The Conundrum of HFpEF Definition: Non-Invasive Assessment Uncertainties and Alternative Diagnostic Strategies

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome including several morphological phenotypes and varying pathophysiological mechanisms. The conventional classification of HF based on left ventricular ejection fraction (LVEF) has created an oversimplification in diagnostic criteria. Although LVEF is a standardized parameter easy to calculate and broadly applied in the large clinical trials, but it is erroneously considered an index of left ventricular (LV) systolic function. Indeed, it is affected by preload and afterload and it has limitations related to reproducibility, reduced sensitivity and scarce prognostic values especially when above 50%. Notably, additional diagnostic parameters have been recently proposed in order to improve diagnostic accuracy and to homogenize the different HFpEF populations. Unfortunately, these algorithms comprise sophisticated measurements that are difficult to apply in the daily clinical practice. Additionally, the scarce diffusion of these diagnostic criteria may have led to neutral or negative results in interventional phase 3 trials. We propose changes to the current HFpEF diagnostic approach mainly based on LVEF stratification measurement aiming towards a more inclusive model taking into consideration an integrative approach starting from the main diseases responsible for cardiac dysfunction through to cardiac structural and functional alterations. Accordingly, with recent universal HF definitions, a stepwise model could be helpful in recognizing patients with early vs. overt HFpEF by the appraisal of specific Doppler echocardiographic variables. Thus, we would encourage the application of new criteria in order to better identify the different phenotypes and to move towards more personalized medicine.     

Cardiac magnetic resonance in heart failure with preserved ejection fraction: myocyte,interstitium, microvascular,and metabolic abnormalities

Heart failure (HF) with preserved ejection fraction (HFpEF) is a chronic cardiac condition whose prevalence continues to rise, with high social and economic burden, but with no specific approved treatment. Patients diagnosed with HFpEF have a high prevalence of comorbidities and exhibit a high misdiagnosis rate. True HFpEF is likely to have multiple pathophysiological causes – with these causes being clinically ill‐defined due to limitations of current measurement techniques. Myocyte, interstitium, microvascular, and metabolic abnormalities have been regarded as key components of the pathophysiology and potential therapeutic targets. Cardiac magnetic resonance (CMR) has the capability to look deeper with a number of tissue characterization techniques which are closer to the underlying specific abnormalities and which could be linked to personalized medicine for HFpEF. This review aims to discuss the potential role of CMR to better define HFpEF phenotypes and to infer measurable therapeutic targets.     

Current Management and Future Directions of Heart Failure With Preserved Ejection Fraction: a Contemporary Review

Heart failure with preserved ejection fraction (HFpEF), a complex and debilitating syndrome, is commonly seen in elderly populations. Exacerbation of HFpEF is among the most common reasons for hospital admission in the USA. The high rate of morbidity and mortality from this condition underscores the fact that HFpEF is heterogeneous, complex, and poorly characterized. Randomized, controlled trials have been very successful at identifying treatments for HF with reduced ejection fraction (HFrEF), but effective treatment options for HFpEF are lacking. Here, we discuss (1) the pathophysiology of HFpEF, (2) a standardized diagnostic and therapeutic approach, (3) a comparison of the management of recent guidelines, and (4) challenges and future directions for HFpEF management. The authors believe that it is important to identify new subtypes of HFpEF to better classify genotypes and phenotypes of HFpEF and to develop novel targeted therapies. It is our hypothesis that big data analytics will shine new light on unique HFpEF phenotypes that better respond to treatment modalities.     

Cardiac mechanics in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical entity associated with significant morbidity and mortality. Common comorbidities including hypertension, coronary artery disease, diabetes, chronic kidney disease, obesity, and increasing age predispose to preclinical diastolic dysfunction that often progresses to frank HFpEF. Clinical HFpEF is typically associated with some degree of diastolic dysfunction, but can occur in the absence of many conventional diastolic dysfunction indices. The exact biologic links between risk factors, structural changes, and clinical manifestations are not clearly apparent. Innovative approaches including deformation imaging have enabled deeper understanding of HFpEF cardiac mechanics beyond conventional metrics. Furthermore, predictive analytics through data-driven platforms have allowed for a deeper understanding of HFpEF phenotypes. This review focuses on the changes in cardiac mechanics that occur through preclinical myocardial dysfunction to clinically apparent HFpEF.     

