inhibition in HFpEF failed to reach a positive outcome. This failure was recently attributed to distinct systemic and myocardial signaling in HFpEF and to diversity of HFpEF phenotypes. In this review, an HFpEF treatment strategy is proposed that addresses HFpEF-specific signaling and phenotypic diversity. In HFpEF, extracardiac comorbidities such as metabolic risk, arterial hypertension, and renal insufficiency drive left ventricular remodeling and dysfunction through systemic inflammation and coronary microvascular endothelial dysfunction. The latter affects left ventricular diastolic dysfunction through macrophage infiltration, resulting in interstitial fibrosis, and through altered paracrine signaling to cardiomyocytes, which become hypertrophied and stiff because of low nitric oxide and cyclic guanosine monophosphate. Systemic inflammation also affects other organs such as lungs, skeletal muscle, and kidneys, leading, respectively, to pulmonary hypertension, muscle weakness, and sodium retention. Individual steps of these signaling cascades can be targeted by specific interventions: metabolic risk by caloric restriction, systemic inflammation by statins, pulmonary hypertension by phosphodiesterase 5 inhibitors, muscle weakness by exercise training, sodium retention by diuretics and monitoring devices, myocardial nitric oxide bioavailability by inorganic nitrate-nitrite, myocardial cyclic guanosine monophosphate content by neprilysin or phosphodiesterase 9 inhibition, and myocardial fibrosis by spironolactone. Because of phenotypic diversity in HFpEF, personalized therapeutic strategies are proposed, which are configured in a matrix with HFpEF presentations in the abscissa and HFpEF predispositions in the ordinate.
Introduction
Heart failure (HF) with preserved ejection fraction (EF; HFpEF) currently accounts for >50% of all heart failure cases and its prevalence relative to HF with reduced EF (HFrEF) continues to rise at an alarming rate of 1% per year.1 In the past 3 decades, HFrEF evolved to a distinct therapeutic entity partly because large outcome trials demonstrated the efficacy of neurohumoral inhibition. No similar evolution has occurred in HFpEF, where large trials testing neurohumoral inhibition consistently failed to reach a positive primary outcome either individually2 or on meta-analysis.3 In trials testing angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), or mineralocorticoid receptor antagonists, a modest positive trend was sometimes observed but only for secondary outcomes4 or retrospectively defined subgroups.5,6 The failure of neurohumoral inhibition in the large HFpEF outcome trials led some investigators to challenge HFpEF as a distinct HF phenotype.7–9 More recent views attributed this failure to different systemic and myocardial signaling in HFpEF and HFrEF10 or to diverse phenotypes within the HFpEF patient population.11–14 In line with these views, the current HFpEF treatment roadmap first addresses HFpEF-specific systemic and myocardial signaling, subsequently configures HFpEF phenotypes in a matrix of predispositions and presentations, and finally discusses therapeutic inroads that fit into the phenotypic framework.
Systemic and Myocardial Signaling
Large outcome trials and registries all revealed HFpEF patients to be of advanced age and predominantly women and to have multiple comorbidities such as overweight/obesity (84%),15 arterial hypertension (60%–80%),16 type 2 diabetes mellitus (20%–45%),16 renal insufficiency, and sleep apnea. Aging and the aforementioned comorbidities may initiate chronic systemic inflammation as manifest from biomarker profiles which revealed high plasma levels of soluble interleukin 1 receptor-like 1, C-reactive protein, and growth differentiation factor 15 in HFpEF.17–20 Initial studies revealed plasma levels to be similarly elevated in HFpEF and HFrEF,17 but recent studies observed them to be higher in HFpEF19 and therefore suggested a larger involvement of systemic inflammation in HFpEF. Systemic inflammation may affect myocardial remodeling and dysfunction in HFpEF through a signaling cascade, which begins with coronary microvascular endothelial dysfunction (Figure 1).10,21 It subsequently involves myocardial infiltration by activated macrophages, which induce reactive interstitial fibrosis22 and altered paracrine communication between endothelial cells and surrounding cardiomyocytes.21 The latter deprives cardiomyocytes of nitric oxide (NO) and of cyclic guanosine monophosphate (cGMP), which renders them hypertrophied and stiff.23 High cardiomyocyte stiffness is caused by diminished distensibility of the giant cytoskeletal protein titin, whose elastic properties are dynamically modulated by isoform shifts, phosphorylation, and oxidation.24,25 Strong support for an extramyocardial origin of HFpEF came from parabiosis experiments in which hearts of young animals acquired HFpEF-like features when exposed to blood from old animals and vice versa, because hearts of old animals reversed HFpEF-like features when exposed to blood of young animals.26
Figure 1. Systemic and myocardial signaling in HFPEF. Comorbidities induce systemic inflammation, evident from elevated plasma levels of inflammatory biomarkers such as soluble interleukin 1 receptor-like 1 (IL1RL1), C-reactive protein (CRP), and growth differentiation factor 15 (GDF15). Chronic inflammation affects the lungs, myocardium, skeletal muscle, and kidneys leading to diverse HFpEF phenotypes with variable involvement of pulmonary hypertension (PH), myocardial remodeling, deficient skeletal muscle oxygen extraction (ΔA-Vo2) during exercise (Ex), and renal Na+ retention. Myocardial remodeling and dysfunction begins with coronary endothelial microvascular inflammation manifest from endothelial expression of adhesion molecules such as vascular cell adhesion molecule (VCAM) and E-Selectin. Expression of adhesion molecules attracts infiltrating leukocytes secreting transforming growth factor β (TGF-β), which converts fibroblasts to myofibroblasts with enhanced interstitial collagen deposition. Endothelial inflammation also results in the presence of reactive oxygen species (ROS), reduced nitric oxide (NO) bioavailability, and production of peroxynitrite (ONOO–). This reduces soluble guanylate cyclase (sGC) activity, cyclic guanosine monophosphate (cGMP) content, and the favorable effects of protein kinase G (PKG) on cardiomyocyte stiffness and hypertrophy. HFpEF indicates heart failure with preserved ejection fraction.
