Study of Sacubitril/ValsarTan on MyocardIal OxygenatioN and Fibrosis in Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is increasing in incidence and accounts for one third to one half of all heart failure admissions worldwide. It portrays a significant burden in terms of prevalence, morbidity and mortality. It is a complex clinical syndrome characterized by multiple pathophysiological mechanisms affecting the cardiac structure and function culminating to increased ventricular filling pressures. The definition of HFpEF remains an evolving concept and the exact definition by various learned societies is not uniform. The recent ANZ heart failure guidelines defines HFpEF as the presence of typical symptoms with or without signs of heart failure, with a measured left ventricular ejection fraction of at least 50% and objective evidence of relevant structural heart disease or diastolic dysfunction without an alternative cause. Despite some common clinical features, there is heterogeneity in the causes of HFpEF, and it is likely that it represents a broad cohort of patients with a range of comorbid conditions. In addition to clinical variability, there is morphological and functional variability at the myocardial level. For instance, whilst left ventricular hypertrophy and left atrial dilatation are traditionally considered morphological hallmarks, they are not universally present, and one third to one half of patients do not demonstrate one or both of these features. Furthermore whilst diastolic dysfunction is considered a sine qua non of the disease, and is recognised in the current guidelines, up-to one third of HFpEF patients in echocardiographic sub-studies have normal diastolic function even in the presence of elevated natriuretic peptides.

The heterogeneous phenotypes in HFpEF have potentially confounded previous trials. Therefore, the identification of various structural phenotypes capable of segmenting the HFpEF population into relevant pathophysiologic categories represents a promising approach. Post-mortem endomyocardial biopsy studies from HFpEF patients have suggested that some of the cardiac structural phenotypes are related to myocyte hypertrophy, interstitial fibrosis, myocardial inflammation due to oxidative stress and epicardial coronary artery disease. In addition, a better understanding of the mechanisms that contribute to the pathophysiology of HFpEF is emerging from pre-clinical, interventional and mechanistic studies. In HFpEF, proinflammatory cardiovascular and non-cardiovascular coexisting conditions (e.g., hypertension, obesity) lead to systemic microvascular endothelial inflammation. This results in myocardial inflammation and fibrosis, increases in oxidative stress and alterations in cardiomyocyte signalling pathways. These alterations promote cardiomyocyte remodeling and dysfunction as well as coronary microvascular dysfunction. A recent study showed that there is a high prevalence of coronary microvascular dysfunction in HFpEF even in the absence of unrevascularized macrovascular coronary artery disease and was correlated with markers of heart failure severity.

Cardiac imaging is pivotal in the evaluation of patients with suspected HFpEF. 2D Echocardiography is able to non-invasively measure left ventricular systolic and diastolic dysfunction, as well as characterise left ventricular filling pressures. Echocardiographic data adds incremental prognostic information in patients with HFpEF. These include assessment of left ventricular hypertrophy, left atrial volume, E/e' ratio, tricuspid regurgitation velocity, right ventricular function and global longitudinal strain. However, echocardiography is unable to easily characterise myocardial tissue nor assess myocardial microvascular function. The application of Cardiovascular Magnetic Resonance (CMR) imaging is increasingly recognised and is currently the standard modality for assessing atrial / ventricular volumes, quantifying ejection fraction and left ventricular mass. It is uniquely able to provide information on morphology, function, perfusion, viability, and tissue characterization in a single examination. Hence, CMR is an ideal tool to delineate the various cardiac structural phenotypes that have been described in HFpEF patients. In addition to routinely used CMR parameters, there are a number of emerging CMR applications that have the potential in advancing our understanding of HFpEF. The important amongst them are the assessment of myocardial oxygenation using Oxygen Sensitive CMR (OS-CMR) and diffuse myocardial fibrosis using T1 mapping. OS-CMR can directly assess the myocardial tissue oxygenation and potentially measure mismatches in myocardial oxygen demand and supply. OS-CMR is based on the principle of changes of paramagnetic properties of haemoglobin due to the effects of oxygenation. The change from oxygenated to de-oxygenated haemoglobin leads to a change in the magnetic resonance signal intensity (SI). An increased myocardial de-oxygenation is reflected as a drop in SI on the T2 weighted CMR images. Hence, this allows in vivo assessment of myocardial ischaemia at the tissue level, relying on accumulation of de-oxyhaemoglobin following vasodilator stress. The change in SI is quantified as a percentage of signal change. Myocardial fibrosis has been implicated in the pathophysiology of HFpEF. Both focal replacement fibrosis and interstitial fibrosis promote adverse ventricular remodelling in HFpEF. The pattern of interstitial fibrosis is diffuse in HFpEF and cannot be detected using the late gadolinium enhancement technique. Recent improvements in parametric mapping techniques (such as T1, T2 and T2*) has made non-invasive assessment of diffuse interstitial and fibrotic changes clinically feasible. CMR T1 parametric mapping techniques enable quantification of the extracellular volume (ECV), a surrogate marker of diffuse fibrosis, and have been validated histologically. Hence it is possible that CMR along with OS-CMR, parametric imaging and late gadolinium enhancement represents the ideal non-invasive modality to study and understand the various pathophysiological mechanisms in HFpEF patients.