Galectin‐3 in heart failure with preserved ejection fraction

In the last decades it has been appreciated that many patients with heart failure (HF) suffer from HF with preserved ejection fraction (HFpEF). The diagnosis and treatment of HFpEF is difficult, as we lack specific markers of the disease and no specific treatments have been identified. Galectin‐3 has a strong relationship to several aspects of the pathophysiology of HF, especially myocardial fibrosis, the transition from compensated to decompensated HF, and co‐morbidities such as renal disease and diabetes. Many of these traits are very commonly observed in patients with HFpEF, and this suggests that galectin‐3 may be particularly important and useful in the study of HFpEF. This review summarizes our knowledge of the role of galectin‐3 in fibrosis, specifically in experimental models of HF and HFpEF. Galectin‐3 may be a marker and also a causal factor, and experimental studies suggested that galectin‐3 may be a target for therapy in HFpEF. The detrimental effects of aldosterone may, in part, be conferred via galectin‐3, and there are data to suggest that aldosterone blockers are of more benefit in patients with high levels of galectin‐3. Furthermore, the relationship of galectin‐3 to clinical correlates of developing HFpEF in human subjects is discussed, and the association between increased levels of galectin‐3 and new‐onset HF and mortality in the general population is highlighted. Additionally, the usefulness of galectin‐3 in patients with established HFpEF is described. We conclude that galectin‐3 may be useful for early detection, phenotyping, risk stratification, and therapeutic targeting of individuals with early or established HFpEF in which fibrosis is a major contributor to the disease. Finally, we propose areas of further research that should validate the role of galectin‐3 in HFpEF.     

Clinical Phenotypes of Heart Failure across the spectrum of Ejection Fraction: A Cluster Analysis

Introduction: Heart failure (HF), and especially HF with preserved ejection fraction (HFpEF), remains a challenging condition to define. The heterogenous nature of this population may be related to a variety of underlying etiologies interacting myocardial dysfunction. Method: Alberta HEART study was a prospective, observational cohort that enrolled participants along the spectrum of heart failure including: healthy controls, people at risk of HF, and patients with HF and preserved (HFpEF) or reduced ejection fraction (HFrEF). We aimed to explore phenotypes of patients with HF and at-risk of developing HF. Utilising 27 detailed clinical, echocardiographic and biomarker variables, latent class analysis with and without multiple imputation was undertaken to identify distinct clinical phenotypes. Results: Of 621 participants, 191 (30.8%) and 169 (27.2%) were adjudicated by cardiologists to have HFpEF and HFrEF respectively. In the overall cohort, latent class analysis identified four distinct phenotypes. Phenotype A (n=152, 24.5%) was a healthy and low risk group. Phenotype B (n=129, 20.8%) demonstrated increased left ventricular mass and end-diastolic volumes, with elevated natriuretic peptides and clinical features of congestion. Phenotype C (n=128, 20.6%) was primarily characterised by obesity (80%) and normal indexed cardiac chamber sizes, low natriuretic peptide levels and minimal features of congestion.  Phenotype D (n=212, 34.1%) consisted of elderly patients with clinical features of congestions. Phenotypes B and D demonstrated the highest risk of mortality and hospitalization over a median follow-up of 3.7 years. Conclusion: Phenotypes with congestive features demonstrated increased risk profiles. Heart failure is a heterogenous classification which requires further work to appropriately categorise patients based on the underlying etiology or mechanism of impairment.     

Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 1): Physiologic and Technical Considerations

A better understanding of the pathophysiology of heart failure with a preserved left ventricular ejection fraction (HFpEF) is important. Detailed phenotyping of pulsatile hemodynamics has provided important insights into the pathophysiology of left ventricular remodeling and fibrosis, diastolic dysfunction, microvascular disease, and impaired oxygen delivery to peripheral skeletal muscle, all of which contribute to exercise intolerance, the cardinal feature of HFpEF. Furthermore, arterial pulsatile hemodynamic mechanisms likely contribute to the frequent presence of comorbidities, such as renal failure and dementia, in this population. Our therapeutic approach to HFpEF can be enhanced by clinical phenotyping tools with the potential to “segment” this population into relevant pathophysiologic categories or to identify individuals exhibiting prominent specific abnormalities that can be targeted by pharmacologic interventions. This review describes relevant technical and physiologic aspects regarding the deep phenotyping of arterial hemodynamics in HFpEF. In an accompanying review, the potential of this approach to enhance our clinical and therapeutic approach to HFpEF is discussed.     

Reframing the association and significance of co‐morbidities in heart failure

Several co‐existing diseases and/or conditions (co‐morbidities) are present in patients with heart failure (HF), with diverse clinical relevance. Multiple mechanisms may underlie the co‐existence of HF and co‐morbidities, including direct causation, associated risk factors, heterogeneity, and independence. The complex inter‐relationship of co‐morbidities and their impact on the cardiovascular system contribute to the features of HF, both with reduced (HFrEF) and preserved ejection fraction (HFpEF). The purpose of this work is to provide an overview of the contribution of major cardiac and non‐cardiac co‐morbidities to HF development and outcomes, in the context of both HFpEF and HFrEF. Accordingly, epidemiological evidence linking co‐morbidities to HF and the effect of prevalent and incident co‐morbidities on HF outcome will be reviewed.     

L’insuffisance cardiaque à fraction d’éjection préservée : une maladie de système ?

When the syndrome of heart failure (HF) is due to left ventricular (LV) systolic dysfunction the clinical manifestations and natural history of the syndrome depend primarily on the severity of LV systolic dysfunction. In contrast, when the syndrome is attributed to LV diastolic dysfunction multiple comorbidities are responsible for the clinical manifestations and the natural history of the syndrome. The present review underscores the multifactorial pathogenesis of the syndrome of HF associated with LV diastolic dysfunction that nowadays is more properly referred to as HF with preserved LV ejection fraction (HFpEF) than to diastolic HF. The prognosis is similarly poor whether HF is due to systolic dysfunction or associated with diastolic dysfunction. The cause of death that is commonly non-cardiovascular in HFpEF supports the pathogenic importance of comorbidities in this condition. Hypertension, chronic kidney disease (CKD), diabetes, obesity and sleep disorder breathing are among the most frequent comorbidities in HFpEF. These comorbidities account for the multiple clinical presentations of the syndrome of HFpEF. Limited functional capacity is in HFpEF largely related to the downward spiral between CKD mediated fluid accumulation and LV stiffness as well as altered ventricular-vascular coupling. The diagnosis of HFpEF currently relies on 2D-Doppler echocardiography findings of impaired LV relaxation and increased LV stiffness and to a lesser extent on biomarkers. Owing to both lack of stringent inclusion and exclusion enrollment criteria and mistaken therapeutic target, placebo-controlled randomized therapeutic trials have been so far negative in HFpEF.     

Insulin Growth Factor Phenotypes in Heart Failure With Preserved Ejection Fraction,an INSPIRE Registry and CATHGEN Study

BackgroundThe insulin-like growth factor (IGF) axis emerged as an important pathway in heart failure with preserved ejection (HFpEF). We aimed to identify IGF phenotypes associated with HFpEF in the context of high-dimensional proteomic profiling.MethodsFrom the INtermountain Healthcare Biological Samples Collection Project and Investigational REgistry for the On-going Study of Disease Origin, Progression and Treatment (Intermountain INSPIRE Registry), we identified 96 patients with HFpEF and matched controls. We performed targeted proteomics, including IGF-1,2, IGF binding proteins (IGFBP) 1–7 and 111 other proteins (EMD Millipore and ELISA). We used partial least square discriminant analysis (PLS-DA) to identify a set of proteins associated with prevalent HFpEF, pulmonary hypertension and 5-year all-cause mortality. K-mean clustering was used to identify IGF phenotypes.ResultsPatients with HFpEF had a high prevalence of systemic hypertension (95%) and coronary artery disease (74%). Using PLS-DA, we identified a set of biomarkers, including IGF1,2 and IGFBP 1,2,7, that provided a strong discrimination of HFpEF, pulmonary hypertension and mortality with an area under the curve of 0.91, 0.77 and 0.83, respectively. Using K mean clustering, we identified 3 IGF phenotypes that were independently associated with all-cause 5-year mortality after adjustment for age, NT-proBNP and kidney disease (P = 0.004). Multivariable analysis validated the prognostic value of IGFBP-1 and 2 in the CATHeterization GENetics (CATHGEN) biorepository.ConclusionIGF phenotypes were associated with pulmonary hypertension and mortality in HFpEF.     

