Nonpharmacological Approaches to Managing Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a common subtype of heart failure marked by impaired left ventricular diastolic function and decreased myocardial compliance. Given the limited availability of evidence-based pharmacological treatments for HFpEF, there is a growing interest in nonpharmacological interventions as viable therapeutic alternatives. This review aims to explore the pathophysiology of HFpEF and present recent advancements in nonpharmacological management approaches, encompassing noninvasive therapies, invasive procedures and targeted treatments for comorbidities. An extensive literature review was undertaken to identify and synthesize emerging nonpharmacological treatment options for HFpEF, assessing their potential to enhance patient outcomes. Nonpharmacological strategies, such as vagus nerve stimulation, percutaneous pulmonary artery denervation, renal denervation, transcatheter insertion of atrial shunts and pericardial resection, demonstrate promising potential for alleviating HFpEF symptoms and improving patient prognosis. Moreover, addressing comorbidities, such as hypertension and diabetes, may offer additional therapeutic benefits. These cutting-edge techniques, in conjunction with well-established exercise therapies, pave the way for future research and clinical applications in the field. Nonpharmacological interventions hold promise for advancing HFpEF patient care and fostering a deeper understanding of these treatment approaches, which will facilitate new clinical applications and contribute to the development of more targeted therapies.

Heart failure with preserved ejection fraction epidemiology, pathophysiology, diagnosis and treatment strategies.

The prevalence of HF with preserved ejection raction (HFpEF, with EF ≥50%) is increasing across all populations with high rates of hospitalization and mortality, reaching up to 80% and 50%, respectively, within a 5-year timeframe. Comorbidity-driven systemic inflammation is thought to cause coronary microvascular dysfunction and increased epicardial adipose tissue, leading to downstream friborsis and molecular changes in the cardiomyocyte, leading to increased stiffness and diastolic dynsfunction. HFpEF poses unique challenges in terms of diagnosis due to its complex and diverse nature. The diagnosis of HFpEF relies on a combination of clinical assessment, imaging studies, and biomarkers. An additional important step in diagnosing HFpEF involves excluding certain cardiac diagnoses that may be specific underlying causes of HFpEF or may be masquerading as HFpEF and require specific alternative treatment approaches. In addition to administering sodium-glucose cotransporter 2 inhibitors to all patients, the most effective approach to enhance clinical outcomes may involve tailored therapy based on each patient's unique clinical profile. Exercise should be recommended for all patients to improve the quality of life. Glucagon-like peptide-1 1 agonists are a promising treatment option in obese HFpEF patients. Novel approaches targeting inflammation are also in early phase trials.

Prognostic Models for Mortality and Morbidity in Heart Failure With Preserved Ejection Fraction.

Importance: Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. Objective: To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Design, Setting, and Participants: Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Exposures: Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Results: Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. Conclusions and Relevance: In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

Impact of epicardial adipose tissue on cardiac function and morphology in patients with diastolic dysfunction.

AIMS: This study aimed to identify the impact of increased epicardial adipose tissue (EAT) and its regional distribution on cardiac function in patients with diastolic dysfunction. METHODS AND RESULTS: Sixty-eight patients with exertional dyspnoea (New York Heart Association ≥II), preserved ejection fraction (≥50%), and diastolic dysfunction (E/e' ≥ 8) underwent rest and stress right heart catheterization, transthoracic echocardiography, and cardiovascular magnetic resonance (CMR). EAT volumes were depicted from CMR short-axis stacks. First, the impact of increased EAT above the median was investigated. Second, the association of ventricular and atrial EAT with myocardial deformation at rest and during exercise stress was analysed in a multivariable regression analysis. Patients with high EAT had higher HFA-PEFF and H2FPEFF scores as well as N-terminal prohormone of brain natriuretic peptide levels (all P < 0.048). They were diagnosed with manifest heart failure with preserved ejection fraction (HFpEF) more frequently (low EAT: 37% vs. high EAT: 64%; P = 0.029) and had signs of adverse remodelling indicated by higher T1 times (P < 0.001). No differences in biventricular volumetry and left ventricular mass (all P > 0.074) were observed. Patients with high EAT had impaired atrial strain at rest and during exercise stress, and impaired ventricular strain during exercise stress. Regionally increased EAT was independently associated with functional impairment of the adjacent chambers. CONCLUSIONS: Patients with diastolic dysfunction and increased EAT show more pronounced signs of diastolic functional failure and adverse structural remodelling. Despite similar morphological characteristics, patients with high EAT show significant cardiac functional impairment, in particular in the atria. Our results indicate that regionally increased EAT directly induces atrial functional failure, which represents a distinct pathophysiological feature in HFpEF.

