Heart Failure With Preserved Ejection Fraction Phenotypes Research Articles

Abstract 4129533: Phenotypes and clinical outcome of heart failure with preserved ejection fraction (HFpEF) patients in China: Findings from the Chinese Cardiovascular Association Database-Heart Failure Center Registry

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous syndrome with 5 phenotypes. We aimed to evaluate the clinical outcome of HFpEF patients with various phenotypes in China. Methods and Results: Data from the Chinese Cardiovascular Association (CCA) Database-HF Center Registry between January 2017 and December 2021 were analyzed, 51,466 hospitalized HFpEF patients with 1-year follow-up results were included in this analysis. The patients were categorized into five phenotypes based on published phenotyping method. Clinical characteristics and 1-year outcome and related risk factors of HFpEF patients with various phenotypes were explored. Results demonstrated significant differences in baseline characteristics and clinical outcomes among the phenotypes, patients with phenotype-3 (right heart and pulmonary-related HFpEF), phenotype-4 (valvular- and rhythm-related HFpEF) and phenotype-5 (extracardiac disease-related HFpEF) exhibited high incidence of adverse outcomes. Phenotype-3 and -4 exhibited high risk of heart failure rehospitalization, whereas phenotype-5 showed high cardiovascular mortality. The independent prognostic risk factors varied across different phenotypes as well. Conclusion: One-year outcome differs among HFpEF patients with various phenotyping. Future studies are warranted to validate if personalized treatment strategies based on HFpEF phenotypes could improve the individual outcome of HFpEF patients, especially for phenotype-3, -4 and -5 HFpEF patients. Keywords: Heart failure with preserved ejection fraction, phenotype, prognosis, population study, risk factors.

Abstract 4123391: CardioMEMS and Mavacamten: A Synergistic Approach in Managing Hypertrophic Obstructive Cardiomyopathy with HFpEF Phenotype

Introduction: Mavacamten is a cardiac myosin inhibitor that has been approved for obstructive hypertrophic cardiomyopathy (oHCM). The CardioMEMS PA (pulmonary artery) sensor allows remote pulmonary artery diastolic (PAD) pressure monitoring to adjust diuresis in heart failure with preserved ejection fraction (HFpEF). We present the case of a patient with oHCM and HFpEF where data extrapolated from CardioMEMS provided valuable insight to the hemodynamic impact of cardiac myosin inhibitors. Case: A 66-year-old female with hypertension, obesity and oHCM presented with worsening dyspnea and was evaluated for septal myectomy. However, surgery was deferred because of decompensated HFpEF, as evidenced by significant leg edema on exam, and severely elevated left and right-side filling pressure, with restrictive physiology on right heart catheterization. A CardioMEMS PA sensor was implanted to guide decongestion, however, escalation of diuresis was limited due to severe left ventricular outflow tract (LVOT) obstruction. PAD remained elevated at 20-30 mmHg. Due to the refractory LVOT obstruction and despite the use of maximally tolerated beta blockers, Mavacamten was initiated and escalated according to protocol. LVOT obstruction resolved on follow up echocardiogram. Without any adjustment in her diuretic regimen, her PAD decreased to 15-20 mmHg. On follow-up visit, the patient reported improvement in dyspnea and reduction in lower extremity edema. Discussion: Managing oHCM is challenging, particularly when complicated by HFpEF. Mavacamten has shown promise in reducing LVOT gradients and improving symptoms in oHCM. However, managing fluid status in these patients can be difficult due to the risk of exacerbating LVOT obstruction while optimizing filling pressures. Our case provides direct evidence that treating LVOT obstruction with a cardiac myosin inhibitor leads to improvement in decompensated heart failure, as evidenced by the reduction in PAD. Conclusion: Addressing LVOT obstruction is key to decongesting and managing heart failure in oHCM patients. In our case, the use of CardioMEMS PA sensor system allowed a novel perspective of assessing hemodynamic impact of cardiac myosin inhibitors.

Abstract 4134456: Hybrid Cardiac Targeting Peptide Ameliorates HFpEF Phenotype in Mice

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure which is rapidly rising in incidence in the US today. Despite this, no therapies with mortality benefit exist for this syndrome. Previous work with our novel hybrid cardiac targeting peptide (hCTP), a cardiomyocyte-specific cell penetrating peptide, has shown multiple beneficial biological effects (improved calcium handling, anti-inflammatory properties) beyond its transduction abilities. Therefore, we hypothesized that treatment with hCTP in a mouse model of HFpEF would ameliorate the pathophysiology of this disease. Methods: To establish a HFpEF model, 6-week-old, C57BL/6NJ mice were placed on a high-fat diet (HFD), 60% kCal from lard, and water with 0.5 g/L of an iNOS inhibitor (N-Nitro-L-arginine methylester) to induce hypertension. After 5 weeks of the diet, HFD mice and their littermate controls underwent baseline exercise testing and echocardiograms. Exercise capacity was measured after 2 days of exercise training with 2 days of rest in between; mice were placed on a treadmill at a 10-degree angle and made to run at increasingly fast speeds (5-30 m/min) until exhaustion. Echocardiograms were performed under 1.5% inhalational isoflurane. After baseline testing, the mice were treated with vehicle, or either 2.5 or 5 mg/Kg hCTP, either 3 or 5 days a week (five groups, n = 3 per group). After four weeks of treatment, the mice were again subjected to the same battery of tests and euthanized. Data was compared using two way ANOVA with Sidak’s test to compare measurements pre- and post-treatment. Results: Treatment with hCTP at either concentration for five days/week led to an increase in running distance from 39.8 m to 116.3 m (p = 0.03, n = 6), compared to changes in control distance from 208.4 m to 157.8 m (p = 0.399). Running distance did not correlate with weight (R 2 < .001). Treatment with 5 mg/Kg hCTP for 5 days/week led to a normalization of the E/e’ ratio, from 43.3 to 26.9 (p = 0.004, n = 3) compared to a change in the control of 34.7 to 26.1 (p = 0.312). Ejection fractions remained consistent (>55%) across all groups. Conclusions: Our data suggests that hCTP appears to be a promising treatment in ameliorating some of the physiological effects in a murine model of HFpEF. Gene and protein expression studies in heart tissue are underway. Further work is warranted with a larger sample size.