Sex‐related differences in contemporary biomarkers for heart failure: a review

The use of circulating biomarkers for heart failure (HF) is engrained in contemporary cardiovascular practice and provides objective information about various pathophysiological pathways associated with HF syndrome. However, biomarker profiles differ considerably among women and men. For instance, in the general population, markers of cardiac stretch (natriuretic peptides) and fibrosis (galectin‐3) are higher in women, whereas markers of cardiac injury (cardiac troponins) and inflammation (sST2) are higher in men. Such differences may reflect sex‐specific pathogenic processes associated with HF risk, but may also arise as a result of differences in sex hormone profiles and fat distribution. From a clinical perspective, sex‐related differences in biomarker levels may affect the objectivity of biomarkers in HF management because what is considered to be ‘normal’ in one sex may not be so in the other. The objectives of this review are, therefore: (i) to examine the sex‐specific dynamics of clinically relevant HF biomarkers in the general population, as well as in HF patients; (ii) to discuss the overlap between sex‐related and obesity‐related effects, and (iii) to identify knowledge gaps to stimulate research on sex‐related differences in HF.     

Contribution of cardiac and extra‐cardiac disease burden to risk of cardiovascular outcomes varies by ejection fraction in heart failure

Aims

Patients with heart failure (HF) often have multiple co‐morbidities that contribute to the risk of adverse cardiovascular (CV) and non‐CV outcomes. We assessed the relative contribution of cardiac and extra‐cardiac disease burden and demographic factors to CV outcomes in HF patients with reduced (HFrEF) or preserved (HFpEF) left ventricular ejection fraction (LVEF).

Methods and results

We utilized data from the CHARM trial, which enrolled HF patients across the ejection fraction spectrum. We decomposed the previously validated MAGGIC risk score into cardiac (LVEF, New York Heart Association class, systolic blood pressure, time since HF diagnosis, HF medication use), extra‐cardiac (body mass index, creatinine, diabetes mellitus, chronic obstructive pulmonary disease, smoker), and demographic (age, gender) categories, and calculated subscores for each patient representing the burden of each component. Cox proportional hazards models were used to estimate the population attributable risk (PAR) associated with each component to the outcomes of death, CV death, HF, myocardial infarction, and stroke relative to patients with the lowest risk score. PARs for each component were depicted across the spectrum of LVEF. in 2675 chronic HF patients from North America [HFrEF (LVEF ≤40%): n = 1589, HFpEF (LVEF >40%): n = 1086] with data available for calculation of the MAGGIC score, the highest risk of death and CV death was attributed to cardiac burden. This was especially evident in HFrEF patients (PAR: 76% cardiac disease vs. 58% extra‐cardiac disease, P < 0.05). Conversely, in HFpEF patients, extra‐cardiac burden accounted for a greater proportion of risk for death than cardiac burden (PAR: 15% cardiac disease vs. 49% extra‐cardiac disease, P < 0.05). For HF hospitalization, the contribution of both cardiac and extra‐cardiac burden was comparable in HFpEF patients (PAR: 42% cardiac disease vs. 53% extra‐cardiac disease, P = NS). In addition, demographic burden was especially high in HFpEF patients, with 62% of deaths attributable to demographic characteristics.