The extramyocardial origin of HFpEF differs from the intramyocardial origin of HFrEF, where remodeling is driven by cardiomyocyte cell death because of ischemia, infection, or toxicity.27 Distinct origins of HFpEF and HFrEF are mirrored by unequal left ventricular (LV) structural and ultrastructural remodeling (Table). Biomarker profiles in HFpEF and HFrEF are consistent with the distinct origins of both HF phenotypes because they show lower markers of myocardial injury (high-sensitivity troponin T) or of myocardial stress (N-terminal pro brain natriuretic peptide [N-terminal pro-BNP]) in HFpEF.17–20,28–30 Lower high-sensitivity troponin T is explained by less cardiomyocyte damage as a result of limited upregulation in HFpEF myocardium of nicotinamide adenine dinucleotide phosphate oxidase 2 evident in infiltrating macrophages or endothelial cells but not in cardiomyocytes.21 Lower N-terminal pro-BNP is explained by concentric LV remodeling/hypertrophy in HFpEF in contrast to eccentric LV remodeling/hypertrophy in HFrEF31 and by visceral distribution of adipose tissue in the mostly overweight or obese HFpEF patients,32 which is associated with decreased production and increased clearance of natriuretic peptides (NPs).
| HFpEF | HFrEF | |
|---|---|---|
| LV structure/function | ||
| End-diastolic volume | ↔ | ↑ |
| End-systolic volume | ↔ | ↑ |
| Wall thickness | ↑ | ↔ |
| Mass | ↑ | ↑ |
| Mass/volume ratio | ↑ | ↓ |
| Remodeling | Concentric | Eccentric |
| Ejection fraction | ↔ | ↓ |
| Stroke work | ↔ | ↓ |
| End-systolic elastance | ↔ | ↓ |
| End-diastolic stiffness | ↑ | ↓ |
| LV ultrastructure | ||
| Myocyte diameter | ↑ | ↔ |
| Myocyte length | ↔ | ↑ |
| Myocyte remodeling | Concentric | Eccentric |
| Fibrosis | Interstitial/reactive | Focal/replacement |
In HFpEF, chronic systemic inflammation affects not only the myocardium, but also other organs such as lungs, skeletal muscles, and kidneys (Figure 1). Although HFpEF patients may stop exercising because of a rapid and brisk rise in LV filling pressures,33–38 in a substantial subset of patients, effort tolerance is limited by inappropriate pulmonary vasoconstriction evident from pulmonary hypertension, or by inadequate peripheral skeletal muscle vasodilation, perfusion, and oxygen use evident from absent widening of arteriovenous oxygen difference.39–43 Systemic inflammation also affects the renal microcirculation and the ability of the kidneys to excrete a sodium load.44 Inability to excrete a sodium load contributes to the progressive volume expansion observed during transition from chronic compensated to acute decompensated HFpEF45,46 and explains the efficacy of diuretics because they restore the pressure-natriuresis relationship.
Phenotypic Framework
HFpEF clinically presents as a diverse syndrome initiated by a variety of comorbidities and inflammatory mediators with extracardiac manifestations and cardiac abnormalities.13,47–49 Despite the diversity of the HFpEF syndrome, the treatment strategy thus far has focused on a one-size-fits-all approach that has worked relatively well for chronic HFrEF. However, virtually all clinical syndromes benefit from more tailored, personalized therapy, and this may also be true of HFpEF. Successfully addressing the diversity of HFpEF is an active area of investigation, and solutions for the problem range from simple (eg, stratifying based on type of clinical presentation47) to sophisticated (eg, machine-learning techniques to perform data reduction to classify patients based on intrinsic patterns in dense phenotypic data49). Although the field of machine learning is not new,50 its application to clinical medicine is still relatively novel, and these techniques will require iterative testing and application to clinical trials before they can be applied clinically on a routine basis.
In the absence of compelling outcome data to support individual therapies, we propose a matrix configuration combining predisposition phenotypes with clinical presentation phenotypes as a starting point to guide current clinical care and future prospective research (Figure 2). Rare etiologies such as constrictive pericarditis, valvular heart disease, high-output failure, or infiltrative cardiomyopathies are presumed to be excluded beforehand. Figure 2 displays a stepwise approach that begins in the left hand upper corner of the matrix with general treatment recommendations, presumed to be beneficial to the vast majority of HFpEF patients because they address the presentation phenotype of lung congestion and the predisposition phenotype of overweight/obesity present in >80% of HFpEF patients.15 Subsequently, supplementary recommendations are suggested for additional predisposition-related phenotypic features when moving downward in the matrix and for additional presentation-related phenotypic features when moving rightward in the matrix. Arterial hypertension, renal dysfunction, and coronary artery disease are proposed as additional predisposition phenotypes (Figure 2). Additional clinical presentation phenotypes, in which specific therapeutic interventions could be meaningful, are chronotropic incompetence, pulmonary hypertension (especially combined precapillary and postcapillary pulmonary hypertension), skeletal muscle weakness and atrial fibrillation. Apart from use of diuretics, caloric restriction diet, exercise training, and anticoagulation in the presence of atrial fibrillation, all recommendations need to be confirmed by prospective outcome trials in the respective phenotypic subsets.