Discrepancy in the Diagnosis of Heart Failure With Preserved Ejection Fraction Between Supine Versus Upright Exercise Hemodynamic Testing.

Invasive exercise right heart catheterization is a gold standard in diagnosing heart failure with preserved ejection fraction (HFpEF). Body positions during the test influence hemodynamics. However, the discrepancy in HFpEF diagnosis between exercise testing in supine versus upright position is unknown. We conducted a 2-center prospective study enrolling patients referred for exercise right heart catheterization for HFpEF. We performed a Supright protocol integrating submaximal supine bicycle ergometry (20 W) followed by maximal upright bicycle ergometry with a breath-by-breath oxygen analyzer. HFpEF hemodynamic criteria specific to testing positions were applied. Patients were considered to have concordant HFpEF if they met criteria in both positions or discordant HFpEF if they met criteria only in the supine position. Of 36 patients who met HFpEF criteria in supine position, 18 (50%) did not meet criteria in upright position (discordant HFpEF). Discordant HFpEF had less atrial fibrillation (0% versus 55%; P<0.001), lower left atrial volume (60±14 versus 77±21 mL; P=0.010), and lower H2FPEF score (2.1±1.3 versus 5.1±2.3; P<0.001). In supine position, pulmonary arterial wedge pressure was lower in discordant HFpEF at rest (15±4 versus 19±7 mm Hg; P=0.040). In upright position, pulmonary arterial wedge pressure was lower in discordant HFpEF both at rest (8±4 versus 14±6 mm Hg; P=0.002) and at peak exercise (14±4 versus 27±7 mm Hg; P<0.001). Pulmonary arterial wedge pressure/cardiac output slope was lower in discordant HFpEF (1.6±1.7 versus 3.6±2.9; P<0.001). Maximal workload (46±18 versus 49±24 W; P=0.59) or peak oxygen consumption (11.4±2.8 versus 12.9±3.4 mL/[kg·min]; P=0.15) was similar between groups. Half of patients who met HFpEF criteria in the supine position did not meet the criteria in the upright position. Patients with a discordant HFpEF phenotype had less structural and hemodynamic abnormalities compared with those with concordant HFpEF. A Supright exercise right heart catheterization approach is feasible and merits further investigation to determine the clinical implications of discordant exercise hemodynamic findings in supine and upright positions.

NCOR1 orchestrates macrophage inflammation in heart failure with preserved ejection fraction: a translational study

Abstract Background/Introduction Inflammatory response is a key player in heart failure with preserved ejection fraction (HFpEF) but the underlying mechanisms are poorly understood. Recent studies have shown a critical involvement of cardiac macrophage activation in myocardial remodeling thus contributing to HFpEF. Purpose To investigate the role of cardiac macrophage inflammation in experimental and human HFpEF. Methods We employed a translational approach combining human and murine LV myocardial tissue, FACS analysis of cardiac immune cells, in vitro experiments in RAW 264.7 cells exposed to metabolic stress by palmitic acid (PA), bone marrow-derived macrophages from healthy and HFpEF mice, cardiomyocytes (H9c2), endothelial cells (HAECs) as well as ex vivo functional analyses in LV tissues. Human LV myocardial samples were used to evaluate the pro-inflammatory activity of macrophages in the HFpEF myocardium. Induction of HFpEF in mice was done through a validated mouse model combining metabolic (high-fat diet) and hemodynamic stress (L-NAME). Cardiac function was investigated by high resolution ultrasound imaging (Vevo3100) and the LV myocardial samples were used to study the macrophage polarization and their inflammatory activity. Based on interrogation of available RNA-seq datasets – showing the transcriptional repressor NCOR1 as a relevant signature in macrophages during cardiac inflammation, we generated myeloid cell-specific NCOR1 knockout (Ncor1-KO) transgenic mice to investigate the in vivo effects of NCOR1 deletion on the HFpEF phenotype. Results The expression of macrophage markers in human LV specimens showed an increase in pro-inflammatory macrophages (M1) and a decrease in regulatory macrophages (M2) as compared to age-matched control mice. HFpEF mice showed increased expression of vascular adhesion molecules (ICAM1, ICAM2, E-selectin) and a significant recruitment of M1 macrophages as proved by qPCR, WB, and flow cytometry analysis. Of interest, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) – and lung congestion were significantly reduced in mice with macrophage NCOR1 deletion as compared to WT littermates, while exercise tolerance was significantly improved. These findings were associated with a reduction of myocardial inflammation (TNF-a, IL6, IL-1b) in Ncor1-KO mice. In vitro assays showed that stimulation of macrophages with PA induced M1 type switch and increased NCOR1, TNF-a, IL-6, and IL-1b levels, whereas NCOR1 depletion prevented detrimental changes of macrophage secretome (Fig.2). Conclusion NCOR1 is a crucial regulator of immune response and macrophage inflammation in the heart. Our findings highlight its potential as a target for therapies aimed at preventing myocardial damage in HFpEF.

