Chronic heart failure: advances in pharmacological treatment and future perspectives

DOI: https://doi.org/10.4414/smw.2019.20036

Introduction

After almost two decades without ground-breaking changes in the pharmacological management of heart failure (HF), a set of promising new drugs has successfully entered the clinical arena of HF treatment. Moreover, the classification of HF phenotypes based on the left ventricular ejection fraction (LVEF) has recently been refined by defining the following three entities: HF with preserved ejection fraction (HFpEF) if the LVEF is ≥50%; HF with mid-range ejection fraction (HFmrEF) if the LVEF is 40‒49%; and HF with reduced ejection fraction (HFrEF) if the LVEF is <40% [1]. Whereas diagnosis and treatment are best defined for HFrEF, diagnosis of HFpEF still remains a matter of debate. Similarly, and despite considerable progress in the mechanistic understanding of HFpEF based on more recent data from preclinical and clinical studies, disease-modifying therapies with a prognostic impact are still lacking. In this review we focus on the latest advances in the pharmacological treatment of HF and discuss the newly proposed diagnostic algorithms for HFpEF.

Paradigm shift in HF therapy: from neurohormonal inhibition to neurohormonal modulation

The overshooting and sustained activation of the sympathetic nervous system (SNS) and the renin angiotensin aldosterone system (RAAS) constitutes the basis of the HF syndrome. Although initially adaptive to increase cardiac performance in response to a variety of short-lasting physiological and pathophysiological stressors, these systems remain chronically activated and thus become maladaptive in HF [2]. The notion of the central role of neurohormonal activation in the perpetuation of the HF syndrome has paved the way for the successful use of neurohormonal antagonists such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs) and beta-blockers. Their striking benefit in reducing morbidity and mortality in HFrEF has been demonstrated in a multitude of large, randomized, controlled landmark trials during the last three decades [3–8]. Therefore, complete SNS and RAAS inhibition by using the maximum tolerated doses of a beta-blocker, an ACE inhibitor (or an ARB in the case of ACE-inhibitor intolerability) and an MRA has become the international standard to treat HFrEF for many years. Only in 2014, with the publication of the PARADIGM-HF trial [9], did this long-lasting paradigm of isolated neurohormonal inhibition change with the introduction of a new class of medication, the angiotensin receptor-neprilysin inhibitor (ARNI), which combines the inhibition of RAAS neurohormones with the activation of beneficial neurohormones, the natriuretic peptides (fig. 1).

Figure 1 Actions of ARNI in the neurohormonal cascade. The angiotensin II receptor/neprilysin inhibitor valsartan/sacubitril combines traditional neurohormonal inhibition targeting the renin-angiotensin-aldosterone system with an enhancement of the natriuretic peptide system through inhibition of natriuretic peptide degradation, thereby promoting their beneficial effects. ANP: atrial natriuretic peptide; BNP: brain (or B-type) natriuretic peptide; CNP: C-type natriuretic peptide; NPR: natriuretic peptide receptor; RAAS: renin-angiotensin-aldosterone system; Ang II: angiotensin II; AT1R: angiotensin II type 1 receptor; LV: left ventricular.

Natriuretic peptides are vasoactive peptides that are released in response to distension of the myocardial wall (B-type natriuretic peptide, BNP, and atrial natriuretic peptide, ANP) or by the vascular endothelium (C-type natriuretic peptide, CNP). Natriuretic peptides have various beneficial haemodynamic and cardioprotective effects, including vasodilation, natriuresis and diuresis, as well as anti-fibrotic and anti-hypertrophic properties [10]. This beneficial cardiovascular profile counteracts the deleterious cardiovascular effects of sustained SNS and RAAS activation. Endogenous augmentation of natriuretic peptides has become, therefore, a main focus of novel HF therapies. Because natriuretic peptides are degraded enzymatically by neprilysin, one way to increase endogenous natriuretic peptide levels is to inhibit neprilysin, which is predominantly expressed in the kidneys [11]. In the early 1980s, the first neprilysin-inhibitors were studied as a monotherapy in the setting of arterial hypertension, but proved ineffective at lowering blood pressure. Because angiotensin II and endothelin-1 are also degraded by neprilysin, neprilysin inhibition resulted in a consecutive increase in these potent vasoconstrictors [12]. As a result, subsequent studies combined neprilysin-inhibitors with ACE inhibitors. Omapatrilat was the most prominent combined neprilysin- and ACE-inhibitor. It was tested in a series of HF and hypertension trials, but was later retracted because of a high incidence of life-threatening angioedema due to a marked reduction in the breakdown of bradykinin [13–15]. Eventually, the goal of safe combined RAAS-neprilysin inhibition was achieved with the use of an ARB instead of an ACE-inhibitor. This change circumvents the issue of bradykinin accumulation whilst preserving the benefits of combined RAAS-neprilysin inhibition. This led to the advent of a new class of medications: ARNIs.

