Heart Failure And Preserved Ejection Fraction Research Articles

Abstract 14559: Anti-Arrhythmic Effects of Exosomes Isolated From Cardiosphere-Derived Cells in Rats With Heart Failure and Preserved Ejection Fraction

Introduction: Cardiosphere-derived cells (CDCs) reverse electrical remodeling and reduce inducible ventricular arrhythmias in rats with heart failure and preserved ejection fraction (HFpEF). Exosomes isolated from CDCs (CDCexo) have anti-arrhythmic effects in various animal models but have not been tested in models of HFpEF. Hypothesis: CDCexo, when given intravenously, reverse electrical remodeling and reduce spontaneous ventricular arrhythmias in rats with HFpEF. Methods: Dahl salt-sensitive rats were fed high-salt diet (containing 8% NaCl) to induce HFpEF from 7 weeks of age. Ambulatory electrocardiogram (ECG) devices were implanted in the peritoneum at 13 weeks of age to monitor spontaneous ventricular arrhythmias. Exosomes were harvested from media conditioned by human CDCs after 48 hours of exposure to hypoxia. Echocardiogram-verified HFpEF rats (at 14 weeks of age) were injected via tail vein with human CDCexo (n=8) vs. vehicle (IMDM media, n=8) weekly for 4 weeks. ECG parameters and spontaneous development of ventricular arrhythmias were compared between the two groups. Results: QTc interval was reduced in CDCexo-injected HFpEF rats compared to vehicle-injected HFpEF rats (262±15 ms vs. 287±25 ms, p=0.0001). Two of the eight HFpEF rats injected with vehicle showed a maximal premature ventricular contraction (PVC) burden per minute of 50% while only one HFpEF rat injected with CDCexo manifested 25% maximal PVC burden per minute. Five of eight HFpEF rats injected with vehicle showed non-sustained ventricular tachycardia (VT) while only one HFpEF rat infused with CDCexo developed non-sustained VT. One rat in the vehicle group undergoing telemetry monitoring died suddenly and the cause of death was sustained VT degenerating into ventricular fibrillation (VF). The number of VT/VF episodes per rat (including non-sustained VT and sustained VT/VF) was reduced in the CDCexo group compared to the vehicle group (0.4 [0-3] vs. 13 [0-56] episodes per rat, p=0.0443). Conclusions: CDCexo recapitulated the beneficial effects of CDCs in HFpEF rats: reversing electrical remodeling and reducing ventricular arrhythmias. More importantly, an intravenous delivery route was effective for CDCexo to confer their salutary effects to rats with HFpEF.

Abstract 13669: Ascending Aortic Augmentation Pressure Does Not Decrease During Exercise in HFpEF: Implications for SV Reserve Impairment

Aortic augmentation pressure (aAP; difference between first [aP1] and second [aP2] peaks of the aortic pressure waveform) decreases during exercise in young healthy individuals, lowering mid-late systolic afterload, an important determinant of cardiac work and stroke volume (SV). In patients with heart failure and preserved ejection fraction (HFpEF), SV responses to exercise (i.e. SV reserve) are often abnormal (≤ 50%). A lack of fall in aAP during exercise in HFpEF could contribute to impairments in SV reserve. Therefore, we studied 15 HFpEF patients (age, 71 ± 6 years; 10 women; BMI 39.2 ± 6.2 kg/m 2 ) in the seated upright position. During rest and six-minutes of cycling at 20 Watts, we recorded beat-by-beat radial arterial blood pressure and estimated ascending aortic blood pressure waveforms in real-time via a generalized inverse transfer function (SphygmoCor). SV was calculated from cardiac output (Qc, acetylene rebreathe) and heart rate (ECG), with total peripheral resistance (TPR) calculated as the quotient of radial MAP and Qc. HR (Rest: 75 ± 14 vs 20W: 93 ± 12 bpm, P < 0.0001), SV (Rest: 61 ± 17 vs 20W: 84 ± 19 ml, P = 0.0003) and Qc (Rest: 4.5 ± 1.0 vs 20W: 7.7 ± 1.6 L/min, P < 0.0001) increased from rest to 20 Watts, whilst TPR decreased (Rest: 21.3 ± 4.4 vs 20W: 14.0 ± 3.8 mmHg/L/min, P < 0.0001); SV reserve was 43 ± 33 %. Aortic diastolic pressure did not change (Rest: 70 ± 12 vs 20W: 76 ± 15 mmHg, P = 0.0976), whereas aP1 (Rest: 112 ± 18 vs 20W: 130 ± 20 ml, P = 0.0002) and aP2 (Rest: 123 ± 26 vs 20W: 142 ± 25 ml, P = 0.0021) increased during exercise (Figure). Notably, aAP was not different between rest and exercise (Rest: 11 ± 11 vs 20W12 ± 11 mmHg, P = 0.4969). Therefore, the contribution of aAP to mid-late systolic afterload is unchanged during exercise in HFpEF, unlike in young healthy adults. Unchanged aAP may be a mechanism of high mid-late systolic afterload during exercise in HFpEF, which could contribute to impairments in SV reserve related to reduced ventricular contractile reserve.

