Prognostic relevance of elevated plasma osmolality on admission in acute decompensated heart failure with preserved ejection fraction: insights from PURSUIT-HFpEF registry.

BACKGROUND: Complicated pathophysiology makes it difficult to identify the prognosis of heart failure with preserved ejection fraction (HFpEF). While plasma osmolality has been reported to have prognostic importance, mainly in heart failure with reduced ejection fraction (HFrEF), its prognostic meaning for HFpEF has not been elucidated. METHODS: We prospectively studied 960 patients in PURSUIT-HFpEF, a multicenter observational study of acute decompensated HFpEF inpatients. We divided patients into three groups according to the quantile values of plasma osmolality on admission. During a follow-up averaging 366 days, we examined the primary composite endpoint of cardiac mortality or heart failure re-admission using Kaplan-Meier curve analysis and Cox proportional hazard testing. RESULTS: 216 (22.5%) patients reached the primary endpoint. Kaplan-Meier curve analysis revealed that the highest quantile of plasma osmolality on admission (higher than 300.3 mOsm/kg) was significantly associated with adverse outcomes (Log-rank P = 0.0095). Univariable analysis in the Cox proportional hazard model also revealed significantly higher rates of adverse outcomes in the higher plasma osmolality on admission (hazard ratio [HR] 7.29; 95% confidence interval [CI] 2.25-23.92, P = 0.0009). Multivariable analysis in the Cox proportional hazard model also showed that higher plasma osmolality on admission was significantly associated with adverse outcomes (HR 5.47; 95% CI 1.46-21.56, P = 0.0113) independently from other confounding factors such as age, gender, comorbid of atrial fibrillation, hypertension history, diabetes, anemia, malnutrition, E/e', and N-terminal pro-B-type natriuretic peptide elevation. CONCLUSIONS: Higher plasma osmolality on admission was prognostically important for acute decompensated HFpEF inpatients.

Waist to height ratio is associated with an increased risk of mortality in Chinese patients with heart failure with preserved ejection fraction.

BACKGROUND: Abdominal obesity as a predominant comorbidity has played a key role in the incidence and worsening of heart failure with preserved ejection fraction (HFpEF), and waist-to-height ratio (WHtR) behaves better than waist circumference or body mass index in evaluating abdominal obesity. While the association between WHtR and all-cause death in Chinese patients with HFpEF remains unclear. METHODS: Patients with stable HFpEF (N = 2041) who presented to our hospital from January 2008 to July 2019 were divided into low-WHtR (< 0.5, N = 378) and high-WHtR (≥ 0.5, N = 1663). Multivariable Cox proportional-hazard models were used to examine the association of WHtR with all-cause death. RESULTS: The average age was 76.63 ± 11.44 years, and the mean follow-up was 4.53 years. During follow-up, 185 patients (9.06%) reached the primary outcome of all-cause death. As for the secondary outcome, 79 patients (3.87%) experienced cardiovascular death, 106 (5.19%) had non-cardiovascular death, and 94 (4.61%) had heart failure rehospitalization. After multivariable adjustment, a higher WHtR was significantly associated with the increased risks of all-cause death [adjusted hazard ratios (HR) 1.91, 95% confidence interval (CI) 1.06-3.45, p = 0.032], cardiovascular death (adjusted HR 2.58; 95% CI 1.01-6.67, p = 0.048), and HF rehospitalization (adjusted HR 3.04; 95% CI 1.26-7.31, p = 0.013). CONCLUSIONS: Higher WHtR is an independent risk factor for all-cause death in Chinese patients with HFpEF.

Feature Tracking of Global Longitudinal Strain by Using Cardiovascular MRI Improves Risk Stratification in Heart Failure with Preserved Ejection Fraction.