A number of biomarkers associated with heart failure are well recognized and measuring their concentrations in circulation can provide valuable information about the diagnosis, prognosis, and management. These biomarkers have significantly enhanced the understanding of the pathophysiology of HFpEF, however only a few are currently being used in clinical practice. The measurement of natriuretic peptides (BNP or NT-proBNP) is recommended by current guidelines as they provide incremental value. Cardiac troponin testing is recommended to establish prognosis in acute heart failure and may be used for prognostication in chronic heart failure as well. Novel biomarkers are increasingly becoming validated and recognized in the care of patients with heart failure. These include galectin-3, ST2, renin and cGMP and they alter in response to cardiac remodelling and fibrosis. However, the role of these biomarkers in microvascular dysfunction has not been systematically studied in HFpEF.

Currently, there are no proven pharmacological therapies for patients with HFpEF. This is evident on HFpEF patients trial on beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers which have failed to demonstrate a significant clinical benefit. The first-in-class angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan holds promise based on its pharmacodynamic profile. It simultaneously blocks the renin-angiotensin-aldosterone system and the endopeptidase neprilysin. Neprilysin is a ubiquitous enzyme that is responsible for the breakdown of many vasoactive peptides, including the biologically active natriuretic peptides. Sacubitril/valsartan has reduced cardiovascular and all-cause mortality in patients with heart failure and reduced ejection fraction, compared with enalapril. In addition, the biomarkers associated with profibrotic signalling are significantly decreased with ARNI therapy in patients with reduced ejection fraction. In HFpEF patients, the PARAMOUNT-HF Phase II trial has demonstrated significant reduction of NT-proBNP with ARNI in comparison with Valsartan.However, in the recently published PARAGON-HF trial, sacubitril/valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with HFpEF. In patients with HFpEF, the effect of ARNI therapy on the various emerging pathophysiological mechanisms remains unknown. Myocardial fibrosis is an important pathophysiological mechanism in HFpEF. Treatment options to block or reverse fibrosis in HFpEF have proven elusive. Angiotensin-receptor blockers have been shown to induce regression of severe myocardial fibrosis in hypertensive patients. In mouse models, ARNI ameliorates maladaptive cardiac remodeling and fibrosis in pressure overload-induced hypertrophy. Although not approved for use in HFpEF, ARNI is an attractive option to mitigate myocardial hypertrophy, fibrosis, ischaemia, and impaired ventricular-arterial coupling, which are all closely related to increased left ventricular filling pressures, a common hallmark of this multifaceted syndrome.

Thus, there remains an enormous unmet need for effective therapy in the group of HFpEF patients. HFpEF is a heterogeneous syndrome, with different degrees of contribution from various pathophysiological processes. In patients with HFpEF, the effect of ARNI therapy on the various postulated structural phenotypes remain unexplored. ARNI has the potential to reduce both ischaemia and fibrosis, and both can be accurately measured utilizing CMR. Therefore, by combining CMR with echocardiography, the investigators aim to assess the effect of ARNI on myocardial deoxygenation at stress and myocardial fibrosis, and correlate this to changes in myocardial systolic and diastolic function in HFpEF patients.