Abstract 13676: Sublingual Nitroglycerin Lowers Aortic Augmentation Pressure at Rest and During Exercise in Patients With HFpEF

Infusion or inhalation of organic nitrates lower ascending aortic pressures, and reduce mid-late systolic afterload via a reduction in augmentation pressure (aAP, the difference between the first [aP1] and second [aP2] peaks of the aortic pressure waveform) at rest and during exercise in patients with heart failure and preserved ejection fraction (HFpEF). Sublingual nitroglycerin (NTG) is more accessible for patients as compared to the infusion or inhalation of nitrates. It is unknown whether NTG spray (400μg) elicits these same effects as organic nitrates on aortic hemodynamics at rest and during exercise. Therefore, in 15 patients with HFpEF (age, 71 ± 6 years; 10 women; BMI 39.2 ± 6.2 kg/m 2 ), as part of our ongoing clinical trial, we measured beat-by-beat radial artery blood pressure and estimated aortic pressure in real-time via a generalized inverse transfer function (SphygmoCor). Data were collected in the seated upright position at rest and throughout six-minutes of cycling at 20 Watts during either a placebo or NTG condition (randomized order). Stroke volume (SV) was calculated from cardiac output (Qc, acetylene rebreathe) and heart rate (ECG). NTG lowered stroke volume at rest, but not during exercise (Table); however, SV responses to exercise were similar (Placebo: Δ22 ± 19 vs NTG: Δ25 ± 18 ml, P = 0.1991). Aortic diastolic pressure was not different at rest with NTG compared to placebo (Table). aP1 and aP2 were lower at rest with NTG, with greater reductions in aP2 (Table). NTG lowered aAP during rest (Placebo: 11 ± 11 vs NTG: 0 ± 14 mmHg, P = 0.0002) and exercise (Placebo: 12 ± 11 vs NTG: 4 ± 12 mmHg, P < 0.0001). These results suggest patients with HFpEF do not augment SV responses to exercise despite a lower aAP contribution to (mid-late) systolic afterload with NTG. The inability to take advantage of a lower aAP during exercise may reflect impairments in contractile function and end-systolic reserve.

Abstract 15835: Deep Learning Based Personalized Treatment Recommender System for HFpEF Patients in the TOPCAT Americas Population

Introduction: The NHLBI supported TOPCAT trial (NCT00094302) investigated whether treatment with spironolactone (SPL) reduces hospitalization due to heart failure (hHF) in 3,445 adults with prior heart failure and preserved ejection fraction (HFpEF). We reused publicly available patient-level data from NHLBI Data Repository (BioLINCC) to perform hypothesis-generating secondary analyses with deep learning (DL) on the American TOPCAT cohort to generate treatment recommendations for HFpEF. Methods: Clinical phenogroups based on baseline characteristics of the American TOPCAT cohort (n = 1,053) were created using KPrototypes, suited for mixed data clustering. Treatment outcomes were assessed for hHF by DeepSurv, a DL generalization of Cox proportional hazards model, and Random Survival Forest (RSF), a tree-based survival analysis model. Comparison of survival probabilities from both models was used to create a recommender system used to guide treatments. Results: Cluster 1 was composed of younger patients with high cardiometabolic risk compared with Cluster 2. Diabetic patients (type 1 and type 2) comprised 93.2% of patients in cluster 1 and 10.1% of patients in Cluster 2. Among both clusters, DeepSurv and RSF trained well based on calculated C-indices, with DeepSurv often outperforming the RSF model (C-index = 0.797 vs. 0.698). Both approaches corroborated with each other and recommended the SPL treatment for the majority of patients in Cluster 1 (Figure 1). The models also recommended the SPL treatment for the majority of patients in cluster 2, although DeepSurv was less confident in this suggestion than RSF (Figure 1). Conclusions: This preliminary analysis shows the potential effectiveness of tailoring SPL as a treatment for HFpEF. The efficacy of deep learning models shows how advanced techniques can be used to promote precision medicine. Further analyses will be done to establish guided treatment efficacy in DL-generated subgroups of HFpEF patients.

Neuregulin-1β, Biomarkers of Inflammation and Myocardial Fibrosis in Heart Failure Patients