Figure 2. Phenotype-specific HFpEF treatment strategy using a matrix of predisposition phenotypes and clinical presentation phenotypes. A stepwise approach is proposed that begins in the left hand upper corner of the matrix with general treatment recommendations, presumed to be beneficial to the vast majority of HFpEF patients as they address the presentation phenotype of lung congestion and the predisposition phenotype of overweight/obesity present in >80% of HFpEF patients. Subsequently, supplementary (+) recommendations are suggested for additional predisposition-related phenotypic features when moving downward in the matrix and for additional presentation-related phenotypic features when moving rightward in the matrix. Arterial hypertension, renal dysfunction, and coronary artery disease are proposed as additional predisposition phenotypes. Additional clinical presentation phenotypes, in which specific therapeutic interventions could be meaningful, include chronotropic incompetence, pulmonary hypertension (especially combined precapillary and postcapillary pulmonary hypertension [CpcPH]), skeletal muscle weakness, and atrial fibrillation. Only therapeutic measures indicated in bold are currently established. All other therapeutic measures require further testing in specific phenotypes. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blockers; CAD, coronary artery disease; DM, diabetes mellitus; HFpEF, heart failure with preserved ejection fraction; and PDE5I, phosphodiesterase 5 inhibitor.
Phenotypic Treatment Strategy
Numerous steps of the HFpEF signaling cascade, which range from systemic inflammation to myocardial titin elasticity, are valid treatment targets either for the vast majority of the HFpEF population (ie, the lung congestion/metabolic risk phenotype in the upper left hand corner of Figure 2) or for specific presentation/predisposition HFpEF phenotypes (Figure 2).
Lung Congestion/Metabolic Risk Phenotype
The lung congestion/metabolic risk phenotype is considered the garden variety of HFpEF, because, by definition, HF patients have evidence of lung congestion at rest or during exercise and because overweight/obesity (body mass index >25 kg/m2) is highly prevalent in HFpEF (>80%)15 and increasingly recognized to drive HFpEF development. The latter was evident from recent longitudinal noninvasive studies, which revealed close correlations over a 4-year time interval between diastolic LV stiffness and body mass index and concluded that central adiposity predisposed to HFpEF.51,52 Similar evidence was already provided by the ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial), which enrolled patients with arterial hypertension and 1 additional cardiovascular risk factor, and observed a high body mass index at enrolment to be the strongest predictor of HFpEF development.53
Diuretics
Lowering of LV filling pressures with diuretics is of paramount importance for HFpEF patients to achieve symptomatic benefit, to reduce pulmonary artery pressures, and to improve right ventricular (RV) loading.54 Their efficacy relates to a restored pressure-natriuresis relationship in the presence of renal microvascular inflammation.55 Administration of diuretics can be guided by the use of implantable hemodynamic monitors that either directly and continuously measure diastolic LV pressures or provide surrogates of pressure.45 Studies evaluating hemodynamic monitoring have demonstrated that, even in HFpEF patients considered by expert HF clinicians to be compensated, diastolic LV pressures are elevated and these elevations have important prognostic implications.56 When transition to decompensated HF occurs, diastolic LV pressures progressively increase over weeks. During this time interval, hemodynamic monitoring allows for early uptitration of diuretics, which improves outcome as demonstrated in the CHAMPION trial (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients). In this study, treatment guided by implantable hemodynamic monitoring significantly decreased cardiovascular death and HF hospitalizations in HFPEF patients.57,58
Caloric Restriction
Because increased body adiposity promotes inflammation and impairs cardiac, arterial, renal, and skeletal muscle function, weight loss should be considered in a treatment strategy for the vast majority of HFpEF patients. Kitzman et al59 recently reported that a 20-week caloric restriction diet was feasible and appeared safe in older, obese HFpEF patients, and significantly improved their symptoms, peak oxygen consumption (Vo2), and quality-of-life scores (Figure 3). The quality-of-life improvement was significantly greater with diet than exercise. The combination of diet with endurance exercise training was additive and produced a large (2.5 mL·kg–1·min–1) increase in peak Vo2 (Figure 3), similar to or larger than what most drug or other treatments produced in HFrEF patients. The validity of the increase in peak Vo2 was supported by significant increases in 5 other measures of physical performance that are independent of body mass: Vo2 reserve, exercise time to exhaustion, workload, 6-minute walk distance, and leg power. The increase in peak Vo2 was strongly correlated with reduced body fat mass, increased percent lean body mass, higher thigh muscle/intermuscular fat ratio, and lower biomarkers of inflammation all of which support the hypothesis that overweight/obesity contributes to exercise intolerance in HFpEF through systemic inflammation.59
Figure 3. Effects of a 20-week caloric restriction diet on exercise capacity and quality of life in HFpEF. The graph displays percent changes ± standard errors at the 20-week follow-up relative to baseline by randomized group for peak Vo2 (mL·kg–1·min–1, A), and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score (Quality of Life Score; B). P values represent effects for AT and CR. AT indicates aerobic exercise training; and CR, caloric restriction diet.
Statins
The presence of systemic inflammation supports the use of statins in HFpEF. Statins improve endothelial redox balance and restore NO bioavailability, independently of low-density lipoprotein lowering.60,61 Analysis of endomyocardial biopsy material revealed statin-treated HFpEF patients to have less myocardial nitrotyrosine, higher myocardial protein kinase G (PKG) activity, less cardiomyocyte hypertrophy, and lower cardiomyocyte resting tension.10 In an observational study, statin-treated HFpEF patients were also less prone to develop atrial fibrillation.62 These findings support the positive outcome of small phase 2 trials and HF registries that showed statin use to improve outcome of HFpEF patients.63–65 It remains to be explored whether other novel approaches to treat systemic inflammation might be effective in HFpEF.66
Inorganic Nitrite/Nitrate
In the HFpEF signaling cascade, cardiomyocytes are deprived of NO and cGMP because of altered paracrine communication between inflamed microvascular endothelial cells and cardiomyocytes (Figure 1). Organic NO donors were therefore suggested to be potentially useful in HFpEF because they could restore myocardial NO content and concomitantly correct the elevated arterial load. Recently however, Redfield et al67 demonstrated in patients with HFpEF that the organic nitrate isosorbide mononitrate tended to reduce chronic activity levels measured by accelerometry, with no improvement in submaximal exercise capacity. This result might be interpreted as disproving the NO hypothesis in HFpEF, but there are some important caveats to consider. Organic nitrates may produce greater than expected hypotensive effects in people with HFpEF or potentially impair cardiac output because of excessive preload reduction.68 Organic nitrates tonically increase local NO levels and require bioactivation in the tissues. The latter can cause pharmacological tolerance, whereas the former can chronically lower renal perfusion pressure, which, as alluded to before, is countered by renal sodium retention. This may override any beneficial reduction in filling pressures, a phenomenon known as pseudotolerance. Perhaps more importantly, organic nitrates such as isosorbide mononitrate have also been shown to cause endothelial dysfunction69,70 which plays a central role in the HFpEF signaling cascade.