Background In heart failure with preserved ejection fraction (HFpEF), echocardiographic studies suggest that global longitudinal strain (GLS) has an impact on survival. Feature-tracking cardiovascular MRI also allows for strain analysis; however, to the knowledge of the authors, little is known about its prognostic value and whether it reflects severity of diffuse fibrosis, as assessed by cardiovascular MRI T1 mapping. Purpose To investigate the association between myocardial strain at cardiovascular MRI with extracellular volume by T1 mapping and outcome in participants with HFpEF. Materials and Methods In this secondary analysis of a prospective study (NCT03405987), consecutive participants with HFpEF underwent cardiovascular MRI between July 2012 and March 2018, including T1 mapping and three-dimensional strain analysis. Extracellular volume and strain results were assessed to determine if there was a correlation between these two factors. Cox regression was performed to determine the prognostic relevance of MRI-derived myocardial strain for a combined end point (events) of heart failure hospitalizations and cardiovascular death. Results In total, 206 consecutive participants with HFpEF (mean age, 71 years ± 8 [standard deviation]; 69% women) were included. Median myocardial global longitudinal strain (GLS) at MRI was -8.5% and showed low correlation with extracellular volume (r = 0.28; P = .003). A total of 109 events (53%) were recorded during a follow-up of 38 months ± 29. Participants with a GLS above the median had higher event rates (log-rank test, P < .001). By multivariable Cox regression analysis, GLS remained independently associated with outcome (hazard ratio, 1.06 per 1% strain increase; 95% confidence interval: 1.01, 1.11; P = .03) when corrected for risk factors including age, diabetes, renal function, N-terminal pro-b-type natriuretic peptide serum concentration, and right ventricular size and function. Conclusion In participants with heart failure with preserved ejection fraction, global longitudinal strain at cardiovascular MRI was correlated with extracellular volume by T1 mapping and was associated with cardiovascular events. © RSNA, 2020 Online supplemental material is available for this article.

Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients.

AIMS: Diastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. However, its cellular mechanisms are not fully understood, and presently there is no effective treatment. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold great potential for investigating the mechanisms underlying DD in HCM and as a platform for drug discovery. METHODS AND RESULTS: In the present study, beating iPSC-CMs were generated from healthy controls and HCM patients with DD. Micropatterned iPSC-CMs from HCM patients showed impaired diastolic function, as evidenced by prolonged relaxation time, decreased relaxation rate, and shortened diastolic sarcomere length. Ratiometric Ca2+ imaging indicated elevated diastolic [Ca2+]i and abnormal Ca2+ handling in HCM iPSC-CMs, which were exacerbated by ß-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF/Δ[Ca2+]i) in HCM iPSC-CMs. These results were confirmed with genome-edited isogenic iPSC lines that carry HCM mutations, indicating that cytosolic diastolic Ca2+ overload, slowed [Ca2+]i recycling, and increased myofilament Ca2+ sensitivity, collectively impairing the relaxation of HCM iPSC-CMs. Treatment with partial blockade of Ca2+ or late Na+ current reset diastolic Ca2+ homeostasis, restored diastolic function, and improved long-term survival, suggesting that disturbed Ca2+ signalling is an important cellular pathological mechanism of DD. Further investigation showed increased expression of L-type Ca2+channel (LTCC) and transient receptor potential cation channels (TRPC) in HCM iPSC-CMs compared with control iPSC-CMs, which likely contributed to diastolic [Ca2+]i overload. CONCLUSION: In summary, this study recapitulated DD in HCM at the single-cell level, and revealed novel cellular mechanisms and potential therapeutic targets of DD using iPSC-CMs.

Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction.

Aims: Coronary microvascular ischaemia, cardiomyocyte injury and stiffness may play an important role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). To date, the relationship between coronary flow reserve (CFR), myocardial injury, diastolic dysfunction, and future HFpEF risk is unknown. Methods and results: Consecutive patients (n = 201) undergoing evaluation for suspected coronary artery disease (CAD) with stress myocardial perfusion positron emission tomography, serum troponin, and transthoracic echocardiography who did not have flow-limiting CAD or reduced left ventricular ejection fraction were identified. Patients were followed up (median 4.1 years) for cardiovascular death and hospitalization for non-fatal myocardial infarction or heart failure. Coronary flow reserve was quantified as stress/rest myocardial blood flow. Early diastolic flow (E) and relaxation (e') velocities were obtained via transmitral and tissue Doppler, respectively. Patients with impaired CFR (<2, n = 108) demonstrated linearly decreasing e' and increasing E/e' consistent with worsening diastolic function (P for trend <0.0001). A detectable troponin was associated with diastolic dysfunction only in the presence of impaired CFR (interaction P = 0.002). In adjusted analyses, impaired CFR was independently associated with diastolic dysfunction (E/e'septal > 15, adjusted OR 2.58, 95%CI 1.22-5.48) and composite cardiovascular outcomes or HFpEF hospitalization alone (adjusted HR 2.47, 95%CI 1.09-5.62). Patients with both impaired CFR and diastolic dysfunction demonstrated >five-fold increased risk of HFpEF hospitalization (P < 0.001). Conclusion: In symptomatic patients without overt CAD, impaired CFR was independently associated with diastolic dysfunction and adverse events, especially HFpEF hospitalization. The presence of both coronary microvascular and diastolic dysfunctions was associated with a markedly increased risk of HFpEF events.