Neuregulin-1 β (NRG-1) is an emerging biomarker of heart failure (HF). The mechanisms of its action in HF patients are yet to be investigated. Cardioprotective and anti-inflammatory effects of NRG-1 have been reported. Aim . To assess NRG-1 levels in HF patients and investigate the association between NRG-1 and biomarkers of inflammation and myocardial fibrosis. Material and Methods. NRG-1, biomarkers of inflammation and fibrosis (hsCRP, IL-6, sVCAM-1, MMP-9, Galectin-3, ST2, TGF- β ) were assessed in 47 patients with HF and preserved ejection fraction (HFpEF); 39 patients with HF and reduced ejection (HFrEF) and 40 healthy participants. The associations between NRG-1 and biomarkers of inflammation and fibrosis, as well as the composite outcomes of cardiovascular death and HF hospitalisations were assessed. Results. Median NRG-1 levels in HFpEF were 0.969 (0.348; 1.932) ng/ml, in HFrEF – 0.63 (0.348; 1.932), in healthy participants 0.379 (0.195; 0.861) ng/ml, and was significantly higher in HFpEF compared to healthy volunteers (р=0.004). There was no difference in NRG-1 concentration between HFpEF and HFrEF. In HF patients, all biomarkers of inflammation and fibrosis were higher than in controls. ST2, IL-6 and TGF- β were significantly higher in HFrEF compared to HFpEF patients, while hsCRP, sVCAM-1, MMP-9, and Galectin-3 levels were comparable. In HFpEF, NRG-1 was associated with hsCRP (r s =0.378, p=0.023) and IL-6 (r s =0.378, p=0.014). Median follow-up time in patients with HFpEF and in patients was 312 (236; 388) days, in HFrEF – 147 (98; 237) days. In HFpEF, 2 patients died and 19 were hospitalized due to HF. In HFrEF, 10 deaths and 19 hospitalizations were registered. Kaplan-Mayer analysis showed that HFpEF patients with increased NRG-1 and IL-6 had higher levels of HF hospitalisation (log rank test, р=0.046 and р=0.012, respectively). In a multivariable cox proportional hazard model, the association between the NRG-1 and outcomes remained significant after adjustment for age, gender and NTproBNP but diminished when hsCRP and IL-6 were included in the model. Conclusion. NGR-1 level significantly higher in HFpEF compared to healthy participants, and comparable with NRG-1 concentrations in HFrEF. In HFpEF, NRG-1 was associated with biomarkers of inflammation and fibrosis. The prognostic value of NRG-1 in HF requires further investigations.

Nitro-oxidative stress impairs single cardiomyocyte adrenergic reserve in a murine model of HFpEF

Abstract Background Exercise intolerance is the central symptom of patients with heart failure and preserved ejection fraction (HFpEF). Underlying reduced cardiac functional reserve in response to adrenergic stimuli (stress testing) has been suggested but the molecular mechanisms are insufficiently understood. In cardiomyocytes, nitric oxide (NO) modifies contractility and is required to achieve a full adrenergic response. Recently, dysregulation of NO release has been described to contribute to HFpEF. In a murine model of HFpEF, we investigated cardiomyocyte's adrenergic functional reserve and the role of NO in cardiomyocyte contractility, calcium handling and adrenergic reserve. Methods Firstly, the effects of NO on sarcomere shortening and calcium handling (Fura-2) were studied in isolated, adult ventricular cardiomyocytes (AMVMs) from 8–10 weeks old, male C57BL/6J mice. Secondly, male C57BL/6J mice (12w) were fed regular CHOW (Sham) or a high fat diet (D12492, Research Diet) and L-NAME (1g/l, via the drinking water) for 15 weeks to induce HFpEF. At week 27, mice underwent echocardiography and exercise testing (treadmill). In AMVMs isolated from HFpEF and Sham mice, we quantified sarcomere shortening, calcium handling (Fura-2), release of NO (CuFL2) and reactive oxygen species (DCF) before and after the addition of isoproterenol (ISO, 1μM), in the absence and presence (40 min preincubation) of an inhibitor of inducible NO Synthase (1400W) or a denitrosylating agent (glutathione). Results In AMVMs, addition of the NO donor SNAP (10μM) increased calcium transient amplitude and accelerated relaxation time. Inhibition of NO synthesis with L-NAME (100μM) impaired adrenergic response upon exposure to ISO. HFpEF mice (evident by diastolic dysfunction (e/e' ratio) and lung edema (wet lung weight / TL)) exhibited significantly reduced exercise capacity (running distance). In AMVMs isolated from HFpEF mice, NO and ROS release were increased at baseline, associated with an increased sarcomere shortening amplitude and faster relaxation and calcium removal as compared to Sham. Strikingly, after the addition of ISO, the adrenergic functional reserve (cellular inotropy and lusitropy) was significantly lower in HFpEF vs. Sham AMVMs. Preincubation with the iNOS inhibitor 1400W or glutathione restored adrenergic inotropic and lusitropic reserve in HFpEF AMVMs. Conclusion In HFpEF, adrenergic reserve is impaired on a single cardiomyocyte level. This is at least partially related to an increase in NO release. Pharmacologic inhibition of iNOS improved adrenergic reserve in HFpEF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DFG

Impact of aortic regurgitation on long-term outcomes in heart failure with preserved ejection fraction