Conclusion

In North American HF patients enrolled in the CHARM trials, the relative contribution of cardiac and extra‐cardiac disease burden to CV outcomes and death differed depending on LVEF. The high risk of events attributable to non‐cardiac disease burden may help explain why cardiac disease‐modifying medication proven to be efficacious in HFrEF patients has not proven beneficial in HFpEF.

     

The associations among co-morbidity,cardiac geometries and mechanics in hospitalized heart failure with or without preserved ejection fraction

Background: The associations among chronic health conditions, ventricular geometric alterations or cardiac contractile mechanics in different phenotypes heart failure (HF) remain largely unexplored. Methods: We studied 438 consecutive hospitalized patients (mean age: 64.9 ± 16.6 years, 52.5% female) with or without clinical evidence of HF. We examined the associations among clinical co-morbidities, LV geometries and systolic mechanics in terms of global myocardial strains. Results: Increasing clinical co-morbidities was associated with greater LV mass, worse longitudinal deformations and higher proportion of admission with HF diagnosis, which was more pronounced in HFpEF (from 6.4% to 40.7%, X² < 0.001). The independent association between co-morbidity burden and longitudinal functional decay remained unchanged after adjusting for age and sex for all admissions and in HFpEF (Coef: 0.82 & 0.71, SE: 0.13 & 0.21, both p≤0.001). By using co-morbidity scores, the area under receiver operating characteristic curves (AUROC) in identifying HFpEF was 0.71 (95% CI: 0.65 to 0.77), 0.64 (95% CI: 0.58 to 0.71) for HFrEF and 0.72 for both (95% CI: 0.67 to 0.77). Co-morbidity burden superimposed on LV mass index and LV filling pressure (E/E’) further expanded the AUROC significantly in diagnosing both types HF (c-statistics from 0.73 to 0.81, p for ΔAUROC: 0.0012). Conclusion: Chronic health conditions in the admission population were associated with unfavorable cardiac remodeling, impair cardiac contractile mechanics and further added significantly incremental value in HF diagnosis. Our data suggested the potentiality for better cardiac function by controlling baseline co-morbidities in hospitalized HF patients, especially HFpEF.

Abbreviations:

CAD: coronary artery disease; CKD: chronic kidney disease; DT: deceleration time; eGFR: Estimated glomerular filtration rate; HF: heart failure; IVRT: iso-volumic relaxation time; LV: left ventricular; LVEF: left ventricular ejection fraction; RWT: relative wall thickness; TDI: Tissue Doppler imaging     

Longitudinal Changes in Cardiac Troponin and Risk of Heart Failure Among Black Adults

BackgroundAmong Black adults, high-sensitivity cardiac troponin I (hs-cTnI) is associated with heart failure (HF) risk. The association of longitudinal changes in hs-cTnI with risk of incident HF, HF with reduced and preserved ejection fraction (HFrEF and HFpEF, respectively), among Black adults is not well-established.Methods and ResultsThis study included Black participants from the Jackson Heart Study with available hs-cTnI data at visits 1 (2000–2004) and 2 (2005–2008) and no history of cardiovascular disease. Cox models were used to evaluate associations of categories of longitudinal change in hs-cTnI with incident HF risk. Among 2423 participants, 11.6% had incident elevation in hs-cTnI at visit 2, and 16.9% had stable or improved elevation (≤50% increase in hs-cTnI), and 4.0% had worsened hs-cTnI elevation (>50% increase). Over a median follow-up of 12.0 years, there were 139 incident HF hospitalizations (64 HFrEF, 58 HFpEF). Compared with participants without an elevated hs-cTnI, those with incident, stable or improved, or worsened hs-cTnI elevation had higher HF risk (adjusted hazard ratio 3.20 [95% confidence interval, 1.92–5.33]; adjusted hazard ratio 2.40, [95% confidence interval, 1.47–3.92]; and adjusted hazard ratio 8.10, [95% confidence interval, 4.74–13.83], respectively). Similar patterns of association were observed for risk of HFrEF and HFpEF.ConclusionsAmong Black adults, an increase in hs-cTnI levels on follow-up was associated with a higher HF risk.Lay SummaryThe present study included 2423 Black adults from the Jackson Heart Study with available biomarkers of cardiac injury and no history of cardiovascular disease at visits 1 and 2. The majority of participants did not have evidence of cardiac injury at both visits (67.5%), 11.6% had evidence of cardiac injury only on follow-up, 14.5% had stable elevations, 4.0% had worsened elevations, and 2.4% had improved elevations of cardiac injury biomarkers during follow-up. Compared with participants without evidence of cardiac injury, those with new, stable, and worsened levels of cardiac injury had a higher risk of developing heart failure.TweetAmong Black adults, persistent or worsening subclinical myocardial injury is associated with an elevated risk of HF.     