Prevalence of respiratory failure and use of mechanical ventilation in heart failure patients undergoing left atrial appendage occlusion device implantation.

BACKGROUND: We sought to evaluate respiratory complications in heart failure patients undergoing left atrial appendage occlusion (LAAO) for stroke prevention in atrial fibrillation. METHODS: Adult admissions (>18 years) undergoing LAAO during 2016-2020 were identified from the National Inpatient Sample. Heart failure (HF) was stratified into systolic (SHF) and diastolic heart failure (DHF) and were compared to those without HF. Outcomes of interested included acute respiratory failure, use of non-invasive and invasive mechanical ventilation, and in-hospital mortality. RESULTS: Of 74,440 admissions for atrial fibrillation undergoing LAAO, SHF and DHF were noted in 8335 (11.2%) and 10,925 (14.7%), respectively. The SHF cohort was predominantly male (78%) whereas DHF cohort were female (53%). Compared to those without HF, presence of SHF (2.3% vs. 0.6%; adjusted odds ratio [OR] 1.61 [95% confidence interval {CI} 1.10-2.36]; p = 0.01) and DHF (2.8% vs. 0.6%; adjusted OR 2.20 [95% CI 1.58-3.06]; p < 0.001) were associated with higher rates of acute respiratory failure. SHF (1.7% vs. 0.6%; adjusted OR 1.70 [95% CI 1.07-2.71]; p = 0.02) group but not DHF (1.2% vs. 0.6%; adjusted OR 1.21 [95% CI 0.78-1.89]; p = 0.39) was associated with higher rates of non-invasive ventilation, whereas the DHF group (0.9% vs. 0.2%; adjusted OR 1.91 [95% CI 1.08-3.34]; p = 0.02) but not SHF (0.8% vs. 0.2%; adjusted OR 1.54 [95% CI 0.83-2.84]; p = 0.17) was associated with higher rates of invasive mechanical ventilation use. In-hospital mortality was comparable between cohorts. CONCLUSION: Compared to those without HF, atrial fibrillation admissions with HF undergoing LAAO had higher rates of acute respiratory failure and mechanical ventilation rates without differences in in-hospital mortality.

Effect of different types of aerobic training on peak VO2 and ejection fraction for diastolic heart failure patients; a comparative randomized control trial.

BACKGROUND: Heart failure is described by a lack of confirmed efficient therapies and exercise intolerance. Engagement in physical activity decreases the possibility of adverse cardiovascular consequences involving heart failure. THE PURPOSE OF THE STUDY: Determine the effect of different types of aerobic training on peak VO2 and ejection fraction in diastolic heart failure patients. SUBJECT AND METHODS: The study was designed as a randomized control trail. Forty-eight eligible male patients with diastolic heart failure, aged between 50 and 65 years old, enrolled in this study. They were picked up from Police hospital outpatient clinic and were assigned to 2 equal groups in numbers. The first group (A) received aerobic exercise for the upper limb in the form of arm ergometer exercises, while the second group (B) received aerobic exercise for the lower limb in the form of cycling. Training duration for both groups was 3 sessions/week for 12 weeks. Peak VO2, and ejection fraction of both groups were measured and compared pre- and post-treatment. RESULTS: There was no significant difference (p > 0.05) in the ejection fraction between groups post-treatment. However, a significant increase (p < 0.001) was observed in the peak VO2 of group B when compared to group A post-treatment. CONCLUSION: There is no effect of different types of aerobic training on ejection fraction in diastolic heart failure patients, but lower limb exercise is more effective than upper limb exercise in improving peak VO2 in diastolic heart failure patients. Therefore, the current study recommended the use of lower limb exercise over upper limb exercise in training diastolic heart failure patients. CLINICAL TRIAL REGISTRATION: The study was registered in ClinicalTrial.gov as a clinical trial ID (NCT05637125).