Abstract Background Aortic Regurgitation (AR) may aggravate the clinical course in patients with heart failure and preserved ejection fraction (HFpEF) by increasing filling pressures and triggering LV remodelling. Objective To assess AR's prevalence and long-term prognostic implications in patients with HFpEF. Methods The study population consisted of 458 consecutive patients (age 77.5±9.2 y, 57.9% females) hospitalized with de novo or worsened HFpEF. Patients with more than moderate aortic and/or mitral valve disease were excluded. Data on cardiovascular death, HF re-hospitalization and their composite (MACE) were collected. Results Out of 309 (67.5%) patients with any AR, 156 (34.0%) and 153 (33.5%) had mild-AR and moderate-AR, respectively. The remaining 149 (32.5%) individuals had no-AR. Patients with versus without AR were significantly older with larger LV and LA volumes and a higher prevalence of diastolic dysfunction (all p<0.05). During a median follow-up of 33±25 months, a total of 114 patients (24.9%) died from cardiovascular causes, 126 patients (27.5%) were re-hospitalized for HF, while 272 (59.4%) had the composite endpoint (MACE). In multivariable Cox regression analysis, any AR emerged as an only independent predictor of MACE (HR=1.90, 95% CI 1.26–2.87, p=0.002). Mild-AR and Moderate AR increased the risk of MACE by 77% and 92%, respectively, compared to the No-AR (Figure). Conclusions In patients with HFpEF, mild-to-moderate AR is highly prevalent, and it seems to identify individuals with worse long-term outcomes. This suggests that even mild AR should be considered a high-risk prognostic marker in patients with HFpEF. Funding Acknowledgement Type of funding sources: None.

Effects of empagliflozin in patients with heart failure and preserved ejection fraction according to baseline diuretic use: results from the EMPEROR-Preserved trial

Abstract Background In the EMPEROR-Preserved trial, empagliflozin reduced the risk of hospitalizations for heart failure (HHF) or cardiovascular (CV) death in patients with heart failure and preserved ejection fraction (HFpEF). Almost one in five patients in the trial were not on baseline diuretic therapy. Purpose To evaluate the efficacy and safety of empagliflozin according to baseline diuretic treatment, as well as change in diuretic therapy after initiation of empagliflozin. Methods Patients were categorized into subgroups as no diuretic and furosemide-equivalent diuretic dose of <40, 40 and >40mg and were compared for first HHF or CV death, HHF, CV death, total HHF, change in eGFR slope, and change in Kansas City Cardiomyopathy Questionnaire – Clinical Summary Scores (KCCQ-CSS) between patients on empagliflozin vs. placebo. Changes in diuretic therapy in the two treatment groups were also compared. Results Amongst 5815 patients with data on diuretic dose, 1179 (20%) were on no diuretic, 2039 (35%) were on <40mg, 1700 (29%) were on 40mg, and 897 (15%) were on >40mg at baseline. Patients on higher diuretic doses at baseline were more likely to be diabetic, had a higher body weight and NT-proBNP, and lower estimated glomerular filtration rate (eGFR) on average. Patients on higher diuretic doses also had worse health status based on NYHA class and KCCQ-CSS estimates. The reduction of the risk of CVD or HHF, total HHF, preservation of eGFR, and KCCQ-CSS improvement with empagliflozin were consistent across all doses of diuretics (Table 1). The findings for all outcomes were consistent in patients on diuretics (any dose) vs. not on diuretics. Treatment with empagliflozin was associated with decreased rates of initiation (HR: 0.73 [0.59,0.90; p=0.004) or intensification (HR: 0.74; [0.65, 0.84]; p<0.001) of diuretics, while there were increased rates in permanent discontinuation of diuretics (HR: 1.46 [1.17, 1.82]; p<0.001) or diuretic dose reduction (HR: 1.22 [1.06, 1.42]; p=0.007). The incidence of adverse events were similar between treatment arms, irrespective of baseline use of diuretics. Volume depletion events were more common with empagliflozin amongst patients treated with diuretics (7.4 vs 5.7 events per 100 patient-years for empagliflozin vs placebo). Conclusion Empagliflozin improved clinical outcomes and health status in patients with HFpEF irrespective of baseline use of diuretics. Additionally, empagliflozin was associated with increased de-escalation or discontinuation of diuretics and decreased chances of initiation or intensification. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance

Rhythm versus rate control for atrial fibrillation in heart failure with preserved ejection fraction.

There are few prospective studies assessing the benefits of rhythm control of atrial fibrillation (AF) in patients with heart failure and preserved ejection fraction (HFpEF), which accounts for 50% of all heart failure patients. Conduct a meta-analysis to assess the effects of rhythm control (ablation and/or antiarrhythmic medications) vs rate control on all-cause mortality in AF patients with HFpEF. Databases were searched for studies reporting the effect of rhythm control vs rate control on mortality in patients with HFpEF (Ovid MEDLINE, EMBASE, Scopus, Web of Science, Google Scholar, and EBSCO CINAHL). The search was not restricted to time or publication status. The primary endpoint was all-cause mortality. The minimum duration of follow-up required for inclusion was 1 year. The literature search identified 1210 candidate studies; 5 studies and 16,825 patients were included. The study population had 57% men with a mean age of 71± 2.5 years. Rhythm control for AF was associated with lower all-cause mortality (odds ratio 0.735, 95% confidence interval 0.665-0.813; P < .001) as compared to rate control. Rhythm control for AF in patients with HFpEF was associated with decreased all-cause mortality.