In contrast to organic nitrates, the inorganic nitrate-nitrite pathway represents an important alternative route to restore NO signaling in HFpEF.71 Formerly considered as an inert byproduct of NO metabolism, nitrite is now known to function as an important in vivo NO reservoir. Importantly, nitrite is preferentially reduced to NO in the presence of hypoxia and acidosis, which occurs during physical exercise, thus delivering NO at the time and locations (ie, skeletal and cardiac muscles) of greatest need. Nitrate-nitrite preparations have been shown to improve conduit artery stiffness in healthy volunteers and improve systemic vasodilation during exercise in patients with HFpEF.72,73 More recently, acute infusion of sodium nitrite was shown in a placebo-controlled trial of patients with HFpEF to preferentially reduce diastolic LV pressures and pulmonary artery pressures during exercise while restoring cardiac output reserve toward normal (Figure 4).74 Part of this benefit was mediated by vasodilation, but evidence for a direct myocardial benefit, such as increased stroke work, was also observed. Another recent study found that inorganic nitrate, delivered as 1 week of once-daily beetroot juice consumption, improved submaximal exercise endurance.75
Figure 4. Effects of acute infusion of inorganic nitrite on exercise hemodynamics in HFpEF. ΔPCWPEX indicates change in exercise-induced pulmonary capillary wedge pressure (A); ΔExerciseCO, increase in exercise induced cardiac output (B); mean PAP, mean pulmonary artery pressure (C); and ΔCO/ΔVo2, ratio of exercise-induced increase in cardiac output over exercise-induced increase in oxygen consumption (D).
Sacubitril and Other PKG-Stimulating Drugs
A substantial number of HFpEF patients have pathological ventricular hypertrophy, with interstitial fibrosis and diastolic chamber stiffening. This has encouraged efforts to block key activators and to stimulate intrinsic suppressors of these changes. Among the attractive pathways representing the latter approach are those coupled to cGMP and its cognate kinase, PKG. PKG stimulation has potent antifibrotic and antihypertrophic effects in cultured myocytes and fibroblasts,76–79 and has been protective in a wide array of experimental cardiac disease models including pressure-overload hypertrophy.80–82 Moreover, there are multiple therapeutic approaches to stimulate PKG already in clinical use or under active investigation, which increases the potential translational relevance of this pathway.
Stimulation of PKG requires cGMP, which is either synthesized by soluble guanylate cyclase (sGC) activated by NO or by receptor guanylate cyclase linked to the NP receptor.83–85 This is, in turn, counterbalanced by hydrolysis of cGMP back to GMP by select members of the phosphodiesterase (PDE) superfamily, and their inhibition, which leads to increased cGMP, can also increase PKG activity (Figure 5). cGMP also controls cAMP levels by feedback modulation of PDE2 and PDE3. At low levels of cGMP, proinotropic effects via cAMP have been observed, whereas, at higher levels and with cAMP costimulation, cGMP induces an antiadrenergic effect. Four members of the PDE superfamily (PDE1, PDE2, PDE5, and PDE9 of which both PDE5 and PDE9 are selective for cGMP) regulate cGMP in the heart. PDE5 and PDE9 are not redundant, but target different intracellular pools, with PDE5 largely impacting NO-sGC–derived cGMP, whereas PDE9 regulates NP- receptor guanylate cyclase –derived pools.80 These local pools impact different intracellular compartments of PKG, as detected by differences in net phosphokinomes and effects on transcriptional regulation.80
Figure 5. Myocardial cGMP signaling and pharmacological interventions in HFpEF. Nitric oxide (NO) produced by NO synthases (NOS) stimulates soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), which activates protein kinase G (PKG). Inorganic nitrate/nitrite, sGC stimulators and phosphodiesterase (PDE) 5 inhibitors target this pathway. The natriuretic peptides ANP and BNP attach to the natriuretic peptide receptors A/B (NPRA/NPRB). This stimulates receptor guanylate cyclase (rGC) to produce cGMP, which again activates PKG. Neprilysin inhibitors such as sacubitril and PDE9 inhibitors act through this pathway. ANP indicates atrial natriuretic peptide; and BNP, brain natriuretic peptide.