Immune mechanisms in heart failure

Elevated levels of circulating pro‐inflammatory biomarkers in patients with both ischaemic and non‐ischaemic heart failure (HF) correlate with disease severity and prognosis. Experimental studies have shown activation of immune response mechanisms in the heart to provoke cardiac adverse remodelling and cause left ventricular dysfunction. Consequently, most of the clinical trials targeting elements of the immune response in HF attempted to modulate the inflammatory response. Surprisingly, clinical studies targeting immune effectors were either neutral or even increased pre‐specified clinical endpoints, and some studies resulted in worsening of HF. This review discusses immune mediators involved in the pathogenesis and progression of HF and potential therapeutic applications targeting inflammation in HF. Besides more obvious settings featuring immune activation such as inflammatory or ischaemic cardiomyopathy, the relevance of immune activation in acute or chronic HF of other origins, including volume overload or valvular heart disease, is highlighted. Understanding how cell‐specific and molecular mechanisms of the immune response interfere with cardiac remodelling in HF may open new avenues to design biomarkers or druggable targets.     

Acutely decompensated heart failure with preserved and reduced ejection fraction present with comparable haemodynamic congestion

Aims

Congestion is a central feature of acute heart failure (HF) and its assessment is important for clinical decisions (e.g. tailoring decongestive treatments). It remains uncertain whether patients with acute HF with preserved ejection fraction (HFpEF) are comparably congested as in acute HF with reduced EF (HFrEF). This study assessed congestion, right ventricular (RV) and renal dysfunction in acute HFpEF, HFrEF and non‐cardiac dyspnoea.

Methods and results

We compared echocardiographic and circulating biomarkers of congestion in 146 patients from the MEDIA‐DHF study: 101 with acute HF (38 HFpEF, 41 HFrEF, 22 HF with mid‐range ejection fraction) and 45 with non‐cardiac dyspnoea. Compared with non‐cardiac dyspnoea, patients with acute HF had larger left and right atria, higher E/e', pulmonary artery systolic pressure and inferior vena cava (IVC) diameter at rest, and lower IVC variability (all P < 0.05). Mid‐regional pro‐atrial natriuretic peptide (MR‐proANP) and soluble CD146 (sCD146), but not B‐type natriuretic peptide (BNP), correlated with echocardiographic markers of venous congestion. Despite a lower BNP level, patients with HFpEF had similar evidence of venous congestion (enlarged IVC, left and right atria), RV dysfunction (tricuspid annular plane systolic excursion), elevated MR‐proANP and sCD146, and renal impairment (estimated glomerular filtration rate; all P > 0.05) compared with HFrEF.

Conclusion

In acute conditions, HFpEF and HFrEF presented in a comparable state of venous congestion, with similarly altered RV and kidney function, despite higher BNP in HFrEF.

     

Epidemiology of Heart Failure with Preserved Ejection Fraction

The prevalence of heart failure (HF) and its subtype, HF with preserved ejection fraction (HFpEF), is on the rise due to aging of the population. HFpEF is convergence of several pathophysiological processes, which are not yet clearly identified. HFpEF is usually seen in association with systemic diseases, such as diabetes, hypertension, atrial fibrillation, sleep apnea, renal and pulmonary disease. The proportion of HF patients with HFpEF varies by patient demographics, study settings (cohort vs. clinical trial, outpatient clinics vs. hospitalised patients) and cut points used to define preserved function. There is an expanding body of literature about prevalence and prognostic significance of both cardiovascular and non-cardiovascular comorbidities in HFpEF patients. Current therapeutic approaches are targeted towards alleviating the symptoms, treating the associated comorbid conditions, and reducing recurrent hospital admissions. There is lack of evidence-based therapies that show a reduction in the mortality amongst HFpEF patients; however, an improvement in exercise tolerance and quality of life is seen with few interventions. In this review, we highlight the epidemiology and current treatment options for HFpEF.     