Heart failure outcomes according to heart rate and effects of empagliflozin in patients ofthe EMPEROR-Preserved trial.

Empagliflozin reduces cardiovascular death (CVD) or heart failure hospitalization (HHF) in patients with heart failure and preserved ejection fraction (HFpEF). Treatment effects and safety in relation to resting heart rate (RHR) have not been studied. The interplay of RHR and empagliflozin effects in EMPEROR-Preserved was evaluated. We grouped patients (n= 5988) according to their baseline RHR (<70 bpm [n= 2650], 70-75 bpm [n= 967], >75 bpm [n= 1736]) and explored the influence of RHR on CVD or HHF (primary outcome) and its components in sinus rhythm or atrial fibrillation/flutter (AF) and adverse events. We studied the efficacy of empagliflozin across the RHR spectrum. Compared to placebo, empagliflozin did not change heart rate over time. The primary outcome (p for trend=0.0004) and its components CVD (p trend=0.0002), first HHF (p for trend=0.0099) and all-cause death (p < 0.0001) increased with RHR only in sinus rhythm but not AF. The risk increase with RHR was similar in patients with heart failure and mildly reduced ejection fraction (left ventricular ejection fraction [LVEF] 40-49%) and HFpEF (LVEF ≥50%). Baseline RHR had no influence on the effect of empagliflozin on the primary outcomes (p for trend=0.20), first HHF (p for trend=0.49). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the RHR groups. Resting heart rate associates with outcomes only in sinus rhythm but not in AF. Empagliflozin reduced outcomes over the entire RHR spectrum without increase of adverse events.

Cardiac amyloidosis-interdisciplinary approach to diagnosis and therapy.

The vast majority of cardiac amyloidosis (CA) cases are caused by light chain (AL) or transthyretin (ATTR) amyloidosis. The latter is divided into hereditary (ATTRv) and wild-type forms (ATTRwt). The incidence of ATTRwt amyloidosis has significantly increased, particularly due to the improved diagnosis of cardiac manifestations, with relevant proportions in patient populations with heart failure (HF) and preserved ejection fraction (HFpEF). Cardiac amyloidosis should be suspected in HF with indicative clinical scenarios/"red flags" with typical signs of CA in echocardiography. Further noninvasive imaging (cardiovascular magnetic resonance imaging, scintigraphy) and specific laboratory diagnostics are important for the diagnosis and typing of CA into the underlying main forms of ATTR and AL amyloidosis. The histopathologic analysis of an endomyocardial biopsy is necessary if noninvasive diagnostic methods do not enable reliable typing of CA. This is crucial for initiating specific therapy. Therapy of HF in CA is largely limited to the use of diuretics in the absence of evidence on the benefit of classic HF therapy with neurohormonal modulators. Innovative therapies have been developed for amyloidosis with improvement in organ protection, prognosis, and quality of life. These include specific cytoreductive therapies for monoclonal light-chain disease in AL amyloidosis and pharmacologic stabilization or inhibition of transthyretin expression in ATTR amyloidosis. Since the CA underlying amyloidosis is asystemic disease also affecting other organ systems, close interdisciplinary cooperation is crucial for rapid and effective diagnosis and therapy.

Metformin does not prevent the alteration of reticulum-mitochondria Ca2+ coupling and the progression towards early diabetic cardiomyopathy with HFpEF in a diet-induced mouse model of T2D

Diabetic cardiomyopathy, as a major complication of type 2 diabetes (T2D), shows a rising prevalence nowadays. Reticulum-mitochondria Ca2+ uncoupling was recently reported as an early but reversible trigger of cardiac dysfunction using a diet-induced murine model of DCM with heart failure and preserved ejection fraction (HFpEF). Metformin is the first-line treatment prescribed to treat T2D patients, with known protective effects against myocardial infarction. We here aimed to determine if metformin could hinder the alteration of the reticulum-mitochondria Ca2+ coupling and the cardiac dysfunction induced by a high-fat high-sucrose diet (HFHSD) in mice. Mice were either fed a HFHSD or a standard diet for 16 weeks. During the last 6 weeks of diet, HFHSD mice received a daily oral gavage with either metformin or vehicle. Reticulum-mitochondria Ca2+ coupling was assessed: 1) structrally by proximity ligation assay between IP3R and VDAC; and 2) functionally by Ca2+ imaging of the mitochondrial Ca2+ sensor, 4mtD3cpv, expressed by intramyocardial adenoviral injection. Echocardiography was perfomed on lightly anesthetized animals to assess systolic function and hypertrophy. Metformin rescued the glucose tolerance and insulinemia in HFHSD mice, but partially for the cardiac insulin resistance. However, in the HFHSD cardiomyocyte, metformin did not preclude the reduction of the proximity between IP3R and VDAC, and of the histamine-driven reticulum-mitochondria Ca2+ transfer through the IP3R-VDAC complex. Echocardiography also revealed no prevention of HFHSD-induced cardiac hypertrophy and strain rate reduction. Our data report that 6 weeks of metformin treatment did not preserve the reticulum-mitochondria Ca2+ coupling in the diabetic heart and did not prevent the progression towards early DCM with HFpEF.