Myofilament dysfunction in diastolic heart failure.

Diastolic heart failure (DHF), in which impaired ventricular filling leads to typical heart failure symptoms, represents over 50% of all heart failure cases and is linked with risk factors, including metabolic syndrome, hypertension, diabetes, and aging. A substantial proportion of patients with this disorder maintain normal left ventricular systolic function, as assessed by ejection fraction. Despite the high prevalence of DHF, no effective therapeutic agents are available to treat this condition, partially because the molecular mechanisms of diastolic dysfunction remain poorly understood. As such, by focusing on the underlying molecular and cellular processes contributing to DHF can yield new insights that can represent an exciting new avenue and propose a novel therapeutic approach for DHF treatment. This review discusses new developments from basic and clinical/translational research to highlight current knowledge gaps, help define molecular determinants of diastolic dysfunction, and clarify new targets for treatment.

Serum anion gap is associated with mortality in intensive care unit patients with diastolic heart failure.

Serum anion gap (AG) is closely related to mortality in critically ill patients with several diseases. We aimed to determine the relationship between serum AG levels and 28-day intensive care unit (ICU) mortality in patients with diastolic heart failure (DHF). This cohort study enrolled critically ill patients with DHF from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Serum AG levels were calculated using the traditional and albumin-adjusted methods. Multivariate Cox proportional hazards regression and restricted cubic spline curves were used to determine the correlation between serum AG levels and 28-day ICU mortality. We used receiver operating characteristic (ROC) curves and area under the curve (AUC) to compare the ability of traditional and albumin-adjusted AG to predict mortality. Overall, 3290 patients were included. Multivariate analysis showed an association of high levels of traditional (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.1-1.98, p = 0.009) and albumin-adjusted AG (HR, 1.36; 95% CI, 1.02-1.79, p = 0.033) with higher risk of 28-day ICU mortality. Restricted cubic spline curves indicated a linear relationship between AG level and 28-day ICU mortality. Comparison of the ROC curves revealed that albumin-adjusted AG had a greater ability to predict 28-day ICU mortality compared with traditional AG (AUCs of 0.569 [95% CI, 0.536-0.601] and 0.619 [95% CI, 0.588-0.649], respectively). In ICU patients with DHF, higher levels of traditional and albumin-adjusted AG were associated with higher 28-day ICU mortality. Albumin-adjusted AG exhibited greater predictive ability for mortality compared with traditional AG.

Outpatient Worsening Among Patients With Mildly Reduced and Preserved Ejection Fraction Heart Failure in the DELIVER Trial.

BACKGROUND: Hospitalization is recognized as a sentinel event in the disease trajectory of patients with heart failure (HF), but not all patients experiencing clinical decompensation are ultimately hospitalized. Outpatient intensification of diuretics is common in response to symptoms of worsening HF, yet its prognostic and clinical relevance, specifically for patients with HF with mildly reduced or preserved ejection fraction, is uncertain. METHODS: In this prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we assessed the association between various nonfatal worsening HF events (those requiring hospitalization, urgent outpatient visits requiring intravenous HF therapies, and outpatient oral diuretic intensification) and rates of subsequent mortality. We further examined the treatment effect of dapagliflozin on an expanded composite end point of cardiovascular death, HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification. RESULTS: In DELIVER, 4532 (72%) patients experienced no worsening HF event, whereas 789 (13%) had outpatient oral diuretic intensification, 86 (1%) required an urgent HF visit, 585 (9%) had an HF hospitalization, and 271 (4%) died of cardiovascular causes as a first presentation. Patients with a first presentation manifesting as outpatient oral diuretic intensification experienced rates of subsequent mortality that were higher (10 [8-12] per 100 patient-years) than those without a worsening HF event (4 [3-4] per 100 patient-years) but similar to rates of subsequent death after an urgent HF visit (10 [6-18] per 100 patient-years). Patients with an HF hospitalization as a first presentation of worsening HF had the highest rates of subsequent death (35 [31-40] per 100 patient-years). The addition of outpatient diuretic intensification to the adjudicated DELIVER primary end point (cardiovascular death, HF hospitalization, or urgent HF visit) increased the overall number of patients experiencing an event from 1122 to 1731 (a 54% increase). Dapagliflozin reduced the need for outpatient diuretic intensification alone (hazard ratio, 0.72 [95% CI, 0.64-0.82]) and when analyzed as a part of an expanded composite end point of worsening HF or cardiovascular death (hazard ratio, 0.76 [95% CI, 0.69-0.84]). CONCLUSIONS: In patients with HF with mildly reduced or preserved ejection fraction, worsening HF requiring oral diuretic intensification in ambulatory care was frequent, adversely prognostic, and significantly reduced by dapagliflozin. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.