Recent studies have defined multiple targets relevant to the lusitropic, antihypertrophic, and antifibrotic impact of PKG. HFpEF cardiomyocytes display greater passive diastolic stiffness that have been linked to changes in titin phosphorylation at PEVK-region residues (so named because it contains primarily proline [P], glutamate [E], valine [V] and lysine [K] residues) modulated by PKA and PKG.23,86–88 The latter is a particularly potent regulator of titin stiffness, which in turn impacts cardiac muscle stiffness.23 Antihypertrophic and antifibrotic mechanisms include PKG suppression of transforming growth factor-β signaling by phosphorylation of Smad proteins that blocks their nuclear translocation and signaling.89
Data regarding myocardial cGMP/PKG signaling in HFpEF remain fairly limited, but several studies have revealed critical features in this disease that could ultimately dictate how a successful therapy would need to work. Most pertinently, human LV biopsy analysis from HFpEF has reported very low levels of cGMP and associated PKG activity, particularly compared with patients who have HFrEF and aortic stenosis.23 This may help explain reduced titin phosphorylation and muscle stiffening, and contributory signaling to hypertrophy and fibrosis (ie, the brake has been removed). It also raises questions regarding the initiating mechanism. Myocardial oxidative stress coupled with a proinflammatory microvascular environment has been proposed10 and was recently supported by comparative analysis of HFpEF, HFrEF, and aortic stenosis samples, which in HFpEF revealed higher microvascular expression of adhesion molecules and nicotinamide adenine dinucleotide phosphate oxidase 2 with higher hydrogen peroxide and lower nitrite/nitrate content.21
Administration of sGC activators or stimulators could provide downstream correction for the low myocardial NO bioavailability in HFpEF. Use of the sGC activator cinaciguat in HFrEF was hampered by hypotension.90 The oral sGC stimulator riociguat improved exercise tolerance or quality of life in pulmonary arterial hypertension (PATENT [Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial]),91 in chronic thromboembolic pulmonary hypertension (CHEST [Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial]),92 and in pulmonary hypertension attributable to HFrEF (LEPHT [Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial]).93 In these 3 studies, arterial blood pressure also decreased by up to 9 mm Hg and this is especially worrisome for HFpEF patients because of their limited ability to increase LV stroke volume.68 The use of vericiguat, another sGC stimulator, was well tolerated in HFrEF but failed to lower NP except at the highest dose.94 It is currently being tested in HFpEF in the SOCRATES-PRESERVED trial (Phase IIb Safety and Efficacy Study of Four Dose Regimens of BAY1021189 in Patients With Heart Failure and Preserved Ejection Fraction Suffering From Worsening Chronic Heart Failure).
Because of concentric LV remodeling, NP stimulation is less marked in HFpEF than HFrEF, a finding that may limit counter stimulation via this pathway. NPs are degraded by circulating neprilysin. Inhibition of this peptidase could augment deficient NP-receptor guanylate cyclase signaling and therefore be beneficial in HFpEF, as suggested by the decrease in NP following administration of valsartan/sacubitril in the phase 2 (PARAMOUNT study [Prospective Comparison of ARNI with ARB on Management of Heart Failure With Preserved Ejection Fraction]).95 Use of valsartan/sacubitril is currently being tested in the multicenter PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction).
Another approach is to block PDEs to increase cGMP levels and hence PKG activity. PDE5 upregulation in HFrEF was reported by multiple96,97 but not all98 laboratories. Data in HFpEF did not support a similar elevation,23 and 2 PDE5-inhibitor trials in HFpEF yielded a neutral outcome.99,100 An alternative may therefore be inhibiting PDE9. A recent study found marked upregulation of PDE9 protein in human LV biopsies from HFpEF patients and from HFrEF and aortic stenosis patients, as well.80 This suggests the low cGMP levels might be related to enhanced expression of PDE9, and if so, inhibiting this PDE should have beneficial effects. In mice subjected to sustained pressure overload, blocking PDE9 by gene deletion or selective pharmacological inhibition suppressed hypertrophy, fibrosis, and chamber dysfunction.80 PDE9 inhibition has been previously examined clinically for its potential to alter cognition101 but these new data may trigger interest in HFpEF and other forms of heart failure.
Spironolactone and E-Matrix Modification
The extracellular matrix is composed of fibrillary proteins (such as collagen and elastin), nonfibrillary proteins (such as aminoglycans, fibronectin, laminin), and bioactive proteins (such as transforming growth factor-β, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases , and matricellular proteins). The homeostatic control of collagen is especially important for abnormal diastolic function in HF.102 Important differences in geometry, composition, and homeostatic mechanisms are seen in HFpEF versus HFrEF. HFpEF is more often associated with interstitial, reactive fibrosis and HFrEF with focal, replacement fibrosis (Table). The extent of collagen cross-linking tends to be higher in HFpEF,103 and homeostasis in HFpEF is profibrotic while fibrinolytic in HFrEF.