Tissue Doppler assessment of diastolic function and relationship with mortality in critically ill septic patients: a systematic review and meta-analysis.

BACKGROUND: Myocardial dysfunction may contribute to circulatory failure in sepsis. There is growing evidence of an association between left ventricular diastolic dysfunction (LVDD) and mortality in septic patients. Utilizing echocardiography, we know that tissue Doppler imaging (TDI) variables e' and E/e' are reliable predictors of LVDD and are useful measurements to estimate left ventricular (LV) filling pressures. METHODS: We conducted a systematic review and meta-analysis to investigate the association of e' and E/e' with mortality of patients with severe sepsis or septic shock. In the primary analysis, we included studies providing transthoracic TDI data for e' and E/e' and their association with mortality. Subgroup analyses were conducted according to myocardial regional focus of TDI assessment (septal, lateral or averaged). Three secondary analyses were performed: one included data from a transoesophageal study, another excluded studies reporting data at a very early (<6 h) or late (>48 h) stage following diagnosis, and the third pooled data only from studies excluding patients with heart valve disease. RESULTS: The primary analysis included 16 studies with 1507 patients with severe sepsis and/or septic shock. A significant association was found between mortality and both lower e' [standard mean difference (SMD) 0.33; 95% confidence interval (CI): 0.05, 0.62; P=0.02] and higher E/e' (SMD -0.33; 95% CI: -0.57, -0.10; P=0.006). In the subgroup analyses, only the lateral TDI values showed significant association with mortality (lower e' SMD 0.45; 95% CI: 0.11, 0.78; P=0.009; higher E/e' SMD -0.49; 95% CI: -0.76, -0.22; P=0.0003). The findings of the primary analysis were confirmed by all secondary analyses. CONCLUSIONS: There is a strong association between both lower e' and higher E/e' and mortality in septic patients.

Socioeconomic factors and mortality in diastolic heart failure.

BACKGROUND: Mortality in patients with heart failure with preserved ejection fraction (HFPEF) has remained stable over recent decades. Few studies have explored prognostic characteristics specifically in HFPEF, and none of them has assessed the potential impact of socioeconomic factors. We aimed to evaluate the impact of socioeconomic factors on all-cause and cardiovascular mortality in HFPEF patients. MATERIALS AND METHODS: We used data from the French ODIN cohort. All patients with heart failure and a left ventricular ejection fraction (LVEF) > 45%, included in ODIN between July 2007 and July 2010, were eligible here. Socioeconomic, demographic, clinical, biological and therapeutic data were collected at inclusion. The endpoints were all-cause and cardiovascular mortality between inclusion and 30 September 2011. The impact of patient socioeconomic characteristics on mortality was assessed using Cox regression models. RESULTS: Of 575 HFPEF patients considered, 58·6% were male; their mean age was 71·1 ± 13·5 years, and their mean LVEF was 58·1 ± 8·5%. After adjustment for confounders, living alone and limitations on activities of daily living were associated with all-cause mortality [HR = 1·77, 95%CI(1·11-2·81) and 2·61(1·35-5·03), respectively] and cardiovascular mortality [2·26 (1·24-4·10) and 3·16 (1·33-7·54), respectively]. Having a professional occupation was associated with a lower cardiovascular mortality only [0·37(0·15-0·94)]. CONCLUSIONS: Poor social conditions impair survival in patients with HFPEF. These findings may shed new light on how best to detect HFPEF patients with high health-care needs.