The first-in-class ARNI is sacubitril/valsartan. This drug combines the well-known ARB valsartan with sacubitril, a neprilysin-inhibitor prodrug. After ingestion, sacubitril is rapidly metabolized into the active neprilysin-inhibitor sacubitrilat [16]. In the PARADIGM-HF study, sacubitril/valsartan at a target dose of 97/103 mg twice daily (bid) was compared to the actual gold standard, enalapril (target dose 10 mg bid) in over 8,000 stable, ambulatory HFrEF patients (LVEF <40%) [9]. Due to the overwhelming benefit in the sacubitril/valsartan group, the data-safety monitoring board stopped the trial prematurely after a median follow-up of 27 months. In the PARADIGM-HF study, sacubitril/valsartan reduced the primary composite endpoint of cardiovascular (CV) death or HF hospitalization by 20% with overwhelming statistical evidence (p <0.0000004), resulting in a number needed to treat of 21. Importantly, both components of the composite endpoint were significantly reduced (CV death by 20%, HF hospitalization by 21%) [9]. Sacubitril/valsartan was well tolerated and no cases of angioedema with critical airway compromise were reported, although numerically, simple angioedema was more common in the ARNI group than in the enalapril group (19 versus 10 cases). Symptomatic hypotension was slightly more prevalent in the ARNI group (14% vs. 9%), whereas elevation of serum potassium and creatinine was more frequent in the enalapril group. Subsequent subgroup analyses of PARADIGM-HF revealed the following important benefits of sacubitril/valsartan over enalapril:

• − Reduction in sudden cardiac death risk [17]
• −
• −
• −
• −
• −
• −
• − ­­

The guideline committees of the European Society of Cardiology (ESC) and the American Heart Association (AHA) strongly support the use of ARNI in HFrEF patients with LVEF ≤35% who remain symptomatic (≥NYHA II), despite optimal medical therapy including maximum tolerated doses of an ACE-inhibitor or ARB, a betablocker and a MRA, to reduce the risk of death and HF hospitalization (Class 1b indication) [1]. Practical guidance on the introduction of an ARNI is shown in figure 2.

Figure 2 Guidance on the introduction of an ARNI in clinical practice. Criteria for the commencement of treatment with a combined angiotensin II receptor/neprilysin inhibitor (ARNI) based on the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure [1] are depicted. LVEF: left-ventricular ejection fraction; ACE: angiotensin converting enzyme; ARB: angiotensin receptor blocker.

Sodium-glucose-co-transporter 2 inhibitors: anti-diabetic drugs with a significant impact on HF

Diabetes and HF are vicious twins. Patients with diabetes have a 4-fold increase in the incidence of HF hospitalizations compared to the general population [26], and 30% of diabetic patients have unrecognized HF and ventricular dysfunction [27]. In turn, HF leads to insulin resistance and thereby promotes the development of diabetes [28, 29]. Also, a series of antidiabetic drugs such as sulfonylureas, glitazones and some dipeptidyl peptidase-4 inhibitors have been shown to promote the development of HF in patients with diabetes [30, 31]. Importantly, patients with both conditions, HF and diabetes, have an almost 10-fold increase in mortality compared to patients suffering solely from diabetes [32].

The pivotal role of the kidneys in regulating glucose homeostasis has been known for decades. Only recently has the main glucose regulatory system in the kidney, the sodium-glucose co-transporters (SGLTs), become a therapeutic target in patients with type 2 diabetes. There are two isoforms of SGLTs, SGLT1 and SGLT2, that are expressed in the proximal tubule and absorb glucose coupled to sodium across the Na+ gradient generated by the sodium/potassium pump. The high capacity, low affinity transporter SGLT2 accounts for 90% of glucose reabsorption, whereas SGLT1 reabsorbs the remaining glucose with high affinity [33]. The introduction of SGLT2-inhibitors as antidiabetic drugs brought unexpected cardiovascular outcome results. In two large trials, the SGLT2 inhibitors empagliflozin and canagliflozin consistently reduced the primary composite endpoint of myocardial infarction, stroke and cardiovascular death in patients with type 2 diabetes and established cardiovascular disease or cardiovascular risk factors [34, 35]. It is of note that the observed endpoint reduction was mainly driven by a reduction in cardiovascular death. Importantly, the relative risk of HF hospitalization was reduced by ≥33% in both studies. Although information about the precise HF phenotype, i.e., with reduced versus preserved ejection fraction, is lacking, this consistent reduction in HF events puts SGLT2 inhibitors at the forefront of efforts to prevent HF in patients with type 2 diabetes. Taking into account the results from EMPA-REG OUTCOME, the latest ESC guidelines for the diagnosis and treatment of HF awarded empagliflozin a class IIa indication to reduce the risk of HF in patients with type 2 diabetes [1]. The mechanisms by which SGLT2 inhibitors prevent HF are manifold and not completely understood. Besides haemodynamic effects driven by lowering of blood pressure and natriuresis, effects on the RAAS and changes in myocardial metabolism may play a significant role ( table 1 ). A series of upcoming clinical trials in various HF populations (HFrEF, HFpEF, with or without type 2 diabetes) will hopefully clarify the role of SGLT2 inhibitors in the treatment and prevention of HF.