Resident myocardial fibroblasts control collagen homeostasis in normal hearts. Whether resident fibroblasts remain responsible for increased collagen production or whether recruitment of fibroblasts occurs from a different source, such as bone marrow or microvascular endothelium, remains uncertain. In murine HFpEF models, resident fibroblasts and not bone marrow–derived cells or endothelial-mesenchymal transition were primarily responsible for myocardial collagen production following transverse aortic constriction.105,106 Recruited cells could still be involved through the secretion of cytokines or matricellular proteins, however. Myofibroblasts have also been implicated in collagen deposition in HFpEF because they are closely associated with fibrotic collagen deposition and scar contracture. In HFpEF, fibroblasts are presumed to convert to myofibroblasts because of exposure to transforming growth factor-β as a result of monocyte/macrophage myocardial infiltration.22
Collagen metabolism requires sequential, highly orchestrated and regulated steps: (1) procollagen synthesis and secretion, (2) procollagen postsynthetic processing, (3) collagen posttranslational modification, and (4) collagen degradation. Each of these steps is altered in HFpEF, contributes either individually or in aggregate to LV diastolic dysfunction, is mirrored in plasma biomarkers, and serves as a unique treatment target (Figure 6). Procollagen I and III are synthesized in myocardial fibroblasts and secreted as a soluble molecule with NH2 (N)-terminal and COOH (C)-terminal propeptides attached. These are removed to create insoluble collagen107 and appear in plasma as procollagen I C-terminal peptide, procollagen III C-terminal peptide, procollagen I N-terminal peptide, and procollagen III N-terminal peptide, all of which reflect the rate of collagen synthesis. Subsequent formation of insoluble collagen requires enzymatic formation of cross-links by lysyl- or hydroxylysyloxidase. Nonenzymatic cross-links can also be formed by advanced glycation end products, which can activate profibrotic pathways through binding with the receptor for advanced glycation end products. Insoluble collagen formation is promoted by matricellular proteins (SPARC [secreted protein acidic and rich in cysteine], thrombospondin, osteopontin). To maintain collagen homeostasis, insoluble collagen is continuously degraded by matrix metalloproteinases, which are in turn regulated by tissue inhibitors of matrix metalloproteinases.108 Collagen degradation results in formation of collagen telopeptides (C-telopeptide for type I collagen, C-telopeptide for type III collagen). Matrix metalloproteinases, C-telopeptide for type I collagen, and C-telopeptide for type III collagen can be measured in plasma and, in combination with procollagen I C-terminal peptide, procollagen I N-terminal peptide, procollagen III C-terminal peptide, and procollagen III N-terminal peptide allow for an integrated multibiomarker assessment of collagen homeostasis.103 In HFpEF, such an assessment revealed collagen synthesis to be increased and collagen degradation to be decreased resulting in a net increase in collagen content.109 Additional biomarkers that are useful estimates of myocardial collagen content are galectin-3 and solubleST2. The former is secreted by infiltrating macrophages and stimulates fibroblasts, whereas the latter is a member of the interleukin-1 receptor family which is also profibrotic, because it acts as a decoy for interleukin-33, which inhibits profibrotic signaling.
Figure 6. Sequential steps of collagen metabolism. Collagen metabolism involves sequential steps consisting of procollagen synthesis, procollagen processing to collagen fibrils, posttranslational modification of collagen fibrils and collagen degradation.
To date, 3 pharmaceutical agents that affect the extracellular matrix have been tested in HFpEF: spironolactone in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), valsartan/sacubitril in PARAMOUNT, and torasemide. In TOPCAT, spironolactone (a mineralocorticoid receptor antagonist) failed to reduce the composite primary end point in the overall trial population110 but not in patients with elevated BNP, which was a marker of enrollment in the Americas (P=0.003).111 The neutral outcome in the overall population may have been related to aberrant patient enrollment in Russia/Republic of Georgia rather than to inefficacy of spironolactone. In PARAMOUNT, salutary effects of valsartan/sacubitril consisting of a significant decrease in Nterminal pro-BNP and left atrial volume were observed in HFpEF patients.95 These effects support fibrosis-specific therapy for HFpEF patients with advanced extracellular matrix modification.112 The loop diuretic torasemide affects collagen cross-linking, and its use has been shown to improve diastolic LV dysfunction in patients with hypertensive heart disease.113 Finally, use of mesenchymal stem cells has been examined in Dahl salt-sensitive rats with promising results. In this model, a single intracoronary dose of allogeneic mesenchymal stem cells reduced myocardial collagen volume fraction and normalized diastolic LV function without effect on cardiomyocyte hypertrophy.114
Arterial Hypertension
Arterial hypertension is found in ≥80% of HFpEF patients. Treatment of arterial hypertension in older people without HF reduces incident HF.53 In acutely decompensated HFpEF patients with elevated blood pressure, symptoms may improve markedly with blood pressure lowering alone even before diuresis is achieved. However, in chronic stable HFpEF patients, there is uncertainty about whether adding blood pressure–lowering medications provides additional benefit. A discordance was indeed present between substantial blood pressure lowering and outcome in large trials testing neurohumoral inhibition in HFpEF.2 This was even more surprising, because, along with blood pressure lowering, there were numerous other mechanisms whereby neurohumoral inhibition was expected to benefit HFpEF, including improvements in myocardial hypertrophy, myocardial fibrosis, and vascular stiffness. However, treating arterial hypertension for non-HF–related macrovascular indications (eg, stroke, myocardial infarction) also remains an important goal in HFpEF patients. In this regard, it is worth noting that large outcome trials confirmed ACEIs and ARBs to be safe and well tolerated as antihypertensive medications.2,4 Diuretics, spironolactone, and ACEIs/ARBs are therefore reasonable first choices to control blood pressure based on the currently available data. Although it is true that previously tested ACEIs and ARBs did not reduce mortality, increasing the quality of life may be the better strategy in HFpEF patients because they are often elderly and debilitated. Some previously completed trials of ACEIs/ARBs showed relevant symptomatic benefits, such as reduced HF hospitalization, in these patient populations.2,4
Arterial hypertension can affect myocardial remodeling and dysfunction in HFpEF through myocardial overload115 or systemic inflammation.116 The importance of overload is unclear because, in a concentrically remodeled LV with normal EF, a favorable late-systolic Laplace relation protects LV myocardium from loading increments provoked by large reflected arterial pressure waves. However, in the presence of a minor LV shortening deficit, hypertensive HFpEF patients may develop late-peaking systolic LV wall stress. This may explain the favorable effects in HFpEF patients of nitrate-rich beetroot juice, which reduces the magnitude of reflected arterial pressure waves,75 or of the sodium-restricted DASH (Dietary Approaches to Stop Hypertension) diet, which improves ventricular-arterial coupling.117
Renal Dysfunction
HFpEF and renal dysfunction are mutually promoting (Figure 1).118 HFpEF promotes renal dysfunction by (1) an elevated central venous pressure, which results from pulmonary hypertension and RV dysfunction; (2) inability to increase cardiac output following arterial vasodilation because of chronotropic incompetence and fixed LV stroke volume119; (3) systemic inflammation, endothelial dysfunction, and low NO bioavailability, which reduces renal blood flow55,120 and sodium excretion.44 Renal dysfunction promotes HFpEF by worsening systemic inflammation, endothelial dysfunction, and NO bioavailability, in part, because of renal-specific mediators such as high levels of fibroblast growth factor 23, phosphorus, parathyroid hormone or uremic toxins, and low levels of vitamin D or erythropoietin.118 Limited tolerability of systemic vasodilation and impaired sodium excretion are of therapeutic importance.68 Impaired sodium excretion implies the arterial pressure-natriuresis relationship to be shifted to the right. Under these conditions, a fall in arterial pressure because of systemic vasodilation without cardiac output increase is especially deleterious because it leads to additional sodium retention and extracellular volume expansion, which wipes out any direct beneficial effect of vasodilation on LV filling pressures.68 This mechanism could partially account for the neutral outcome of the RELAX trial (PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure),99 where sildenafil lowered arterial pressure, raised plasma creatinine and urea levels, and failed to improve exercise tolerance.