Diastolic heart failure: the current understanding and approach for management with focus on intensive care unit patients.

Multiple recent epidemiologic studies have highlighted the importance of diastolic heart failure (DHF) as a public health problem. Approximately half of patients presenting with symptomatic heart failure (HF) have DHF and they suffer from morbidity and mortality comparable to those with systolic HF. Our understanding of the pathophysiology of DHF has evolved rapidly over the last decade, and the associated echo-Doppler findings that assist with its diagnosis are greatly refined. Recently, there has been increased recognition of the role of diastolic dysfunction and DHF in the care of critically ill patients, including those admitted to noncardiac units. The purpose of this review is to provide an up-to-date summary of the concepts of the pathophysiology of DHF. In addition, we provide an overview of the diagnostic approaches, prognostic identifiers, and associated comorbidities that make DHF more resistant to manage with a focus of the patients admitted to the intensive care unit. The current approach to managing patients with DHF is also reviewed.

Prevalence and outcome of diastolic dysfunction in children with fluid refractory septic shock--a prospective observational study.

OBJECTIVES: Our primary objective was to determine the prevalence and outcome of diastolic dysfunction in children with fluid refractory septic shock. The secondary objective was to determine possible early predictors of diastolic dysfunction. DESIGN: Prospective observational study. SETTING: PICU of a tertiary care teaching hospital. PATIENTS: Consecutive children 17 years old or younger with fluid refractory septic shock and not on mechanical ventilation admitted to our ICU from June 2011 to August 2012 were included. Survivors were followed up till 1 year of discharge (July 2013). INTERVENTIONS: Children were subjected to 2D echocardiography and qualitative cardiac troponin-T test within the first 6 hours of admission. MEASUREMENTS AND MAIN RESULTS: A total of 56 children were included. Median age was 7 years (interquartile range, 1.5, 14) and majority (52%) were males. Most common underlying diagnoses were meningitis and pneumonia. The prevalence of diastolic dysfunction was 41.1% (95% CI, 27.8-54.4), and mortality rate was 43% in those with diastolic dysfunction. At 1-year follow-up, residual dysfunction was present in only one of 11 of the survivors (11%). On univariable analysis of possible early predictors of diastolic dysfunction, we observed that these children tended to have higher mean central venous pressure (13 vs 6; p < 0.0001) and greater positivity for cardiac troponin-T (70% vs 36%; p = 0.01) compared with others. Although factors such as duration of illness and diastolic blood pressure were also lower in children with diastolic dysfunction compared with others, the difference was not statistically significant. On multivariable analysis, only the variable central venous pressure remained significant (adjusted odds ratio, 1.6; 95% CI, 1.12-2.14; p = 0.008). CONCLUSIONS: Diastolic dysfunction is common in children with fluid refractory septic shock, and immediate outcomes may be poorer in such patients. Increased central venous pressure after initial fluid resuscitation may be an early indicator of diastolic dysfunction and warrant urgent bedside echocardiography to guide further management.

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.

Heart rate and heart failure: the role of ivabradine therapy.

PURPOSE OF REVIEW: The clinical data about the impact of heart rate reduction in heart failure therapy will be reviewed. RECENT FINDINGS: Clinical and experimental studies showed an association between elevated resting heart rate and mortality risk in heart failure patients. This review summarizes that heart rate level at rest and its extent of reduction is a sensitive indicator for outcome in heart failure. In addition to the nonspecific heart rate reducing drugs like ß-blockers, cardiac glycosides and Ca(2+) antagonists, ivabradine is a highly selective heart rate reducing agent without modifying ventricular contractility and atrioventricular conduction in humans and animals, and has recently been shown to improve cardiovascular outcomes in patients with systolic heart failure by lowering the heart rate only. The present and future role of heart rate reduction in the spectrum of heart failure disease and therapy will be outlined and evaluated. SUMMARY: Elevated heart rate at rest represents a key indicator of adverse outcome in heart failure and implies a major treatment target in these patients.

Diastolic dysfunction and mortality in severe sepsis and septic shock.