Increasing the diagnostic accuracy of HFpEF through new algorithms

Difficulties in correctly diagnosing HFpEF pose a major obstacle to real progress regarding its treatment, and a lack of diagnostic accuracy has at best jeopardized, if not hampered, the outcome of large clinical trials. The current diagnostic criteria for HFpEF are based on an expert consensus outlined in the 2016 ESC guidelines for the diagnosis and treatment of HF [1]. Although a major refinement of the previous, 2007 consensus [36], the sensitivity of the 2016 algorithm is still limited, and the absence of exercise testing has been criticized [37].

Recently, Borlaug and colleagues derived and validated a new diagnostic score that allows for the non-invasive pre-screening of euvolemic patients presenting with exertional dyspnea and having an EF ≥50% in order to identify those who would benefit the most from haemodynamic assessment and exercise testing [38]. The 0-9 point H₂FPEF score (which stands for heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder, filling pressure) is based on the presence/absence of the following key contributors and predictors of the disease: atrial fibrillation (3 points), obesity as defined by a BMI>30 kg/m² (2 points), age>60 years, ≥2 antihypertensive drugs, E/e’>9, and estimated systolic pulmonary arterial pressure by echocardiography >35 mmHg (1 point each) (table 2). This score provided a higher diagnostic accuracy (AUC 0.841) than the algorithm based on the 2016 ESC guidelines [1] when using invasive haemodynamic exercise testing as the gold standard. HFpEF could be refuted with a score of 0-1 and established with a score of 6-9, whereas an intermediate score of 2-5 identified patients who should be further evaluated with invasive exercise testing.

The new ESC Heart Failure Association (HFA) consensus on the diagnosis of HFpEF presented by Burkert Pieske at the 2018 ESC Heart Failure Meeting in Vienna is currently awaiting publication [39]. It follows a similar approach, using a score to identify patients that should be further evaluated with invasive or non-invasive (stress echocardiography) exercise testing. The HF-PEF₂ score encompasses a four-step work-up including a pretest assessment (step 1), an echocardiography and natriuretic peptide score (step 2), a functional exercise echocardiography and haemodynamic work-up (step 3), and strategies to find the etiology (step 4). Similarly to the H₂FPEF score, the most crucial step is step 2, a 0-6 point score, on the basis of which patients are confirmed (5-6 points) or refuted to have HFpEF (<2 points), or identified as needing additional stress testing to corroborate the diagnosis (2-4 points). In contrast to the H₂FPEF score, however, which does not include natriuretic peptide levels, step 2 of the HF-PEF₂ score is exclusively based on comprehensive echocardiography and BNP or NT-BNP levels, whereas age and co-morbidities are included in the pretest assessment of step 1. As a final step, the new HFA consensus proposes advanced imaging (magnetic resonance imaging, myocardial scintigraphy), laboratory testing and/or myocardial biopsy to establish the underlying etiology and to further identify the HFpEF phenotype in order to guide therapy.

Although in many points different from each other, both scores have the potential to significantly increase the number of patients that are correctly diagnosed as having HFpEF, and to allow for better characterization of the individual phenotype of the disease. Furthermore, the exclusion of patients not fulfilling the diagnostic criteria is a prerequisite for clinical trials to be able to generate reliable results, and increases the likelihood that novel therapeutics which benefit real HFpEF patients can be identified in the future.

Current and future treatment concepts of HFpEF

HFpEF is a heterogenous entity driven by various co-morbidities which shape the phenotype of the disease. Similar to the case for HFrEF of ischemic versus non-ischemic origin, etiology and phenotype may determine the treatability of HFpEF. Several therapeutic targets of HFpEF have been identified based on haemodynamic abnormalities, including congestion, diastolic dysfunction, pulmonary hypertension and volume overload; on cellular and structural abnormalities, including systemic microvascular inflammation, cardiomyocyte hypertrophy, stiffening and matrix remodelling; or on metabolic alterations. Nevertheless, a reduction in hospitalizations, symptom relief and/or improved quality of life could only be shown for diuretic use [40, 41] and spironolactone when considering the in-depth analyses, which sorted out the regional discrepancies between Russia and Georgia as opposed to the Americas in the TOPCAT trial [42–44]. In contrast, ACE-inhibitors and ARBs, although beneficial in some studies [45, 46], are mainly recommended for the treatment of concomitant hypertension.