Diabetes Is the Strongest Predictor of Limited Exercise Capacity in Chronic Heart Failure and Preserved Ejection Fraction (HFpEF).

Background and AimType 2 diabetes mellitus (T2DM) is a known risk factor in patients with heart failure (HF), but its impact on phenotypic presentations remains unclear. This study aimed to prospectively examine the relationship between T2DM and functional exercise capacity, assessed by the 6-min walk test (6-MWT) in chronic HF.MethodsWe studied 344 chronic patients with HF (mean age 61 ± 10 years, 54% female) in whom clinical, biochemical, and anthropometric data were available and all patients underwent an echo-Doppler study and a 6-MWT on the same day. The 6-MWT distance divided the cohort into; Group I: those who managed ≤ 300 m and Group II: those who managed >300 m. Additionally, left ventricular (LV) ejection fraction (EF), estimated using the modified Simpson's method, classified patients into HF with preserved EF (HFpEF) and HF with reduced EF (HFrEF).ResultsThe results showed that 111/344 (32%) patients had T2DM, who had a higher prevalence of arterial hypertension (p = 0.004), higher waist/hips ratio (p = 0.041), higher creatinine (p = 0.008) and urea (p = 0.003), lower hemoglobin (p = 0.001), and they achieved shorter 6-MWT distance (p < 0.001) compared with those with no T2DM. Patients with limited exercise (<300 m) had higher prevalence of T2DM (p < 0.001), arterial hypertension (p = 0.004), and atrial fibrillation (p = 0.001), higher waist/hips ratio (p = 0.041), higher glucose level (p < 0.001), lower hemoglobin (p < 0.001), larger left atrium (LA) (p = 0.002), lower lateral mitral annular plane systolic excursion (MAPSE) (p = 0.032), septal MAPSE (p < 0.001), and tricuspid annular plane systolic excursion (TAPSE) (p < 0.001), compared with those performing >300 m. In the cohort as a whole, multivariate analysis, T2DM (p < 0.001), low hemoglobin (p = 0.008), atrial fibrillation (p = 0.014), and reduced septal MAPSE (p = 0.021) independently predicted the limited 6-MWT distance.In patients with HFpEF, diabetes [6.083 (2.613–14.160), p < 0.001], atrial fibrillation [6.092 (1.769–20.979), p = 0.002], and septal MAPSE [0.063 (0.027–0.184), p = 0.002], independently predicted the reduced 6-MWT, whereas hemoglobin [0.786 (0.624–0.998), p = 0.049] and TAPSE [0.462 (0.214–0.988), p = 0.041] predicted it in patients with HFrEF.ConclusionPredictors of exercise intolerance in patients with chronic HF differ according to LV systolic function, demonstrated as EF. T2DM seems the most powerful predictor of limited exercise capacity in patients with HFpEF.

Catheter ablation of atrial fibrillation in patients with heart failure and preserved ejection fraction: A meta-analysis.

BackgroundCatheter ablation (CA) is an effective treatment for patients with atrial fibrillation (AF). The potential of CA to benefit AF patients with heart failure and preserved ejection fraction (HFpEF) is uncertain.HypothesisCA may be safe and effective for patients with HFpEF.MethodsThe Medline, PubMed, Embase, and Cochrane Library databases were searched for studies evaluating CA for AF patients with HFpEF.ResultsA total of seven trials with 1696 patients were included. Pooled analyses demonstrated similar procedure and fluoroscopy time regarding the use of CA for patients with HFpEF and without HF (weighted mean difference [WMD]: 0.40; 95% confidence interval (CI): −0.01–0.81, p = .05 and [WMD: 0.05; 95% CI: −0.18–0.28, p = .68]). Moreover, CA was effective in maintaining sinus rhythm (SR) in patients with HFpEF and noninferior for patients without HF [risk ratio (RR): 0.92; 95% CI: 0.76–1.10, p = .34). Additionally, CA tended to significantly maintain SR (RR: 4.73; 95% CI: 1.86–12.03, p = .001) and reduce rehospitalization for HF compared with medical therapy (RR: 0.36; 95% CI: 0.19–0.71, p = .003). However, no significant differences were found between two groups regarding the mortality rate (p = .59).ConclusionCA is a potential treatment strategy for patients with HFpEF and demonstrates equivalent efficacy to that of patients without HF. Moreover, the benefits of CA in maintaining SR and reducing rehospitalization of HF patients were significantly better than those of medical therapy. Additional randomized controlled trials are warranted to confirm our results.

Defining changes in physical limitation from the patient perspective: insights from the VITALITY-HFpEF randomized trial.