Systolic Heart Failure is Associated with Higher Mortality Among Patients Undergoing Transcatheter Aortic Valve Replacement: A Nationwide Analysis.

Heart failure (HF) is prevalent among patients with aortic stenosis and presents a poor prognosis. In order to better portray outcomes for HF patients undergoing transcatheter aortic valve replacement (TAVR), we evaluated clinical outcomes in patients with systolic vs diastolic heart failure who underwent TAVR in a large nationwide database. We searched the National Inpatient Sample (NIS) for hospitalized adult patients who underwent TAVR with coexisting history of systolic (SHF) or diastolic heart failure (DHF) as a secondary diagnosis using the ICD-10 codes. The primary outcome was in-hospital mortality, with secondary outcomes of cardiac arrest (CA), cardiogenic shock (CS), respiratory failure (RF), Non-ST elevation myocardial infarction (NSTEMI), acute kidney injury (AKI), use of cardiac and respiratory assist device, and health care utilization defined as length of stay, average hospital cost (AHC) and patient charge (APC). Both univariate and multivariate logistic, generalized linear, and Poisson regression analyses were used to evaluate and test the outcomes. A P-value of <0.05 was significant. A total of 106,815 patients were admitted to acute care hospitals for TAVR, and 73% had a secondary diagnosis of heart failure (41% had SHF and 59% DHF). SHF group were older (mean age of 78.9 years [SD ± 8.9] vs 79.9 years [SD ± 8.3]) with more males (61.8% vs 48.2%) and white predominant (whites [85.9% vs 87.9%]). Compared to DHF, SHF had higher inpatient mortality (1.75% vs 1.14%, P = 0.003), CA (1.31% vs 0.81%, P = 0.01), NSTEMI (2.52% vs 1.0%, P = 0.001), RF (10.87% vs 8.01%, P = 0.001), and CS (3.94% vs 1.14%, P = 0.001). In addition, SHF had greater LOS (5.1 days vs. .3.9, P = 0.0001) & AHC ($52,901 vs $48,070, P = 0.0001). HF is common among patients admitted for TAVR. SHF had worse CV outcomes, greater use of hospital resources, and higher acute care hospital mortality compared to those with DHF.

Association of Hypoalbuminemia With Clinical Outcomes in Patients Admitted With Acute Heart Failure.