Recently, numerous new agents have raised hope for the long-awaited therapeutic break-through, but most of them have either failed to improve outcomes in mostly small clinical trials, or their efficacy is still uncertain [47]. This is particularly the case for direct or indirect activators of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase (PK) axis (fig. 3), which include organic [48] or inorganic nitrates [49], phosphodiesterase-5 inhibitors [50] and stimulators of soluble guanylate cyclase (sGC) [51]. These all aim to maintain intracellular cGMP levels. Depletion of intracellular cGMP unleashes intracellular pro-hypertrophic pathways and depresses PKG-mediated phosphorylation of titin, which are associated with cardiomyocyte hypertrophy and stiffening. In this respect, ARNIs may represent a promising new option currently under investigation in larger clinical trials. Because natriuretic peptides signal through cGMP, inhibition of their degradation may help preserve cGMP-mediated intracellular signalling and prevent hypertrophy and stiffening on the cardiomyocyte level. Natriuretic peptides also exert natriuretic and diuretic effects, thus counteracting volume overload, and inhibit fibrosis [10], another key pathogenetic feature of HFpEF which contributes to ventricular stiffness and impaired compliance on the organ level. In addition, neprilysin degrades numerous other targets besides natriuretic peptides, including glucagon-like peptide 1 (GLP-1) [52]. Inhibition of neprilysin-mediated GLP-1 degradation by sacubitril may improve glycaemic control and benefit diabetic patients with HFpEF [20]. In the recently completed PARAMOUNT trial, a phase II trial involving 301 patients, sacubitril/valsartan lowered NT-proBNP levels after 12 weeks and decreased atrial volumes and NYHA functional class after 26 weeks in patients with HFpEF [53]. Whether these early beneficial effects translate into improvements of “hard endpoints” such as mortality is currently being tested in the ongoing PARAGON-HF trial.

Figure 3 The NO-cGMP-PK axis as a potential therapeutic target in HFpEF. Intracellular cGMP may be maintained through the action of nitric oxide (NO)-mediated activation of soluble guanylate cyclase (sGC), through direct stimulation of sGC or through inhibition of the phosphodiesterase-(PDE) mediated degradation. Alternatively, natriuretic peptides (NPs) induce cGMP through activation of the receptor guanylate cyclase (rGC). PKG: protein kinase G; CMC: cardiomyocyte.

Similarly, SGLT2 inhibitors have the potential to add to the therapeutic repertoire of treatments for HFpEF in the future. There are several properties which make them interesting drug candidates, especially in patients presenting with the obesity-associated phenotype. Through the inhibition of glucose reabsorption, they act as osmotic diuretics and contribute to the correction of plasma volume expansion [54, 55], which is of particular importance in obese HFpEF patients [56]. SGLT2 inhibitors also exert anti-inflammatory and anti-fibrotic properties. Through the reduction of visceral – and epicardial – fat, they lower the secreted load of adipocytokines such as leptin. This mitigates their paracrine pro-inflammatory and pro-fibrotic actions in neighbouring organs, including the heart [57–59]. The EMPEROR-Preserved trial (NCT03057951) is a phase III randomized, double-blind and placebo-controlled trial currently testing the safety and efficacy of empagliflozin on top of guideline-directed therapy to delay cardiovascular death or HF hospitalization in HFpEF patients irrespective of concomitant diabetes. While awaiting the results of these and other currently ongoing pharmacological trials, optimal risk factor management and control of contributing factors, which include atrial fibrillation (rhythm control), obesity (exercise training, weight loss), hypertension (blood pressure control) and coronary artery disease (revascularization), remain the cornerstones of the treatment of patients with HFpEF.

Transthyretin amyloid cardiomyopathy

Senile systemic amyloidosis is a condition caused by the deposition of wild-type transthyretin (ATTRwt) and a common cause of cardiomyopathy associated with HFpEF in the elderly. Its prevalence is estimated at roughly 13% of HFpEF patients [60], but this is likely to be an underestimate due to the limited availability and/or application of specific non-invasive diagnostic options such as scintigraphy. Transthyretin is a protein synthesized in the liver. It is involved in the binding and transportation of thyroxine and retinol-binding protein-retinol complex (vitamin A) [61]. Originally secreted as a more or less stable tetramer, transthyretin can dissociate into less stable monomers that may undergo misfolding and polymerize to form amyloid fibrils [62] (fig. 4). Whereas dissociation and denaturation of monomers occurs more frequently in the elderly (i.e., >60 years-old), with a predominance in men [63], there is also a hereditary, autosomal dominant form. There are so far more than 120 known mutations in the transthyretin gene (ATTRm) which cause this hereditary form. Survival is limited in patients with transthyretin amyloid cardiomyopathy, ranging from 2‒6 years after diagnosis [64, 65]. Recently, several strategies have been designed to either inhibit transthyretin secretion, stabilize the transthyretin tetramer or inhibit amyloid deposition. Among those strategies, tafamidis has now emerged as a promising new therapy to treat ATTR cardiomyopathy. Tafamidis is a benzoxazole derivative binding to the thyroxine-binding sites of transthyretin, thereby stabilizing its tetramer formation. In the double-blind and placebo-controlled ATTR-ACT trial, 441 patients with ATTR cardiomyopathy (both ATTRwt and ATTRm) were randomly assigned to receive tafamidis or placebo with a treatment duration of 30 months. The first results now show that tafamidis significantly decreased all-cause mortality and cardiovascular hospitalizations and reduced the decline in functional capacity and quality of life when compared to placebo [66]. Identification and consecutive treatment of patients presenting with HFpEF that exhibit ATTR cardiomyopathy may help to lower the HFpEF disease burden in elderly patients in the future.