AimsClinically important thresholds in patient‐reported outcomes measures like the Kansas City Cardiomyopathy Questionnaire (KCCQ) have not been defined for patients with heart failure and preserved ejection fraction (HFpEF). The aim of this study was to estimate meaningful thresholds for improvement or worsening in the KCCQ physical limitation score (PLS) in patients with HFpEF.Methods and resultsIn this pre‐specified analysis from VITALITY‐HFpEF, anchor‐ and distribution‐based approaches were used to estimate thresholds for improvement or worsening in the KCCQ‐PLS using Patient Global Impression of Change (PGIC) as an anchor. The KCCQ‐PLS contains six elements, with each increment in response resulting in a change of 4.17 points when converted to a 0–100 scale. The mean change in KCCQ‐PLS from baseline to week 12 was calculated for each PGIC group to estimate a meaningful within‐patient change. Of 789 patients enrolled, 698 had complete KCCQ‐PLS and PGIC data at week 12. The mean (± standard deviation) changes in KCCQ‐PLS corresponding to PGIC changes of ‘a little better’, ‘better’, and ‘much better’ were 5.7 ± 18.6, 11.6 ± 19.3, and 18.4 ± 25.3 points, respectively. The scores of patients who responded ‘a little better’ (n = 177) overlapped substantially with those who reported ‘no change’ (n = 193; mean change 2.8 ± 18.9). The mean change in KCCQ‐PLS for patients responding ‘a little worse’ (n = 32) was −2.6 ± 18.0 points. The threshold for meaningful within‐patient change in KCCQ‐PLS based on distribution‐based analyses was 12.3 points. Using area under the curve (AUC) analyses of KCCQ‐PLS, the sensitivity and specificity of a 4.17‐point change were 0.61 and 0.57, for an 8.33‐point change they were 0.49 and 0.64, and for a 12.5‐point change they were 0.44 and 0.72 for being at least a little better on the PGIC (AUC = 0.54).ConclusionIn the VITALITY‐HFpEF trial, a change in KCCQ‐PLS of ≥8.33 points (corresponding to an improvement in ≥2 response categories of KCCQ‐PLS) may represent the minimal clinically important difference for improvement and a change of ≤ −4.17 points (corresponding to a worsening in ≥1 response category of KCCQ‐PLS) may suggest deterioration in patients with HFpEF.

Anisocytosis is associated with myocardial fibrosis and exercise capacity in heart failure with preserved ejection fraction

BackgroundRed Blood Cell Distribution Width (RDW), a measure of variability in size of circulating red blood cells and is a marker of inflammation. ObjectivesWe sought to test the hypothesis that RDW reflects an inflammatory milieu permissive for cardiac fibrosis in those with Heart Failure and preserved ejection fraction (HFpEF). MethodsWe analyzed the association between RDW and fibrosis in two separate cohorts. Cohort 1 (n = 200) was a retrospective analysis of blood biomarkers measured in the RELAX trial (Clinicaltrials.gov NCT00763867) and Cohort 2 (n = 160) included a single center cohort of patients with preserved ventricular function referred for cardiac magnetic resonance imaging (cMRI). Linear regression was used to adjust for potential confounders, and a mediation analysis used to explore relationships with exercise intolerance (peak VO2 max). ResultsWithin Cohort 1, anisocytosis (RDW > 14.5) was prevalent (49.5%) and was associated with greater baseline clinical comorbidities, a lower Peak VO2 and more frequent heart failure hospitalizations. The RDW was associated with biomarkers of inflammation and cardiac fibrosis. In Cohort 2, RDW was associated with cMRI myocardial fibrosis (extracellular volume; Spearman's rho=0.38, P<0.001) which was independent of age, sex, LV ejection fraction, and hematocrit (P = 0.026). Individuals with both anisocytosis and myocardial fibrosis identified a subgroup of at high risk for 2-year mortality (HR 16.28 [4.30–61.66], P<0.001). ConclusionsIn two independent cohorts of patients with HFpEF, elevated RDW is associated reduced exercise capacity and greater fibrosis as measured by serum biomarkers and cMRI. Additional studies are needed to validate this novel relationship.

Benefits of a comprehensive care model in patients with heart failure and preserved ejection fraction: The UMIPIC program

BackgroundPatients with heart failure (HF) and preserved ejection fraction (HFpEF), in contrast to those with reduced ejection fraction, are older, have more comorbidities, and are not candidates for effective therapeutic measures. Therefore, they are at high risk for hospital admission and mortality. This study evaluated the benefit of a comprehensive continuous care program (UMIPIC program) in patients with HFpEF. MethodsWe prospectively analyzed data on 2401 patients with HFpEF attended to in internal medicine departments who form part of the RICA registry. They were divided into 2 groups: one was followed-up on in the UMIPIC program (UMIPIC group, n: 1011) and another received conventional care (RICA group, n: 1390). A total of 753 patients in each group were selected by propensity score matching and admissions and mortality were assessed during 12 months of follow-up after an episode of hospitalization due to HF. ResultsCompared to the RICA group, the UMIPIC group had a lower rate of HF admissions (19.2% versus 36.5%, respectively; hazard ratio [HR] = 0.56; 95% confidence interval [CI]: 0.45–0.68; p < 0.001) and mortality (12.6% versus 28%, respectively; HR = 0.40; 95% CI: 0.31−0.51; p < 0.001). There were no differences in hospitalizations for non-HF causes. ConclusionsImplementation of the UMIPIC program, which is based on comprehensive continuous care, for patients with HFpEF and a high degree of comorbidity reduces both admissions and mortality in the first year of follow-up.