Obesity plays a key role in inducing myocardial and vascular dysfunction in a translational model of heart failure with preserved ejection fraction in rats

Abstract Background Exploring experimental models of heart failure with preserved ejection fraction (HFpEF) may help to understand the mechanisms leading to this challenging condition. Purpose In a translational model, we aimed to assess the relative contribution of hypertension and obesity in inducing structural, functional and hemodynamic changes associated to the HFpEF phenotype. Methods We investigated 3 groups of male 40 weeks old rats: control Wistar Kyoto (WKY, n=10), Spontaneous Hypertensive Rats (SHR, n=10) and SHR with obesity induced by consumption of cafeteria diet during 28 weeks (Ob-SHR, n=9). Animals were submitted to assessment of: body weight, systolic (SBP) and diastolic (DBP) blood pressure; in vivo structural and functional changes evaluated by high resolution Echocardiography including left atrial dimension (LA), left ventricle (LV) diastolic dimension (LVDD), LV posterior wall thickness (LVPW), LV wall relative thickness (LVWRT), LV ejection fraction (LVEF). Invasive hemodynamic evaluation assessed the intraventricular pressure curves obtaining LV end diastolic pressure (LVEDP) and calculation of LV diastolic time constant (Tau). After euthanasia, thoracic aorta was used for vascular function assessment by measuring the maximal cumulative concentration-effect curves of contraction to phenylephrine (PE), expressed as Emax (%). Protein expression of Intercellular Adhesion Molecule 1 (ICAM-1) was determined in myocardial tissue (% in relation to WKY). Results were expressed as mean ± SEM and effects of groups vs time were compared with mixed ANOVA. Results The results are shown in the table. We observed higher levels of SBP and DBP in SHR and Ob-SHR when compared to WKY, but with similar values between SHR and Ob-SHR groups. Regarding the structural LV changes, we observed LV remodeling and LA dilation in both SHR and Ob-SHR groups, but with no difference between both hypertensive groups. The Ob-SHR was the only group showing increased LVEDP in comparison to other groups. The Tau was also increased in the Ob-SHR animals. Concordantly, the Ob-SHR group showed increased expression of ICAM-1 (figure - A) that was concomitant to abnormal vascular response with increased contraction to PE (figure - B) as compared to SHR and WK groups. Conclusions In this translational model of HFpEF in rats, the structural changes related to LV remodeling were similar in SHR and Ob-SHR, probably reflecting comparable higher levels of blood pressure observed in both groups. In contrast, elevated EDP, a hallmark of HFpEF, was only seen in the Ob-SHR group and this was concomitant to diastolic dysfunction, endothelial inflammatory activation and altered vascular function. Our results indicate that obesity is a key factor inducing vascular and myocardial changes that triggers HFpEF phenotype in this model.

Left atrial remodeling and novel biomarkers in obese patients with heart failure with preserved ejection fraction compared to type-2-diabetics and obese controls: a cardiac magnetic resonance study

Abstract Background Elevated filling pressures and subsequent left atrial (LA) dilation are common findings in heart failure with preserved ejection fraction (HFpEF), reflecting a chronic state of the disease and holding prognostic value. HFpEF is thought to develop through a long-term pro-inflammatory state triggered by comorbidities, such as obesity and type 2 diabetes mellitus (T2DM). Emerging biomarkers have shown associations with structural remodeling, but also increased myocardial stiffness. Purpose To elucidate the relationship between LA volume and function, and prognostic biomarkers (NT-proBNP, BNP-32, IL1R1, Galectin-3, and Pentraxin-3) in an obese cohort with T2DM or HFpEF and T2DM, versus healthy obese controls. Methods We conducted a prospective cohort study of 35 obese participants, divided into three groups: T2DM (n=16), HFpEF with T2DM (NYHA II-III, n=13), and healthy obese controls (n=6). Each subject underwent comprehensive CMR at a 3T scanner to assess LA strain and volume. Atrial strain was assessed on 2- and 4-chamber view cine images by experienced CMR investigators using dedicated software. Routine labs and serum levels of biomarkers were measured. If labs or images were repeated, the average was calculated. Statistical significance was determined through ANOVA and student’s t-test for group comparisons and Pearson correlation for associations between LA parameters and biomarker levels. Results Cohorts were evenly matched in terms of demographics, vital signs, and ventricular volumes and functions, as depicted in Table 1. Only one patient in the HFpEF subgroup reported history of atrial fibrillation. Both minimum and maximum LA volumes were significantly elevated in the HFpEF group compared to the T2DM and control groups (p &amp;lt; 0.018). LA strain (conduit, reservoir, and booster) was notably compromised in the HFpEF cohort, contrasting with the obese T2DM group where LA strain values did not differ significantly from those observed in obese controls (Figure 1). Biomarker analysis revealed a marked increase of NT-proBNP, BNP-32, Galectin-3, and Pentraxin-3 in the HFpEF cohort. In the HFpEF cohort, IL1R1 was the only biomarker that was strongly associated with higher left ventricular enddiastolic (r=0.69, p=0.003) and endsystolic volumes (r=0.75, p=0.009). Moreover, IL1R1 was the only biomarker associated with atrial functional changes (booster strain, r=-0.57, p=0.043) in the HFpEF patients. Our findings indicate that ILR1 plays a crucial role in the cardiometabolic (obesity-T2DM) HFpEF phenotype, with its activation leading to advanced cardiac remodeling. Conclusion Obese HFpEF patients with T2DM showed severely altered left atrial morphology and function compared to those that are only obese or obese with T2DM. Moreover, our findings revealed that atrial remodeling in this population is driven by pro-fibrotic inflammatory pathways.Characteristics of the study cohortLeft atrial strain analysis