Figure 4 Secretion and metabolism of transthyretin. Transthyretin (TTR) is synthesized and secreted by the liver and assembles to tetramers. Dissociation of the TTR tetramer leads to the occurrence of monomers, which are prone to denaturalization and misfolding either through mutations (ATTRm, hereditary forms) or during aging (ATTRwt). Misfolded TTR polymerizes to form amyloid fibrils that are deposited in various organs including the heart. Tafamidis (and other compounds, e.g., diflunisal) can stabilize TTR in its tetramer formation, thus preventing misfolding and amyloid formation.

HFmrEF: more in common with HFrEF than HFpEF

HFmrEF was introduced as a third category in the 2016 ESC HF guidelines [1]. HFmrEF includes a heterogenous population of patients, who may exhibit an early decline in EF with or without progression to HFrEF, recovery or partial recovery from previous HFrEF, or predominantly diastolic dysfunction with mild compromise of EF. Therefore, the clinical significance of HFmrEF remains poorly defined. Because patients with near-to-normal EF were mostly included in HFpEF trials, the 2016 ESC guidelines primarily recommended a “HFpEF-like approach” for the treatment of HFmrEF [1]. However, recent subgroup analyses of TOPCAT [67] and CHARM [68] suggested that patients with an EF in the lower normal or below-normal EF range were the ones benefitting the most from treatment with spironolactone [67] or candesartan [68] regarding the primary outcome of cardiovascular death and HF rehospitalization. In a very recent study, Cleland et al. re-examined the data from all major double-blind, randomized and placebo-controlled trials on the effect of beta-blocker therapy in HF patients on a single-patient basis stratified by EF [69]. They found that, similar to patients with EF<40%, patients with mrEF, i.e., EF between 40 and 49%, and a sinus rhythm showed a significant reduction in all-cause and cardiovascular mortality when treated with a beta-blocker (on top of ACE inhibitor / ARB) compared to placebo. In contrast, patients with EF≥50% showed no difference in mortality. Taken together, these findings suggest that standard HFrEF therapy is beneficial in patients with HFmrEF, not only by decreasing morbidity, but also by improving prognosis. They therefore support the use of ACE inhibitors or ARBs, betablockers and aldosterone antagonists in all patients with EF<50%.

Conclusions and outlook

Recent years have shown that progress in HF therapy may not necessarily come from obvious sources (e.g., the recently discovered role of the NO-cGMP-PK axis in HFpEF, which has not yet materialized into new clinical therapies), but rather from the unexpected (e.g., SGLT2 inhibitors) or through perseverance (e.g., ARNI). New approaches may include a stronger focus on inflammation and metabolic aspects that were not covered in the present article, or may just as likely come from completely different or even surprising approaches. In the long run, it will pay to stay curious and keep an open mind for the exploration of potential new avenues in the future.

References

1 Ponikowski P , Voors AA , Anker SD , Bueno H , Cleland JGF , Coats AJS , et al.; ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200. doi:.https://doi.org/10.1093/eurheartj/ehw128  

2 Hartupee J , Mann DL . Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol. 2017;14(1):30–8. doi:.https://doi.org/10.1038/nrcardio.2016.163  

3 Group CTS ; CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316(23):1429–35. doi:.https://doi.org/10.1056/NEJM198706043162301  

4 Yusuf S , Pitt B , Davis CE , Hood WB , Cohn JN , Cohn JN ; SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325(5):293–302. doi:.https://doi.org/10.1056/NEJM199108013250501  

5 Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001–7. doi:.https://doi.org/10.1016/S0140-6736(99)04440-2  

6 Pitt B , Zannad F , Remme WJ , Cody R , Castaigne A , Perez A , et al.; Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709–17. doi:.https://doi.org/10.1056/NEJM199909023411001  

7 Cohn JN , Tognoni G ; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667–75. doi:.https://doi.org/10.1056/NEJMoa010713  