Use of sodium–glucose co‐transporter‐2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure

Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF), with recent reports indicating that HF with preserved ejection fraction (HFpEF) may be more common than HF with reduced ejection fraction (HFrEF) in patients with T2D. T2D and HF result in worse outcomes than either disease alone. Sodium–glucose co‐transporter‐2 inhibitors (SGLT‐2is) have significantly improved HF outcomes in patients with T2D and may represent a new therapeutic alternative for patients with T2D at risk for or with HF. Current guidelines recommend prevention of HF through risk factor management. Once developed, treatment of HFrEF should include neurohormonal and haemodynamic modulations; however, there are no specific treatments available for HFpEF. SGLT‐2is are the first class of glucose‐lowering therapy to prevent HF in clinical trials and real‐world studies in patients with T2D (with or without established cardiovascular disease and with or without baseline HF). Mechanistic studies suggest that SGLT‐2is have beneficial effects on both systolic and diastolic function and additional systemic effects that could benefit HF outcomes. In patients with HFrEF, SGLT‐2i treatment as add‐on to standard HF therapy has had beneficial effects on HF outcomes, irrespective of T2D status. These results and those of ongoing outcomes trials with SGLT‐2is may help establish this drug class as a treatment for HF in patients with HFrEF and HFpEF, as well as HF in patients without T2D.     

Molecular and Cellular Basis for Diastolic Dysfunction

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is frequently associated with metabolic risk factors. Patients with HFpEF have only a slightly lower mortality than patients with HF and reduced EF. The pathophysiology of HFpEF is currently incompletely understood, which precludes specific therapy. Both HF phenotypes demonstrate distinct cardiac remodeling processes at the macroscopic, microscopic, and ultrastructural levels. Increased diastolic left-ventricular (LV) stiffness and impaired LV relaxation are important features of HFpEF, which can be explained by changes in the extracellular matrix and the cardiomyocytes. In HFpEF, elevated intrinsic cardiomyocyte stiffness contributes to high diastolic LV stiffness. Posttranslational changes in the sarcomeric protein titin, affecting titin isoform expression and phosphorylation, contribute to elevated cardiomyocyte stiffness. Increased nitrosative/oxidative stress, impaired nitric oxide bioavailability, and down-regulation of myocardial cyclic guanosine monophosphate and protein kinase G signaling could trigger posttranslational modifications of titin, thereby augmenting cardiomyocyte and LV diastolic stiffness.     

Phenomapping for the Identification of Hypertensive Patients with the Myocardial Substrate for Heart Failure with Preserved Ejection Fraction

We sought to evaluate whether unbiased machine learning of dense phenotypic data (“phenomapping”) could identify distinct hypertension subgroups that are associated with the myocardial substrate (i.e., abnormal cardiac mechanics) for heart failure with preserved ejection fraction (HFpEF). In the HyperGEN study, a population- and family-based study of hypertension, we studied 1273 hypertensive patients utilizing clinical, laboratory, and conventional echocardiographic phenotyping of the study participants. We used machine learning analysis of 47 continuous phenotypic variables to identify mutually exclusive groups constituting a novel classification of hypertension. The phenomapping analysis classified study participants into 2 distinct groups that differed markedly in clinical characteristics, cardiac structure/function, and indices of cardiac mechanics (e.g., phenogroup #2 had a decreased absolute longitudinal strain [12.8?±?4.1 vs. 14.6 ± 3.5%] even after adjustment for traditional comorbidities [p?<?0.001]). The 2 hypertension phenogroups may represent distinct subtypes that may benefit from targeted therapies for the prevention of HFpEF.