Moderate intensity exercise training ameliorates the heart failure with preserved ejection fraction phenotype in a preclinical model by improving cardiometabolic fitness

Abstract Introduction and Aim Exercise intolerance is a hallmark feature of patients with heart failure with preserved ejection fraction (HFpEF).While clinical evidence suggests potential benefits of exercise training in HFpEF, its mechanisms remain largely unknown.In this study, we used a translationally relevant murine model of cardiometabolic HFpEF(1) to assess whether moderate intensity continuous training(MICT) can ameliorate the HFpEF phenotype in mice and promote cardiometabolic health. Methods Twenty-five adult, male C57BL/6N were fed with the combination of high fat diet(HFD;D12492,Research diet)and L-NAME(0.5 g/L,in drinking water) for 15 weeks to elicit HFpEF as previously described(1).After the establishment of the HFpEF phenotype, mice were randomized in two groups:sedentary(SED,n= 10) and exercised(MICT,n=15)mice.MICT was carried out according to the protocol:running on 10-degree positive inclination treadmill for 8 consecutive weeks,5 times/week,60 minutes/day,at a speed gradually increasing from 0.1 to 0.2 m/sec on a weekly basis.Morphometry, echocardiography(TTE),isoproterenol-induced stress echocardiography(SE),time domain nuclear magnetic resonance, and treadmill exhaustion tests were performed at the beginning and end of MICT.Additionally, at the end of MICT blood and tissues were collected for proteomics analysis(Fig1).Non-trained male C57BL/6N mice(37w) were used as controls for the HFpEF mice. Results Before randomization, all HFpEF mice were similar in terms of phenotypic characteristics. Compared to SED mice, MICT induced a significantly decrease in body weight driven by a reduction of total fat mass with an increased in lean mass(Fig2A+B).Interestingly, MICT had no impact on skeletal muscle mass for all different muscle groups evaluated (extensor digitorum longus, soleus and tibialis anterior).Importantly, MICT led to a significant improvement in exercise capacity in HFpEF mice, as shown by increased running distance and time, surpassing even the running distance seen in non-HFpEF mice (SED:62.8±18.7,MICT:305.7±13.9,non-HFpEF mice: 129.72±15.2meters,p&amp;lt;0.001).Preclinical surrogate of HFpEF such as pulmonary congestion, evaluated by index lung weights, improved after aerobic training.Following MICT there was a marked improvement in diastolic dysfunction(measured by E/E’ratio) both at rest(SED:36.5±3.3,MICT:23.3±5.09,p&amp;lt;0.001) and after isoproterenol challenge(SED:42.6±15.1,MICT:26.09±3.75,p&amp;lt;0.001)(Fig2C).Moreover, the wet cardiac mass was lower in the MICT group(Fig2A), suggesting potential amelioration in cardiac hypertrophy following aerobic training. Conclusion Eight weeks of supervised MICT on treadmill improves functional status, exercise capacity, and diastolic function in a cardiometabolic HFpEF murine model.The most significant effects were seen on weight loss and fat mass reduction.Our findings suggest a beneficial impact of aerobic exercise in mitigating HFpEF by improving metabolic fitness in the preclinical HFpEF model.Fig1-Study DesignFig2-Characteristics SED vs MICT groups

Real-world evidence for patient phenotypes in heart failure with preserved ejection fraction

Abstract Background Heart failure (HF) with preserved ejection fraction (HFpEF) presents a high mortality risk due to its heterogeneous and multifactorial nature, coupled with limited treatment options. The incompletely understood pathophysiology is influenced by various comorbidities, resulting in different clinical phenotypes. Identifying these could be crucial for tailored HFpEF treatments. While previous studies focused on small, well-characterized patient populations, electronic health records (EHRs) offer the potential to unveil HFpEF phenotypes in larger real-world patient groups. Purpose We aimed to establish a sizable, unselected HFpEF patient population using real-world data. Employing cluster analysis, we intended to uncover distinct groups with varied disease aetiology and medical needs based on comorbidity profiles and prognoses. Methods From EHRs of n = 1,610,101 HF patients, we identified an HFpEF cohort of n = 32,009 patients, by applying thresholds for the LVEF and data availability, and by excluding confounding conditions. Clustering by the relative frequency of common comorbidities aimed to reveal patient populations with unique prognoses, comorbidity profiles, and clinical and demographic characteristics. Results Six clusters of different sizes, comorbidity prevalence, clinical presentation, and all-cause mortality were identified. About 50% of patients (n = 15,445) were predominantly hypertensive, with varying extents of coronary heart disease and diabetes mellitus (DM), and a 5-year mortality of about 30%. Around 22% (n = 7,089) exhibited a cardiometabolic comorbidity profile, with an increased prevalence of obesity and sleep apnea, but also DM and hypertension, and a 5-year mortality of 22.5%. Over 15% of patients (n = 5,298) had a 5-year mortality rate of 45.0%, marked by highest rates of anaemia and chronic kidney disease (CKD) but also DM, elevated N-terminal prohormone of brain natriuretic peptide levels, and a reduced estimated glomerular filtration rate. Conclusion Despite the favourable prognosis, a significant proportion of patients represent a cardiometabolic HFpEF phenotype with notable unmet medical needs regarding cohort size and multimorbidity. Patients simultaneously suffering from CKD, anaemia, and the highest mortality rates may represent a previously underrecognized phenotype. Our study demonstrates that distinct medical needs can be identified in a large, unselected real-world HFpEF cohort. In contrast to clinical trials, this approach enabled access to a broader patient population, revealing novel phenotypes to be targeted by precision medicine in the future.