Relation of left atrial overload indices with prognostic endpoints in heart failure and preserved ejection fraction

AimsConsiderable variation in the relationships between the indices of left atrial (LA) volume and pressure could possibly affect the selection of medications or efforts to improve the prognoses of patients with heart failure and preserved ejection fraction (HFpEF). We aimed to clarify the association between the prognostic endpoint and LA overload indices in elderly patients with HFpEF.Methods and resultsWe analysed 898 patients with HFpEF hospitalized for acute decompensated heart failure (men/women: 406/492). Blood tests and transthoracic echocardiography were performed before discharge. The primary endpoint was re‐admission for heart failure or all‐cause mortality. Stroke volume (SV)/left atrial volume (LAV), an index for LA volume overload, was a significant prognostic factor of re‐admission for heart failure in the multivariable Cox hazard analysis adjusted for comorbidities [hazard ratio (HR) 0.616, 95% confidence interval (CI) 0.430–0.882, P = 0.008]. Additionally, the ratio of diastolic elastance (Ed) to arterial elastance (Ea), an index for LA pressure overload, was also significant (HR 1.444, 95% CI 1.014–2.058, P = 0.041). Furthermore, Ed/Ea, but not SV/LAV, was a significant prognostic factor of all‐cause mortality (HR 1.594, 95% CI 1.102–2.306, P = 0.013).ConclusionsThe index of LA overload for prognosis may differ according to the different endpoints in elderly patients with HFpEF.

The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial

Large traditional clinical trials suggest that sodium-glucose co-transporter 2 inhibitors improve symptoms in patients with heart failure and reduced ejection fraction (HFrEF) and in patients with heart failure and preserved ejection fraction (HFpEF). In the midst of the Coronavirus Disease 2019 pandemic, we sought to confirm these benefits in a new type of trial that was patient centered and conducted in a completely remote fashion. In the CHIEF-HF trial (NCT04252287), 476 participants with HF, regardless of EF or diabetes status, were randomized to 100 mg of canagliflozin or placebo. Enrollment was stopped early due to shifting sponsor priorities, without unblinding. The primary outcome was change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ TSS) at 12 weeks. The 12-week change in KCCQ TSS was 4.3 points (95% confidence interval, 0.8–7.8; P = 0.016) higher with canagliflozin than with placebo, meeting the primary endpoint. Similar effects were observed in participants with HFpEF and in those with HFrEF and in participants with and without diabetes, demonstrating that canagliflozin significantly improves symptom burden in HF, regardless of EF or diabetes status. This randomized, double-blind trial, conducted without in-person interactions between doctor and patient, can serve as a model for future all-virtual clinical trials.

Right atrial pressure represents cumulative cardiac burden in heart failure with preserved ejection fraction.

AimsRight‐sided filling pressure is elevated in some patients with heart failure (HF) and preserved ejection fraction (HFpEF). We hypothesized that right atrial pressure (RAP) would represent the cumulative burden of abnormalities in the left heart, pulmonary vasculature, and the right heart.Methods and resultsEchocardiography was performed in 399 patients with HFpEF. RAP was estimated from inferior vena cava morphology and its respiratory change [estimated right atrial pressure (eRAP)], and patients were divided according to eRAP (3 or ≥8 mmHg). Patients with higher eRAP displayed more severe abnormalities in LV diastolic function as well as right heart structure and function than those with normal eRAP. Cardiac deaths or HF hospitalization occurred in 84 patients over a median follow‐up of 19.0 months (interquartile range 6.7–36.9). The presence of higher eRAP was independently associated with an increased risk of the composite outcome (adjusted hazard ratio 2.20 vs. normal eRAP group, 95% confidence interval 1.34–3.62, P = 0.002). Kaplan–Meier curves separating the patients into four groups based on eRAP and E/e' ratio showed that event‐free survival varied among the groups, providing an incremental prognostic value of eRAP over E/e' ratio. The classification and regression tree analysis demonstrated that eRAP was the strongest predictor of the outcome followed by right ventricular dimension, E/e' ratio, and estimated right ventricular systolic pressure, stratifying the patients into four risk groups (incident rate 8.8–72.2%).ConclusionsThese data may provide new insights into the prognostic role of RAP in the complex pathophysiology of HFpEF and suggest the utility of eRAP for the risk stratification in patients with HFpEF.