Albumin is a protein produced by the liver essential for maintaining blood volume and regulating fluid balance. Hypoalbuminemia is characterized by low levels of albumin in the blood. It is also a marker of malnutrition-inflammatory syndrome. Several studies have demonstrated its prognostic role in patients with chronic heart failure; however, data regarding hypoalbuminemia in acute heart failure admissions are scarce. This study aims to analyze the relationship between hypoalbuminemia and heart failure. We used a retrospective cohort study surveying data from the 2016-2018 combined National Inpatient Sample (NIS) database. Adult hospitalizations for heart failure patients were identified using the ICD-10 codes, stratified into cohorts with and without hypoalbuminemia. Primary outcomes were (1) in-patient mortality, (2) length of stay, and total hospital charge. We also reclassified the HF admissions with hypoalbuminemia to those with systolic or diastolic heart failure to compare any differences in mortality and other in-patient complications. Multivariate linear and logistic regression were used to adjust for confounders and to analyze the outcomes. There were 1,365,529 adult hospitalizations for Congestive Heart Failure (CHF), and among them 1,205,990 (88 %) had secondary diagnoses of hypoalbuminemia. Patients with comorbid hypoalbuminemia were, on average, 8 years older (P < 0.001), predominantly white race, and males (P-value <0.001). HF hospitalizations with hypoalbuminemia had double in-hospital mortality than those without (4.8% vs 2.7%, P < 0.001). However, there was no difference in mortality between patients with Systolic heart failure and Diastolic heart failure with concomitant low albumin levels (from 4.9 % vs 4.7%, P 0.13). We found that patients admitted with HF and concomitant Hypoalbuminemia (HA) had nearly twice the odds of in-patient mortality than those with normal albumin levels. The Length of Stay (LOS) was higher between comparison groups. THC remained statistically indifferent in patients regardless of albumin levels but was greater in hypoalbuminemic patients with Systolic heart failure than Diastolic heart failure ones.

Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Polypharmacy Status.

BACKGROUND: Patients with heart failure (HF) have a high burden of multimorbidity, often necessitating numerous medications. There may be clinical concern about introducing another medication, especially among individuals with polypharmacy. OBJECTIVES: This study examined the efficacy and safety of addition of dapagliflozin according to the number of concomitant medications in HF with mildly reduced or preserved ejection fraction. METHODS: In this post hoc analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, 6,263 participants with symptomatic HF with left ventricular ejection fraction >40% were randomized to dapagliflozin or placebo. Baseline medication use (including vitamins and supplements) was collected. Efficacy and safety outcomes were assessed by medication use categories ("nonpolypharmacy": <5 medications; "polypharmacy": 5 to 9 medications; and "hyperpolypharmacy": ≥10 medications) and continuously. The primary outcome was worsening HF or cardiovascular death. RESULTS: Overall, 3,795 (60.6%) patients met polypharmacy and 1,886 (30.1%) met hyperpolypharmacy criteria. Higher numbers of medications were strongly associated with higher comorbidity burden and increased rates of the primary outcome. Compared with placebo, dapagliflozin similarly reduced the risk of the primary outcome irrespective of polypharmacy status (nonpolypharmacy HR: 0.88 [95% CI: 0.58-1.34]; polypharmacy HR: 0.88 [95% CI: 0.75-1.03]; hyperpolypharmacy HR: 0.73 [95% CI: 0.60-0.88]; Pinteraction = 0.30). Similarly, benefits with dapagliflozin were consistent across the spectrum of total medication use (Pinteraction = 0.06). Although adverse events increased with higher number of medications, they were not more frequent with dapagliflozin, regardless of polypharmacy status. CONCLUSIONS: In the DELIVER trial, dapagliflozin safely reduced worsening HF or cardiovascular death across a broad range of baseline medication use, including among individuals with polypharmacy (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Sodium-glucose cotransporter 2 inhibitors vs. sitagliptin in heart failure and type 2 diabetes: an observational cohort study.

AIMS: The effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure (HF) in routine clinical practice is not extensively studied. This study aimed to evaluate the comparative effectiveness of SGLT2i vs. sitagliptin in older adults with HF and type 2 diabetes and to investigate whether there were any differences between agents within the SGLT2i class or for reduced and preserved ejection fraction. METHODS AND RESULTS: Using Medicare claims data (April 2013 to December 2019), 16 253 SGLT2i initiators vs. 43 352 initiators of sitagliptin aged ≥65 years with type 2 diabetes and HF were included. The primary outcome was a composite of all-cause mortality, hospitalization for HF or urgent visit requiring intravenous diuretics; secondary outcomes included its individual components. Propensity score fine stratification weighted Cox regression was used to adjust for 100 pre-exposure characteristics. Mean age was 74 years; 49.8% were women. Initiation of SGLT2i vs. sitagliptin was associated with a lower risk of the primary composite outcome [adjusted hazard ratio (HR) 0.72; 95% confidence interval 0.67-0.77]. The adjusted HRs were 0.70 (0.63-0.78) for all-cause mortality, 0.64 (0.58-0.70) for hospitalization for HF, and 0.77 (0.69-0.86) for urgent visit requiring intravenous diuretics. Similar associations with the primary composite outcome were observed for all three agents within the SGLT2i class, for reduced and preserved ejection fraction, and subgroups based on demographics, comorbidities, and other HF treatments. Bias-calibrated HRs for the primary endpoint using negative and positive control outcomes ranged between 0.81 and 0.89, suggesting that the observed benefit could not be fully explained by residual confounding. CONCLUSION: In routine US clinical practice, SGLT2i demonstrated robust clinical effectiveness in older adults with HF and type 2 diabetes compared with sitagliptin, with no evidence of heterogeneity across the SGLT2i class or across ejection fraction.