Performance of an automated echocardiographic artificial intelligence model. to detect subclinical heart failure with preserved ejection fraction (HFpEF) in community-dwelling older adults

Abstract Background Heart failure (HF) with preserved Ejection Fraction (HFpEF) is common among older adults and associated with a high burden of morbidity and mortality. Early identification of subclinical HFpEF, defined by abnormalities in cardiac structure and function without symptoms of HF, can prompt early initiation of evidence-based therapies to prevent HFpEF. However, scalable strategies for the identification of subclinical HFpEF are lacking. Purpose To evaluate the performance of a validated, automated echocardiographic artificial Intelligence algorithm (Ultromics, UK) to identify subclinical HFpEF among community-dwelling individuals without HF. Methods The study included participants of the Dallas Hearts and Minds Study without HF who underwent cardiovascular phenotyping with resting and exercise echocardiography and maximal cardiopulmonary exercise testing. The resting apical 4C echocardiographic images were analyzed by the AI echo algorithm to identify the HFpEF phenotype (AI-HFpEF). Subclinical HFpEF was defined by E/e’ &amp;gt;14 and Peak exercise oxygen uptake (VO2peak) &amp;lt;25th percentile for the cohort. The performance of the AI algorithm to detect subclinical HFpEF was determined using the area under the receiver operating curve and decision curve analysis and was compared with the previously validated H2FpEF score. The association between the AI-HFpEF phenotype and the presence of subclinical HFpEF, VO2peak, exercise E/e’, left ventricular strain, and left atrial strain was assessed using multivariable-adjusted logistic and linear regression models. Results The study included 511 participants (mean age: 61 y, 57% women, mean VO2peak = 16.9 ml/kg/min). Using the AI echo algorithm, subclinical HFpEF was detected in 10% of participants (n=76), and 10% were non-diagnostic. The participants with (vs. without) AI-HFpEF phenotype were older and had a higher burden of CVD risk factors, left ventricular hypertrophy, and left atrial dilation. Subclinical HFpEF, as defined by the gold standard criteria, was present in 5.3% of participants. The AUROC for diagnosis of subclinical HFpEF using the AI-HFpEF algorithm was 0.85 vs. 0.78 by the H2FpEF score (see Figure). In the adjusted analysis, the AI-HFpEF phenotype was significantly associated with greater odds of subclinical HFpEF by exercise and echocardiographic phenotyping criteria, higher E/e’ with exercise, lower VO2 peak, and worse LV and LA strain (see Table). In decision curve analysis, the AI-HFpEF algorithm identified 23 additional cases of subclinical HFpEF per 1000 screened participants compared with the H2FpEF score. Conclusion The AI-HFpEF algorithm can reliably identify community-dwelling individuals with subclinical HFpEF characterized by diastolic dysfunction at rest or exercise and impaired exercise capacity. Future studies are needed to assess the utility of the AI-HFpEF algorithm in screening for subclinical HFpEF in health systems.

Albuminuria is associated with progression of diastolic dysfunction in patients at risk for cardiovascular disease

Abstract Background The number of the patients with heart failure with preserved ejection fraction (HFpEF) is increasing as society ages, which indicates that the number of pre-HFpEF patients is increasing even more. To combat this sociomedical burden, it is critical to establish cost-effective and simple biomarkers to identify the high-risk population at early phase of the disease. Recent studies demonstrated the association between albuminuria and incident heart failure, but the prognostic impact of albuminuria on diastolic dysfunction, an early phenotype of HFpEF, has not been elucidated. Purpose To examine the impact of albuminuria on the diastolic function over time in the patients with cardiovascular risks. Methods One hundred and fifty-eight patients with at least one cardiovascular risk factor without history of heart failure were followed up for 5 years. Echocardiogram was conducted at baseline, year 3, and year 5. Diastolic dysfunction was defined as E/e’ &amp;gt;14. Albuminuria was defined as urine albumin-to-creatinine ratio (UACR) 30 ≧mg/gCre. The patients with ejection fraction &amp;lt;40% and those had diastolic dysfunction at baseline were excluded from the study. The relationship between albuminuria at baseline and diastolic function at year 3 and 5 were investigated. Results Among 158 subjects, 27 showed albuminuria at baseline and the prevalence of hypertension, dyslipidemia, and diabetes was not significantly different between patients with and without albuminuria. The baseline E/e’ tended to be higher in patients with albuminuria, although the difference was not statistically significant (Fig1: E/e’ = 10.0±2.4 vs. 9.4±2.2, p = 0.08) . However, the patients with albuminuria showed a steeper increase in E/e’ than those without albuminuria, and the significant difference was observed at year 3, that was even greater at year 5 (Fig1: E/e’ = 11.1±2.8 vs 10.0±2.6, p = 0.04 in year 3, E/e’ = 12.5±4.1 vs 10.3±2.9, p = 0.002 in year 5, respectively). Furthermore, log UACR at baseline showed significant correlation with E/e’ at year 5 (p = 0.02, r = 0.21) and normo-, micro-, and macroalbuminuria (UACR&amp;lt;30, 30-300, and &amp;gt;300mg/gCre, respectively) at baseline showed elevated E/e’ at year 5 in this order ( p = 0.01 for UACR&amp;lt;30 vs. 30-300mg/gCre, and p = 0.04 for UACR&amp;lt;30 vs. &amp;gt;300mg/gCre, reapectively ). The prevalence of incident diastolic dysfunction increased greater in patients with albuminuria throughout the follow-up period and the difference reached statistical significance at year 5 (Fig2: 18.5% vs. 9.2%, p = 0.28 for year 3, and 25.9% vs. 8.4%, p = 0.009 for year 5, respectively). Conclusion In the patients with cardiovascular risk factors, albuminuria was associated with development and progression of diastolic dysfunction over subsequent 5 years. Future prospective study is warranted to investigate the effectiveness of albuminuria-directed care to prevent development of HFpEF.