8 Packer M , Coats AJ , Fowler MB , Katus HA , Krum H , Mohacsi P , et al.; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344(22):1651–8. doi:.https://doi.org/10.1056/NEJM200105313442201  

9 McMurray JJ , Packer M , Desai AS , Gong J , Lefkowitz MP , Rizkala AR , et al.; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004. doi:.https://doi.org/10.1056/NEJMoa1409077  

10 Daniels LB , Maisel AS . Natriuretic peptides. J Am Coll Cardiol. 2007;50(25):2357–68. doi:.https://doi.org/10.1016/j.jacc.2007.09.021  

11 Potter LR . Natriuretic peptide metabolism, clearance and degradation. FEBS J. 2011;278(11):1808–17. doi:.https://doi.org/10.1111/j.1742-4658.2011.08082.x  

12 Bevan EG , Connell JM , Doyle J , Carmichael HA , Davies DL , Lorimer AR , et al. Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension. J Hypertens. 1992;10(7):607–13. doi:.https://doi.org/10.1097/00004872-199207000-00002  

13 Rouleau JL , Pfeffer MA , Stewart DJ , Isaac D , Sestier F , Kerut EK , et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet. 2000;356(9230):615–20. doi:.https://doi.org/10.1016/S0140-6736(00)02602-7  

14 Packer M , Califf RM , Konstam MA , Krum H , McMurray JJ , Rouleau JL , et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106(8):920–6. doi:.https://doi.org/10.1161/01.CIR.0000029801.86489.50  

15 Kostis JB , Packer M , Black HR , Schmieder R , Henry D , Levy E . Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103–11. doi:.https://doi.org/10.1016/j.amjhyper.2003.09.014  

16 Gu J , Noe A , Chandra P , Al-Fayoumi S , Ligueros-Saylan M , Sarangapani R , et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010;50(4):401–14. doi:.https://doi.org/10.1177/0091270009343932  

17 Desai AS , McMurray JJ , Packer M , Swedberg K , Rouleau JL , Chen F , et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J. 2015;36(30):1990–7. doi:.https://doi.org/10.1093/eurheartj/ehv186  

18 Desai AS , Vardeny O , Claggett B , McMurray JJ , Packer M , Swedberg K , et al. Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril: A Secondary Analysis of the PARADIGM-HF Trial. JAMA Cardiol. 2017;2(1):79–85. doi:.https://doi.org/10.1001/jamacardio.2016.4733  

19 Lewis EF , Claggett BL , McMurray JJV , Packer M , Lefkowitz MP , Rouleau JL , et al. Health-Related Quality of Life Outcomes in PARADIGM-HF. Circ Heart Fail. 2017;10(8):10. doi:.https://doi.org/10.1161/CIRCHEARTFAILURE.116.003430  

20 Seferovic JP , Claggett B , Seidelmann SB , Seely EW , Packer M , Zile MR , et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2017;5(5):333–40. doi:.https://doi.org/10.1016/S2213-8587(17)30087-6  

21 Packer M , Claggett B , Lefkowitz MP , McMurray JJV , Rouleau JL , Solomon SD , et al. Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2018;6(7):547–54. doi:.https://doi.org/10.1016/S2213-8587(18)30100-1  

22 Damman K , Gori M , Claggett B , Jhund PS , Senni M , Lefkowitz MP , et al. Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure. JACC Heart Fail. 2018;6(6):489–98. doi:.https://doi.org/10.1016/j.jchf.2018.02.004  

23 Mogensen UM , Gong J , Jhund PS , Shen L , Køber L , Desai AS , et al. Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 2018;20(4):760–8. doi:.https://doi.org/10.1002/ejhf.1139  

24 Mogensen UM , Køber L , Jhund PS , Desai AS , Senni M , Kristensen SL , et al.; PARADIGM-HF Investigators and Committees. Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF. Eur J Heart Fail. 2018;20(3):514–22. doi:.https://doi.org/10.1002/ejhf.1056  

25 Ademi Z , Pfeil AM , Hancock E , Trueman D , Haroun RH , Deschaseaux C , et al. Cost-effectiveness of sacubitril/valsartan in chronic heart-failure patients with reduced ejection fraction. Swiss Med Wkly. 2017;147:w14533.  