Depressed myocardial cross-bridge cycling kinetics in a female guinea pig model of diastolic heart failure.

Cardiac hypertrophy is associated with diastolic heart failure (DHF), a syndrome in which systolic function is preserved but cardiac filling dynamics are depressed. The molecular mechanisms underlying DHF and the potential role of altered cross-bridge cycling are poorly understood. Accordingly, chronic pressure overload was induced by surgically banding the thoracic ascending aorta (AOB) in ∼400 g female Dunkin Hartley guinea pigs (AOB); Sham-operated age-matched animals served as controls. Guinea pigs were chosen to avoid the confounding impacts of altered myosin heavy chain (MHC) isoform expression seen in other small rodent models. In vivo cardiac function was assessed by echocardiography; cardiac hypertrophy was confirmed by morphometric analysis. AOB resulted in left ventricle (LV) hypertrophy and compromised diastolic function with normal systolic function. Biochemical analysis revealed exclusive expression of ß-MHC isoform in both sham control and AOB LVs. Myofilament function was assessed in skinned multicellular preparations, skinned single myocyte fragments, and single myofibrils prepared from frozen (liquid N2) LVs. The rates of force-dependent ATP consumption (tension-cost) and force redevelopment (Ktr), as well as myofibril relaxation time (Timelin) were significantly blunted in AOB, indicating reduced cross-bridge cycling kinetics. Maximum Ca2+ activated force development was significantly reduced in AOB myocytes, while no change in myofilament Ca2+ sensitivity was observed. Our results indicate blunted cross-bridge cycle in a ß-MHC small animal DHF model. Reduced cross-bridge cycling kinetics may contribute, at least in part, to the development of DHF in larger mammals, including humans.

[Diastolic heart failure: 20 years later. Сurrent issues of pathoge-nesis, diagnosis and treatment of heart failure with preserved LVEF].

Relevant aspects of the pathogenesis, diagnosis, And treatment of heart failure with preserved LV EFThis review analyzes results of studies of the recent decade that focus on epidemiology, mechanisms of development, diagnostic methods, and treatments of heart failure with preserved ejection fraction (HFpEF). As expected, the prevalence of HFpEF continues to increase due to the growing contribution of comorbidities to the structure of causes for chronic heart failure (CHF), such as arterial hypertension with left ventricular hypertrophy, obesity, chronic kidney disease, as well as due to ageing of the population and decreased contributions of ischemic heart disease and myocardial infarction. Concomitant diseases are a source of low-intensity microvascular inflammation, which is currently assigned a role of a trigger mechanism eventually provoking energy deficiency, disorders of cardiomyocyte relaxation, and diffuse myocardial fibrosis. Both these processes lead to increased heart muscle rigidity and abnormally high left ventricular filling pressure (LVFP). High LVFP is associated with the development of pulmonary venous congestion and impairment of alveolar blood oxygenation, which form the clinical picture of HFpEF. Detecting high LVEF with tissue Doppler echocardiography by the E / e' value became the instrumental basis for the HFpEF diagnostics. Recognition of inflammation and fibrosis as the key pathogenetic factors marked the main vector of modern therapy for HFpEF (anti-inflammatory and antifibrotic). The best implementation of this vector became possible with the advent of drugs from the class of angiotensin receptor and neprilysin inhibitors (ARNI), sodium-glucose cotransporter type 2 (SGLT2) inhibitors, and aldosterone antagonists. However, the efficacy of such treatments is evident only with the LV EF <60-65% while at higher values, the efficacy substantially decreases. This limitation may result from the heterogenous nature of the disease and requires more advanced methods for verification of HFpEF clinical phenotypes. Among such methods, transcriptomic, metabolomic, and proteomic approaches are considered. With the use of capabilities of the "machine learning" and the artificial intelligence, these approaches can become a new frontier in research to represent an important step towards personalized medicine for patients with HFpEF.