Gradual hypertensive response in aortic alterations and myocardial inflammatory activation in progressing HFpEF in mice

Abstract Introduction Hypertension is the most common comorbidity in patients affected by heart failure with preserved ejection fraction (HFpEF). Early effects of pressure overload and its contribution to the gradual development of cardiac and vascular pathology leading to HFpEF are not well recognized, as patients are diagnosed when the disease has already advanced and show symptoms. Several hypertensive HFpEF mouse models possessing the hallmarks of the clinical-like phenotype are available. Nonetheless, initial and gradual pathological manifestations of hypertensive HFpEF have not been comprehensively described. Purpose This study aimed to investigate the gradual progression of HFpEF phenotype development in mice from the early manifestation of cardiac and vascular pathology to global cardiac dysfunction to multiorgan syndrome in response to hypertension. Methods Hypertensive HFpEF was induced by angiotensin II infusion in C57BL/6JOlaHsd 18-20-week-old male mice that were given low, moderate and high doses (0.5mg/kg/day - 1.5 mg/kg/day) subcutaneously for 4 weeks. Cardiac physiology and alterations in haemodynamics were assessed with echocardiography of heart and aorta, weekly ECG monitoring, and blood pressure measurements from the mouse tail. Extensive histology and immunohistochemistry analyses of cardiac tissue, microvasculature, lungs and kidneys were performed. Results In the low dose group, loss of aortic wall flexibility and presence of aortic root dilatation were detected. This group also demonstrated initiation of concentric remodelling process with the upsurge in macrophage infiltration in myocardium, but the signs of diastolic dysfunction were not yet present. The high dose group exhibited characteristic HFpEF features with diastolic dysfunction, left ventricular hypertrophy and fibrosis. Pathology in cardiac conduction system was noticed in all groups, with prominent ECG waveform abnormalities already on week one. However, only the high dose group experienced non-recovery in impulse propagation, accompanied by significant prolongation of ventricular depolarization. Conclusion This study demonstrates that change in aortic root dimensions and aortic wall dynamics are the first hypertension-sensitive alterations together with myocardial inflammatory cell infiltration that may contribute to myocardial remodelling and subsequent development of HFpEF and systemic effects. Hypertensive angiotensin II-induced HFpEF is a relevant mouse model, recapitulating not only hallmarks of cardiac pathology but also an extensive range of vascular and multiorgan alterations, demonstrating similarities with the clinical phenotype.

Mineralocorticoid receptor antagonists and heart failure with preserved ejection fraction: current understanding and future prospects.

The mineralocorticoid receptor (MR), part of the steroid hormone receptor subfamily within nuclear hormone receptors, is found in the kidney and various non-epithelial tissues, including the heart and blood vessels. When improperly activated, it can contribute to heart failure processes such as cardiac hypertrophy, fibrosis, stiffening of arteries, inflammation, and oxidative stress. MR antagonists (MRAs) have shown clear clinical benefits in patients with heart failure with reduced ejection fraction (HFrEF). However, in cases of heart failure with preserved ejection fraction (HFpEF), there is considerable diversity due to its complex underlying mechanisms, resulting in conflicting findings regarding the effectiveness of MRAs in relevant studies. The concept of phenomapping presents an encouraging avenue for investigating different intervention targets and novel therapies for HFpEF. Post hoc analysis of the TOPCAT trial identified certain HFpEF phenotypes that responded favorably to spironolactone. Growing clinical and preclinical evidence suggests that non-steroidal MRAs, which exhibit greater receptor selectivity, stronger anti-fibrotic and anti-inflammatory properties, and fewer hormone-related side effects, may emerge as another promising treatment option for HFpEF alongside sodium-glucose co-transporter 2 (SGLT2) inhibitors. This review aims to outline the structural and functional characteristics of MR, discuss the physiological effects of its activation and inhibition, and delve into the potential for personalized MRA therapy based on the concept of HFpEF phenotype.

Single-cell transcriptomics reveal distinctive patterns of fibroblast activation in heart failure with preserved ejection fraction

AbstractInflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease-specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF-specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global-longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.

Lifestyle interventions in cardiometabolic HFpEF: dietary and exercise modalities.