HFpEF in the presence of renal dysfunction recently emerged as a distinct phenotype with more LV hypertrophy, a larger LV systolic functional deficit, impaired left atrial mechanics, RV dysfunction, and poor prognosis.121,122 The latter relates to exaggerated reactive pulmonary hypertension and RV dysfunction. Because of RV dysfunction, renal venous congestion importantly contributes to renal dysfunction in HFpEF. Vigorous diuresis (and ultrafiltration if necessary) is therefore important in HFpEF patients with renal dysfunction.
Coronary Artery Disease
The presence of coronary artery disease also identifies a distinct HFpEF phenotype with a larger LV systolic functional deficit, poor prognosis,123,124 and a high incidence of sudden death.125 Use of ACEIs is recommended for prevention of new cardiovascular events. In HFpEF patients with coronary artery disease, observational data suggest that complete revascularization is associated with better preservation of LV systolic function and an improved prognosis, although prospective trial data are still lacking.123
Chronotropic Incompetence
Many patients with HFpEF display marked impairments in cardiac output reserve during exercise, despite normal resting values.126 Impaired cardiac output reserve in HFpEF is related not only to decreased stroke volume augmentation, but also to chronotropic incompetence.127–129 One study actually indicated that chronotropic incompetence was the major contributor to reduced cardiac output reserve in HFpEF.42 The importance of chronotropic incompetence is further supported by the worsened exercise capacity when heart rate was slowed by the If blocker ivabradine.130 Chronotropic incompetence was previously shown to be related to endothelial dysfunction and systemic inflammation131 and therefore fits well into the multiorgan signaling cascade that appears to drive HFpEF development. Because there is a direct relationship between heart rate response to activity and aerobic capacity,128 a clinical trial is currently testing whether rate-adaptive atrial pacing can improve exercise capacity in patients with HFpEF (NCT02145351).
Pulmonary Hypertension
Recent evidence stressed the importance in HFpEF of pathophysiologic targets beyond the heart (Figure 1).54 Pulmonary hypertension is frequently present at rest132 and patients can also develop an exaggerated pulmonary hypertensive response to exercise.36,37,39 In HFpEF, pulmonary pressures can be augmented by increased left atrial pressure and by pulmonary vasoconstriction. When both mechanisms prevail, combined precapillary and postcapillary pulmonary hypertension is present.
Because of pulmonary hypertension and shared predisposing mechanisms, RV dysfunction is common in HFpEF and is associated with increased morbidity and mortality.133–135 The RV in HFpEF displays heightened afterload sensitivity, suggesting favorable potential for benefit from reduction in pulmonary pressures (Figure 7).133 An early single-center trial recruiting mainly combined precapillary and postcapillary pulmonary hypertension patients indeed reported salutary effects on hemodynamics and RV function following treatment with the PDE5 inhibitor sildenafil.136 However, 2 subsequent larger trials in patients with isolated postcapillary pulmonary hypertension and combined precapillary and postcapillary pulmonary hypertension failed to corroborate this finding.99,100 A recent trial reported significant improvement in pulmonary vascular function in response to dobutamine in HFpEF patients, greatly exceeding the pulmonary vasodilatory response seen in non-HF controls.137 Improved right ventricular-pulmonary artery coupling in this study was achieved predominantly through reduction in afterload rather than enhanced RV function, highlighting the importance of management of pulmonary hypertension in HFpEF. A number of trials have or are currently testing the effects of pulmonary vasodilators targeting cGMP,138 endothelin,139 and NO (NCT02713126; NCT02262078) in patients with HFpEF.
Figure 7. Heightened afterload sensitivity of the right ventricle in HFpEF. The relation between echocardiographic right ventricular (RV) fractional area change (FAC) and mean pulmonary artery (PA) pressure is flat in controls but steep in HFpEF patients. HFpEF indicates heart failure with preserved ejection fraction.