AIMS: Systolic dysfunction in septic shock is well recognized and, paradoxically, predicts better outcome. In contrast, diastolic dysfunction is often ignored and its role in determining early mortality from sepsis has not been adequately investigated. METHODS AND RESULTS: A cohort of 262 intensive care unit patients with severe sepsis or septic shock underwent two echocardiography examinations early in the course of their disease. All clinical, laboratory, and survival data were prospectively collected. Ninety-five (36%) patients died in the hospital. Reduced mitral annular e'-wave was the strongest predictor of mortality, even after adjusting for the APACHE-II score, low urine output, low left ventricular stroke volume index, and lowest oxygen saturation, the other independent predictors of mortality (Cox's proportional hazards: Wald = 21.5, 16.3, 9.91, 7.0 and 6.6, P< 0.0001, <0.0001, 0.002, 0.008, and 0.010, respectively). Patients with systolic dysfunction only (left ventricular ejection fraction ≤50%), diastolic dysfunction only (e'-wave <8 cm/s), or combined systolic and diastolic dysfunction (9.1, 40.4, and 14.1% of the patients, respectively) had higher mortality than those with no diastolic or systolic dysfunction (hazard ratio = 2.9, 6.0, 6.2, P= 0.035, <0.0001, <0.0001, respectively) and had significantly higher serum levels of high-sensitivity troponin-T and N-terminal pro-B-type natriuretic peptide (NT-proBNP). High-sensitivity troponin-T was only minimally elevated, whereas serum levels of NT-proBNP were markedly elevated [median (inter-quartile range): 0.07 (0.02-0.17) ng/mL and 5762 (1001-15 962) pg/mL, respectively], though both predicted mortality even after adjusting for highest creatinine levels (Wald = 5.8, 21.4 and 2.3, P= 0.015, <0.001 and 0.13). CONCLUSION: Diastolic dysfunction is common and is a major predictor of mortality in severe sepsis and septic shock.

Impact of peri-transplant heart failure & left-ventricular diastolic dysfunction on outcomes following liver transplantation.

BACKGROUND & AIMS: Assess the prevalence of peri-transplant heart failure and its potential relation to post-transplant morbidity and mortality. METHODS: A retrospective study was performed on 234 consecutive cirrhotic patients undergoing liver transplantation in a single European center from 1999 to 2007 (mean age 52, 30% women, 36% with alcoholic liver disease, 24% with viral hepatitis, 18% cholestatic liver disease). Left ventricular diastolic dysfunction was defined as E/A ratio ≤ 1. We used the Boston classification for heart failure to assess the prevalence of peri-transplant heart failure. Patients were followed up for a mean of 4 years post-transplant (0.5-9 years). RESULTS: Eighteen per cent of patients demonstrated diastolic dysfunction pretransplant. During the peri-transplantation period highly possible heart failure occurred in 27%. In logistic regression analysis, heart failure was independently related to lower mean arterial blood pressure (OR 0.94, 95% CR 0.91-0.98) and prolonged corrected QT time on ECG (OR 9.10, 95% CI 3.77-21.93) pretransplant. Peri-transplant mortality amounted to 5%, and was independently related to heart failure (OR 15.11, 95% CI 1.76-129.62) and the peri-transplant need of dialysis (OR 14.18, 95% CI 1.65-121.89). Heart failure was also associated with longer stay in the intensive care unit and peri-transplant cardiac events (P < 0.05). Long-term transplant-free mortality was independently related to diastolic dysfunction at baseline (Hazard ratio 4.82, 95% CI 1.78-13.06). CONCLUSION: Heart failure occurs in approximately a quarter of patients with cirrhosis following liver transplantation and it is an independent predictor of mortality and morbidity.

Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice.

Heart failure is associated with a change in cardiac energy metabolism. SIRT1 is a NAD(+)-dependent protein deacetylase, and important in the regulation of cellular energy metabolism. To examine the role of SIRT1 in cardiac energy metabolism, we created transgenic mice overexpressing SIRT1 in a cardiac-specific manner, and investigated cardiac functional reserve, energy reserve, substrate uptake, and markers of mitochondrial function. High overexpression of SIRT1 caused dilated cardiomyopathy. Moderate overexpression of SIRT1 impaired cardiac diastolic function, but did not cause heart failure. Fatty acid uptake was decreased and the number of degenerated mitochondria was increased dependent on SIRT1 gene dosage. Markers of reactive oxygen species were decreased. Changes in morphology and reactive oxygen species were associated with the reduced expression of genes related to mitochondrial function and autophagy. In addition, the respiration of isolated mitochondria was decreased. Cardiac function was normal in transgenic mice expressing a low level of SIRT1 at baseline, but the mice developed cardiac dysfunction upon pressure overload. In summary, the constitutive overexpression of SIRT1 reduced cardiac function associated with impaired mitochondria in mice.