Heart failure with preserved ejection fraction (HFpEF) is rapidly growing as the most common form of heart failure. Among HFpEF phenotypes, the cardiometabolic/obese HFpEF - HFpEF driven by cardiometabolic alterations - emerges as one of the most prevalent forms of this syndrome and the one on which recent therapeutic success have been made. Indeed, pharmacological approaches with sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have proved to be effective due to metabolic protective effects. Similarly, lifestyle changes, including diet and exercise are crucial in HFpEF management. Increasing evidence supports the important role of diet and physicalactivity in the pathogenesis, prognosis, and potential reversal of HFpEF. Metabolic derangements and systemic inflammation are key features of HFpEF and represent the main targets of lifestyle interventions. However, the underlying mechanisms of the beneficial effects of these interventions in HFpEF are incompletely understood. Hence,there is an unmet need of tailored lifestyle intervention modalities for patients with HFpEF. Here we present the current available evidence on lifestyle interventions in HFpEF management and therapeutics, discussing their modalities and potential mechanisms.

The oxytocin-oxytocin receptors system — a new pathogenetic mechanism in the development of diabetic phenotype of heart failure with preserved ejection fraction in women

Aim. To determine the pathogenetic role of the oxytocinergic system in the development of myocardium structural and functional changes in women with heart failure with preserved ejection fraction (HFpEF) associated with type 2 diabetes mellitus (DM2T) (diabetic phenotype of HFpEF).Material and methods. The study included 60 women aged 67.0±4.9 years with HFpEF stage I-IIA, FC I-III, 30 of them had DM2T who were admitted for elective coronary artery bypass grafting. The development of HFpEF is caused by coronary artery disease (CAD) and arterial hypertension (AH). Prior to surgery, all patients underwent a standard examination, blood levels of NT-proBNP, oxytocin (Ox), echocardiography were determined to find the types of left ventricular (LV) myocardial remodeling and diastolic dysfunction (DD). Myocardium biopsies of the right atrium auricle obtained during coronary bypass surgery were studied by microscopy, morphometry and immunohistochemistry (the expression of oxytocin receptors (OxR), a marker of proliferation ki-67).Results. According to echocardiography, eccentric LV hypertrophy (46.7/36.7%) and DD type 2 (47/17%, p=0.003) prevailed in the group of women with the diabetic phenotype of HFpEF. A higher content of NT-proBNP (480.72±241.87/434.46±282.78 ng/ml, p=0.06) and a lower concentration of Ox (102.11±35.89/320.37±294.71 pg/ml, p=0.0016) in blood serum were established, as well as an increase in the number of cardiomyocytes (CMC) with a high expression level OxR (63.69±19.47/12.16±23.09%, p=0.000) in patients with the diabetic phenotype of HFpEF. Negative associations were determined between the blood level of Ox and the CMC diameter (r=-0.10, p=0.020), the area of their cytoplasm (r=-0.16, p=0.000) and the area of the nuclei (r=-0.11, p=0.015) in patients of both groups. A decrease in Ox concentration in the blood of patients with diabetic phenotype of HFpEF was accompanied by an increase in the number of CMCs with a high level of OxR expression (r=-0.63, p=0.000).Conclusion. The study has shown the important involvement of oxytocinergic signaling pathways in the HFpEF pathogenesis. HFpEF associated with DM2T in women was characterized by more unfavorable structural and functional changes in the myocardium, a significant increase in the number of hypertrophied CMCs with a high level of OxR expression and Ox decrease in blood serum. The mechanisms of the first-established significant increase in the content of Ox in the blood of patients with HFpEF without diabetes and its significant decrease in patients with diabetic phenotype of HFpEF leading to more pronounced structural and functional changes in the myocardium, require further study.

Vitamin B-6 Prevents Heart Failure with Preserved Ejection Fraction Through Downstream of Kinase 3 in a Mouse Model

BackgroundThere is an urgent need to develop an efficient therapeutic strategy for heart failure with preserved ejection fraction (HFpEF), which is mediated by phenotypic changes in cardiac macrophages. We previously reported that vitamin B-6 inhibits macrophage-mediated inflammasome activation. ObjectivesWe sought to examine whether the prophylactic use of vitamin B-6 prevents HFpEF. MethodsHFpEF model was elicited by a combination of high-fat diet and Nω-nitro-l-arginine methyl ester supplement in mice. Cardiac function was assessed using conventional echocardiography and Doppler imaging. Immunohistochemistry and immunoblotting were used to detect changes in the macrophage phenotype and myocardial remodeling-related molecules. ResultsCo-administration of vitamin B-6 with HFpEF mice mitigated HFpEF phenotypes, including diastolic dysfunction, cardiac macrophage phenotypic shifts, fibrosis, and hypertrophy. Echocardiographic improvements were observed, with the E/E' ratio decreasing from 42.0 to 21.6 and the E/A ratio improving from 2.13 to 1.17. The exercise capacity also increased from 295.3 to 657.7 min. However, these beneficial effects were negated in downstream of kinase (DOK) 3-deficient mice. Mechanistically, vitamin B-6 increased DOK3 protein concentrations and inhibited macrophage phenotypic changes, which were abrogated by an AMP-activated protein kinase inhibitor. ConclusionsVitamin B-6 increases DOK3 signaling to lower risk of HFpEF by inhibiting phenotypic changes in cardiac macrophages.

Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with increased myocardial stiffness and cardiac filling abnormalities. Prior studies implicated increased α-tubulin detyrosination, which is catalyzed by the vasohibin enzymes, as a contributor to increased stabilization of the cardiomyocyte microtubule network (MTN) and stiffness in failing human hearts. We explored whether increased MTN detyrosination contributed to impaired diastolic function in the ZSF1 obese rat model of HFpEF and designed a small-molecule vasohibin inhibitor to ablate MTN detyrosination in vivo. Compared with ZSF1 lean and Wistar Kyoto rats, obese rats exhibited increased tubulin detyrosination concomitant with diastolic dysfunction, left atrial enlargement, and cardiac hypertrophy with a preserved left ventricle ejection fraction, consistent with an HFpEF phenotype. Ex vivo myocardial phenotyping assessed cardiomyocyte mechanics and contractility. Vasohibin inhibitor treatment of isolated cardiomyocytes from obese rats resulted in reduced stiffness and faster relaxation. Acute in vivo treatment with vasohibin inhibitor improved diastolic relaxation in ZSF1 obese rats compared with ZSF1 lean and Wistar Kyoto rats. Vasohibin inhibition also improved relaxation in isolated human cardiomyocytes from both failing and nonfailing hearts. Our data suggest the therapeutic potential for vasohibin inhibition to reduce myocardial stiffness and improve relaxation in HFpEF.

Comparison of clinical characteristics and prognostic factors in patients with heart failure with preserved ejection fraction with and without renal dysfunction.

Heart failure with preserved ejection fraction (HFpEF) with renal dysfunction (RD) is considered to be a specific phenotype of HFpEF. This study aimed to compare the clinical characteristics and prognostic factors for in-hospital mortality between HFpEF-diagnosed patients with and without RD. This multicenter retrospective study included 5867 consecutive patients with acute HFpEF. RD was defined by an estimated glomerular filtration rate (eGFR) of <60 mL/min per 1.73 m2. Kaplan-Meier survival curves and log-rank tests were used to compare the in-hospital mortality between the groups. Univariable and multivariable Cox regression analyses were performed to identify significant prognostic factors. Across the study cohort, 68% of patients had RD. In-hospital mortality was significantly higher in HFpEF patients with RD than in those without RD. The comorbidities and laboratory data differed significantly between the groups. Independent prognostic factors for in-hospital mortality in the HFpEF patients with RD were age (hazard ratio [HR], 1.039), systolic blood pressure (HR, 0.991), eGFR (HR, 0.981), C-reactive protein (CRP; HR, 1.028), diuretics (HR, 0.374), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACE-I/ARBs; HR, 0.680), and beta-blockers (HR, 0.662). In HFpEF patients without RD, age (HR, 1.039), systolic blood pressure (HR, 0.979), and ACE-I/ARBs (HR, 0.373) were independent prognostic factors. Significant differences in the clinical characteristics and prognostic factors, such as CRP and beta-blockers, were observed between the HFpEF patients with and without RD. These results have implications for future research and may help guide individualized patient management strategies.

Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway.

Heart failure with preserved ejection fraction (HFpEF) is closely associated with metabolic derangement. Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) exert anti-HFpEF effects, but the underlying mechanisms remain unclear. In this study, we explored the anti-HFpEF effects of empagliflozin and liraglutide and the underlying molecular mechanisms in a mouse model of HFpEF. This model was established by high-fat diet (HFD) feedingplus Nω-nitro-L-arginine methyl ester (L-NAME) treatment. The mice were treated with empagliflozin (20 mg·kg-1·d-1, i.g.) or liraglutide (0.3 mg·kg-1·d-1, i.p.) or their combination for 4 weeks. At the end of the experimental protocol, cardiac function was measured using ultrasound, then mice were euthanized and heart, liver, and kidney tissues were collected. Nuclei were isolated from frozen mouse ventricular tissue for single-nucleus RNA-sequencing (snRNA-seq). We showed that administration of empagliflozin or liraglutide alone or in combination significantly improved diastolic function, ameliorated cardiomyocyte hypertrophy and cardiac fibrosis, as well as exercise tolerance but no synergism was observed in the combination group. Furthermore, empagliflozin and/or liraglutide lowered body weight, improved glucose metabolism, lowered blood pressure, and improved liver and kidney function. After the withdrawal of empagliflozin or liraglutide for 1 week, these beneficial effects tended to diminish. The snRNA-seq analysis revealed a subcluster of myocytes, in which Erbb4 expression was down-regulated under HFpEF conditions, and restored by empagliflozin or liraglutide. Pseudo-time trajectory analysis and cell-to-cell communication studies confirmed that the Erbb4 pathway was a prominent pathway essential for both drug actions. In the HFpEF mouse model, both empagliflozin and liraglutide reversed Erbb4 down-regulation. In rat h9c2 cells, we showed that palmitic acid- or high glucose-induced changes in PKCα and/or ERK1/2 phosphorylation at least in part through Erbb4. Collectively, the single-cell atlas reveals the anti-HFpEF mechanism of empagliflozin and liraglutide, suggesting that Erbb4 pathway represents a new therapeutic target for HFpEF. Effects and mechanisms of action of empagliflozin and liraglutide in HFpEF mice. HFpEF was induced with a high-fat diet and L-NAME for 15 weeks, and treatment with empagliflozin and liraglutide improved the HFpEF phenotype. Single nucleus RNA sequencing (snRNA-seq) was used to reveal the underlying mechanism of action of empagliflozin and liraglutide.