QRS Fragmentation in Preserved Ejection Fraction Heart Failure: Functional Insights, Pathological Correlates, and Prognosis.

Background Fragmented QRS (fQRS) morphology as a surrogate marker of the possible presence of myocardial scarring has been shown to confer a higher risk in patients with reduced ejection fraction heart failure. We aimed to investigate the pathophysiological correlates and prognostic implications of fQRS in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We consecutively studied 960 patients with HFpEF (76.4±12.7 years, men: 37.2%). fQRS was assessed using a body surface ECG during hospitalization. QRS morphology was available and classified into 3 categories among 960 subjects with HFpEF as non-fQRS, inferior fQRS, and anterior/lateral fQRS groups. Despite comparable clinical features in most baseline demographics among the 3 fQRS categories, anterior/lateral fQRS showed significantly higher B-type natriuretic peptide/troponin levels (both P<0.001), with both the inferior and anterior/lateral fQRS HFpEF groups demonstrating a higher degree of unfavorable cardiac remodeling, greater extent of myocardial perfusion defect, and slower coronary flow phenomenon (all P<0.05). Patients with anterior/lateral fQRS HFpEF exhibited significantly altered cardiac structure/function and more impaired diastolic indices (all P<0.05). During a median of 657 days follow-up, the presence of anterior/lateral fQRS conferred a doubled HF re-admission risk (adjusted hazard ratio 1.90, P<0.001), with both inferior and anterior/lateral fQRS having a higher risk of cardiovascular and all-cause death (all P<0.05) by using Cox regression models. Conclusions The presence of fQRS in HFpEF was associated with more extensive myocardial perfusion defects and worsened mechanics, which possibly denotes a more severe involvement of cardiac damage. Early recognition in such patients with HFpEF likely benefits from targeted therapeutic interventions.

Effect of Training on Vascular Function and Repair in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Exercise training improves peak oxygen uptake (V.O2peak) in heart failure with preserved ejection fraction (HFpEF). Multiple adaptations have been addressed, but the role of circulating endothelium-repairing cells and vascular function have not been well defined. OBJECTIVES: The authors investigated effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on vascular function and repair in HFpEF. METHODS: This study is a subanalysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure) study randomizing patients with HFpEF (n = 180) to HIIT, MICT, or guideline control. At baseline, 3, and 12 months, the authors measured peripheral arterial tonometry (valid baseline measurement in n = 109), flow-mediated dilation (n = 59), augmentation index (n = 94), and flow cytometry (n = 136) for endothelial progenitor cells and angiogenic T cells. Abnormal values were defined as outside 90% of published sex-specific reference values. RESULTS: At baseline, abnormal values (%) were observed for augmentation index in 66%, peripheral arterial tonometry in 17%, flow-mediated dilation in 25%, endothelial progenitor cells in 42%, and angiogenic T cells in 18%. These parameters did not change significantly after 3 or 12 months of HIIT or MICT. Results remained unchanged when confining analysis to patients with high adherence to training. CONCLUSIONS: In patients with HFpEF, high augmentation index was common, but endothelial function and levels of endothelium-repairing cells were normal in most patients. Aerobic exercise training did not change vascular function or cellular endothelial repair. Improved vascular function did not significantly contribute to the V.O2peak improvement after different training intensities in HFpEF, contrary to previous studies in heart failure with reduced ejection fraction and coronary artery disease. (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure [OptimEx-Clin]; NCT02078947).