In contrast to the pulmonary vasculature, changes in the lung parenchyma are less characterized in HFpEF but likely also play an important role. Impairments in pulmonary function predict incident development of HFpEF independent of cardiac function.140 Patients with HFpEF display gas exchange abnormalities manifest by reduced alveolar capillary membrane conductance.141,142 These impairments become more dramatic during exercise because of high LV filling pressures during stress.141 HFpEF patients with increased interstitial pulmonary edema display greater pulmonary vascular abnormalities and RV dysfunction, supporting aggressive therapies to reduce left heart filling pressures chronically in patients with HFpEF.142
Skeletal Muscle Weakness
Exercise intolerance can be objectively measured as peak Vo2. By the Fick equation, Vo2 is the product of cardiac output and arteriovenous oxygen difference (ΔA-Vo2). Multiple studies indicate that peak exercise ΔA-Vo2 is significantly reduced in HFpEF and accounts for ≥50% of their severely reduced peak Vo2.40,143 What are the causes of the reduced peak ΔA-Vo2 in HFpEF patients? HFpEF patients have abnormalities in skeletal muscle mass, composition, capillary density, and oxidative metabolism. Haykowsky et al43 showed that, in comparison with age-matched healthy controls, older HFpEF patients have a significantly reduced percentage of total lean body mass and of leg lean mass. When peak Vo2 was indexed to total lean body mass or leg lean mass, it remained significantly reduced. Thus, HFpEF patients have abnormal O2 use that is independent of and in addition to their reduced muscle mass. HFpEF patients also have abnormal skeletal muscle composition with infiltration of adipose tissue, which is directly related to their reduced peak Vo2.144 Increased intramuscular fat reduces capillary density, thereby increasing the distance O2 must traverse from the capillaries to the muscle fibers. In HFpEF patients, the reduced thigh muscle capillary density is associated with their reduced peak Vo2 (Figure 8).145 Multiple studies indicate that HFpEF patients also have impaired skeletal muscle oxidative metabolism. Kitzman et al145 showed that, in comparison with healthy age-matched controls, HFpEF patients have a shift in skeletal muscle fiber type distribution from oxidative, slow type 1 fibers to glycolytic, fast type 2 fibers, which results in a lower type 1/type 2 fiber ratio. Similar to capillary density, these alterations are also associated with their severely reduced peak exercise Vo2 (Figure 8). A consequence of this fiber type shift is reduced skeletal muscle oxidative metabolism during exercise, which was evident after cessation of exercise from the delayed regeneration of quadriceps muscle phosphocreatine stores by using phosphorus magnetic resonance spectroscopy.146
Figure 8. Peak Vo2 and skeletal muscle histology in HFpEF. Relationship of capillary to fiber ratio (A) and percent type 1 muscle fibers (B) with peak Vo2 in older HFpEF patients (squares) and age-matched healthy controls (triangles). HFpEF indicates heart failure with preserved ejection fraction.
What are the implications of these extensive skeletal muscle abnormalities in HFpEF? First, they confirm that HFpEF is a systemic disorder involving not only the heart, but also other organ systems and that skeletal muscle and cardiac abnormalities are incited by common, circulating factors such as proinflammatory cytokines originating from multiple comorbidities.147 Second, they suggest opportunities for novel interventions. Unlike the myocardium, which is terminally differentiated and has minimal capacity for regeneration, skeletal muscle has robust capacity for rapid repair, regeneration, and growth, which can be exploited by participation in an exercise training program.148 Exercise training, shown in multiple studies to significantly improve peak Vo2 in HFpEF,148–151 achieves this primarily by improving skeletal muscle mitochondrial mass or function.148 Most studies to date have used endurance training; high-intensity and strength training might produce even larger improvements but have not been examined systematically.148
Atrial Fibrillation
Prevalent atrial fibrillation in HFpEF goes along with a more advanced stage of cardiac remodeling evident from a larger left atrium and uniformly carries a worse prognosis.62,152,153 Incident atrial fibrillation in HFpEF also accompanies worse LV diastolic dysfunction and was inversely related to statin use.62 Prevalent atrial fibrillation was shown to be associated with incident HFpEF and prevalent HFpEF with incident atrial fibrillation.154 These interactions suggest atrial fibrillation to beget HFpEF and vice versa and suggest efforts to restore sinus rhythm could be included in a HFpEF treatment strategy. Similar to HFpEF, atrial fibrillation reacts favorably to exercise training and weight loss.155 To restore sinus rhythm, only cardioversion is recommended because catheter ablation of atrial fibrillation had limited long-term success in HFpEF with single- and multiple-procedure drug-free success rates of 27% and 45%, respectively.156 If cardioversion is unsuccessful, rate control and permanent anticoagulation become mandatory.
Conclusions
HFpEF, the most common form of HF, is increasing out of proportion to HFrEF, and is associated with significant morbidity and mortality. Medication trials to date have been largely neutral on their primary outcomes and, so far, only exercise training and weight loss appear to improve exercise intolerance and quality of life. Recent insights provide an understanding of the fundamental basis of LV dysfunction in HFpEF, which involves systemic inflammation, coronary microcirculatory disturbances, cardiomyocyte stiffening, and myocardial fibrosis. These insights also provide a more expanded view on HFpEF that includes involvement of the pulmonary circulation, RV failure, skeletal muscle weakness, and renal dysfunction. These new perspectives on HFpEF open an array of novel therapeutic targets either in the garden-variety phenotype of lung congestion/metabolic risk or in specific phenotypes that may propel future advances in treatment and prevention of this important disorder.
Sources of Funding
Dr Shah is supported by grants from the
Disclosures
Dr Shah has received consulting fees from AstraZeneca, Bayer, Merck, and Novartis, and grant funding from Actelion and Novartis. Dr Kitzman serves as a consultant for Relypsa, Corvia Medical, Abbvie, Merck, Bayer, GSK, and Regeneron, has a trial grant from Novartis, and owns stock in Gilead Sciences and Relypsa. Dr Borlaug has received consulting fees from Amgen, Merck, and Astra Zeneca. Dr Zile receives honoraria as a consultant for Abbott, Amgen, A-Z, Bayer, BMS, BMRC of Singapore-ATTRaCT, CVRx, European Union Research and Innovation, Capricor, Corvia, CVRx, DC Devices, Eli Lilly, Enopace, Idenex, Ironwood, Medtronic, Merck, MicroVide, Novartis, and St. Jude Medical. Dr Kass has received research funding from Pfizer Inc. and has provided consulting for Merck and Ironwood. Dr Paulus has received consulting fees from Amgen and Servier and owns stock in Novartis and Pfizer. Dr van Heerebeek reports no conflicts.
Footnotes
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