26 McMurray JJ , Gerstein HC , Holman RR , Pfeffer MA . Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014;2(10):843–51. doi:.https://doi.org/10.1016/S2213-8587(14)70031-2  

27 Boonman-de Winter LJ , Rutten FH , Cramer MJ , Landman MJ , Liem AH , Rutten GE , et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia. 2012;55(8):2154–62. doi:.https://doi.org/10.1007/s00125-012-2579-0  

28 Paolisso G , De Riu S , Marrazzo G , Verza M , Varricchio M , D’Onofrio F . Insulin resistance and hyperinsulinemia in patients with chronic congestive heart failure. Metabolism. 1991;40(9):972–7. doi:.https://doi.org/10.1016/0026-0495(91)90075-8  

29 Suskin N , McKelvie RS , Burns RJ , Latini R , Pericak D , Probstfield J , et al. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J. 2000;21(16):1368–75. doi:.https://doi.org/10.1053/euhj.1999.2043  

30 Home PD , Pocock SJ , Beck-Nielsen H , Curtis PS , Gomis R , Hanefeld M , et al.; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373(9681):2125–35. doi:.https://doi.org/10.1016/S0140-6736(09)60953-3  

31 Scirica BM , Bhatt DL , Braunwald E , Steg PG , Davidson J , Hirshberg B , et al.; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. doi:.https://doi.org/10.1056/NEJMoa1307684  

32 Bertoni AG , Hundley WG , Massing MW , Bonds DE , Burke GL , Goff DC, Jr . Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27(3):699–703. doi:.https://doi.org/10.2337/diacare.27.3.699  

33 Hummel CS , Lu C , Loo DD , Hirayama BA , Voss AA , Wright EM . Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am J Physiol Cell Physiol. 2011;300(1):C14–21. doi:.https://doi.org/10.1152/ajpcell.00388.2010  

34 Zinman B , Wanner C , Lachin JM , Fitchett D , Bluhmki E , Hantel S , et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117–28. doi:.https://doi.org/10.1056/NEJMoa1504720  

35 Neal B , Perkovic V , Mahaffey KW , de Zeeuw D , Fulcher G , Erondu N , et al.; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644–57. doi:.https://doi.org/10.1056/NEJMoa1611925  

36 Paulus WJ , Tschöpe C , Sanderson JE , Rusconi C , Flachskampf FA , Rademakers FE , et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28(20):2539–50. doi:.https://doi.org/10.1093/eurheartj/ehm037  

37 Obokata M , Kane GC , Reddy YN , Olson TP , Melenovsky V , Borlaug BA . Role of Diastolic Stress Testing in the Evaluation for Heart Failure With Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study. Circulation. 2017;135(9):825–38. doi:.https://doi.org/10.1161/CIRCULATIONAHA.116.024822  

38 Reddy YNV , Carter RE , Obokata M , Redfield MM , Borlaug BAA . A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure With Preserved Ejection Fraction. Circulation. 2018;138(9):861–70. doi:.https://doi.org/10.1161/CIRCULATIONAHA.118.034646  

39Pieske B. Diagnosing heart failure with preserved ejection fraction: The new HFA consensus. escardio.org: European Society of Cardiology, https://www.escardio.org/Congresses-&-Events/Heart-Failure/Congress-resources/News/diagnosing-heart-failure-with-preserved-ejection-fraction-the-new-hfa-consensus, August 11, 2018. 

40 Yip GW , Wang M , Wang T , Chan S , Fung JW , Yeung L , et al. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008;94(5):573–80. doi:.https://doi.org/10.1136/hrt.2007.117978  

41 Adamson PB , Abraham WT , Bourge RC , Costanzo MR , Hasan A , Yadav C , et al. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circ Heart Fail. 2014;7(6):935–44. doi:.https://doi.org/10.1161/CIRCHEARTFAILURE.113.001229  

42 Pitt B , Pfeffer MA , Assmann SF , Boineau R , Anand IS , Claggett B , et al.; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383–92. doi:.https://doi.org/10.1056/NEJMoa1313731  

43 Pfeffer MA , Claggett B , Assmann SF , Boineau R , Anand IS , Clausell N , et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131(1):34–42. doi:.https://doi.org/10.1161/CIRCULATIONAHA.114.013255  

44 de Denus S , O’Meara E , Desai AS , Claggett B , Lewis EF , Leclair G , et al. Spironolactone Metabolites in TOPCAT - New Insights into Regional Variation. N Engl J Med. 2017;376(17):1690–2. doi:.https://doi.org/10.1056/NEJMc1612601  

45 Cleland JG , Tendera M , Adamus J , Freemantle N , Polonski L , Taylor J ; PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27(19):2338–45. doi:.https://doi.org/10.1093/eurheartj/ehl250  

46 Yusuf S , Pfeffer MA , Swedberg K , Granger CB , Held P , McMurray JJ , et al.; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362(9386):777–81. doi:.https://doi.org/10.1016/S0140-6736(03)14285-7  

47 Tschöpe C , Birner C , Böhm M , Bruder O , Frantz S , Luchner A , et al. Heart failure with preserved ejection fraction: current management and future strategies : Expert opinion on the behalf of the Nucleus of the “Heart Failure Working Group” of the German Society of Cardiology (DKG). Clin Res Cardiol. 2018;107(1):1–19. doi:.https://doi.org/10.1007/s00392-017-1170-6  

48 Redfield MM , Anstrom KJ , Levine JA , Koepp GA , Borlaug BA , Chen HH , et al.; NHLBI Heart Failure Clinical Research Network. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015;373(24):2314–24. doi:.https://doi.org/10.1056/NEJMoa1510774  

49 Borlaug BA , Koepp KE , Melenovsky V . Sodium Nitrite Improves Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2015;66(15):1672–82. doi:.https://doi.org/10.1016/j.jacc.2015.07.067  

50 Redfield MM , Chen HH , Borlaug BA , Semigran MJ , Lee KL , Lewis G , et al.; RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268–77. doi:.https://doi.org/10.1001/jama.2013.2024  

51 Pieske B , Maggioni AP , Lam CSP , Pieske-Kraigher E , Filippatos G , Butler J , et al. Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur Heart J. 2017;38(15):1119–27. doi:.https://doi.org/10.1093/eurheartj/ehw593  

52 Plamboeck A , Holst JJ , Carr RD , Deacon CF . Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. Diabetologia. 2005;48(9):1882–90. doi:.https://doi.org/10.1007/s00125-005-1847-7  

53 Solomon SD , Zile M , Pieske B , Voors A , Shah A , Kraigher-Krainer E , et al.; Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851):1387–95. doi:.https://doi.org/10.1016/S0140-6736(12)61227-6  

54 Heise T , Seewaldt-Becker E , Macha S , Hantel S , Pinnetti S , Seman L , et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(7):613–21. doi:.https://doi.org/10.1111/dom.12073  

55 Heise T , Jordan J , Wanner C , Heer M , Macha S , Mattheus M , et al. Pharmacodynamic Effects of Single and Multiple Doses of Empagliflozin in Patients With Type 2 Diabetes. Clin Ther. 2016;38(10):2265–76. doi:.https://doi.org/10.1016/j.clinthera.2016.09.001  

56 Obokata M , Reddy YNV , Pislaru SV , Melenovsky V , Borlaug BA . Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction. Circulation. 2017;136(1):6–19. doi:.https://doi.org/10.1161/CIRCULATIONAHA.116.026807  

57 Yagi S , Hirata Y , Ise T , Kusunose K , Yamada H , Fukuda D , et al. Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2017;9(1):78. doi:.https://doi.org/10.1186/s13098-017-0275-4  

58 Díaz-Rodríguez E , Agra RM , Fernández AL , Adrio B , García-Caballero T , González-Juanatey JR , et al. Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability. Cardiovasc Res. 2018;114(2):336–46. doi:.https://doi.org/10.1093/cvr/cvx186  

59 Bouchi R , Terashima M , Sasahara Y , Asakawa M , Fukuda T , Takeuchi T , et al. Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study. Cardiovasc Diabetol. 2017;16(1):32. doi:.https://doi.org/10.1186/s12933-017-0516-8  

60 González-López E , Gallego-Delgado M , Guzzo-Merello G , de Haro-Del Moral FJ , Cobo-Marcos M , Robles C , et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585–94. doi:.https://doi.org/10.1093/eurheartj/ehv338  

61 Monaco HL , Rizzi M , Coda A . Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science. 1995;268(5213):1039–41. doi:.https://doi.org/10.1126/science.7754382  

62 Colon W , Kelly JW . Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry. 1992;31(36):8654–60. doi:.https://doi.org/10.1021/bi00151a036  

63 Ruberg FL , Berk JL . Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286–300. doi:.https://doi.org/10.1161/CIRCULATIONAHA.111.078915  

64 Rapezzi C , Quarta CC , Riva L , Longhi S , Gallelli I , Lorenzini M , et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat Rev Cardiol. 2010;7(7):398–408. doi:.https://doi.org/10.1038/nrcardio.2010.67  

65 Pinney JH , Whelan CJ , Petrie A , Dungu J , Banypersad SM , Sattianayagam P , et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098. doi:.https://doi.org/10.1161/JAHA.113.000098  

66 Maurer MS , Schwartz JH , Gundapaneni B , Elliott PM , Merlini G , Waddington-Cruz M , et al.; ATTR-ACT Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018;379(11):1007–16. doi:.https://doi.org/10.1056/NEJMoa1805689  

67 Solomon SD , Claggett B , Lewis EF , Desai A , Anand I , Sweitzer NK , et al.; TOPCAT Investigators. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J. 2016;37(5):455–62. doi:.https://doi.org/10.1093/eurheartj/ehv464  

68 Lund LH , Claggett B , Liu J , Lam CS , Jhund PS , Rosano GM , et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur J Heart Fail. 2018;20(8):1230–9. doi:.https://doi.org/10.1002/ejhf.1149  

69 Cleland JGF , Bunting KV , Flather MD , Altman DG , Holmes J , Coats AJS , et al.; Beta-blockers in Heart Failure Collaborative Group. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J. 2018;39(1):26–35. doi:.https://doi.org/10.1093/eurheartj/ehx564