Plasma levels of tumor necrosis factor-α and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase.

OBJECTIVE: The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-α and interleukin-6), diastolic heart failure, and the possible molecular mechanism. DESIGN: Prospective case-controlled cohort and molecular studies. SETTING: University hospital and research laboratory. SUBJECTS: Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure. INTERVENTIONS: Soluble plasma levels of tumor necrosis factor-α and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-α and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated. MEASUREMENTS AND MAIN RESULTS: Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-α and interleukin-6 than the control subjects. Significant correlations (p < .01 for each) were found for tumor necrosis factor-α and E/Em (r = .87) and E/A (r = -0.69), and for interleukin-6 and E/Em (r = .80) and E/A (r = -0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-α, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-α and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes. CONCLUSIONS: Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions.

[Volume regulation in cardiac insufficiency : possibilities of telephone coaching and peritoneal dialysis]. / Volumenregulation bei Herzinsuffizienz : Möglichkeiten des Telefon-Coachings sowie der Peritonealdialyse.

Volume retention is the hallmark of progressive heart failure, both systolic and diastolic (heart failure with preserved ejection fraction). It represents the cause of the main symptoms (dyspnea, edema, liver synthesis) and also the main target of drug therapy. Antagonizing excessive volume retention is also the most important therapy element. Many patients can be stabilized with sequential nephron blockade (thiazide + loop diuretics) combined with afterload reduction [blockade of the RAAS (renin-angiotensin-aldosterone) system]. Personal patient coaching combined with telemetric components (weight, blood pressure) has evolved as another cornerstone of treatment in heart failure patients. If these measures are insufficient to control volume retention, renal replacement therapy is effective and can improve quality of life. More specifically, aquaresis via peritoneal dialysis has been shown to be effective and adequate to control volume overload. Many patients may qualify for this evolving therapy as it effectively prevents repeat hospitalization for heart failure decompensation, can be performed in an out-patient setting and has a low complication rate, thus significantly improving quality of life.

[Diagnosis and therapy of heart failure with normal ejection fraction]. / Diastolische Herzinsuffizienz - Diagnostik und Therapie.

Diastolic heart failure, also termed as heart failure with normal or preserved ejection fraction has a high prevalence and mortality world wide. The clinical manifestation comprises typical symptoms and signs of heart failure along with normal or discretely reduced left ventricular ejection fraction. Though the etiology of diastolic heart failure is incompletely understood, functional and structural abnormalities of cardiomyocytes, the extracellular matrix, and the peripheral vasculature are assumed to contribute to the etiology of diastolic heart failure. The diagnosis requires typical symptoms and signs of heart failure, evidence of elevated natriuretic peptides and an impaired diastolic ventricular function, meanwhile left ventricular systolic function is normal or just slightly impaired. Catheter and MRI exams help to ensure the diagnosis. So far, no therapy has convincingly demonstrated a reduction of morbiditiy and mortality. Therefore, current guidelines emphasize the importance of an adequate treatment of risk factors and myocardial ischemia.

Reciprocal organ interactions during heart failure: a position paper from the ESC Working Group on Myocardial Function.

Heart failure-either with reduced or preserved ejection fraction (HFrEF/HFpEF)-is a clinical syndrome of multifactorial and gender-dependent aetiology, indicating the insufficiency of the heart to pump blood adequately to maintain blood flow to meet the body's needs. Typical symptoms commonly include shortness of breath, excessive fatigue with impaired exercise capacity, and peripheral oedema, thereby alluding to the fact that heart failure is a syndrome that affects multiple organ systems. Patients suffering from progressed heart failure have a very limited life expectancy, lower than that of numerous cancer types. In this position paper, we provide an overview regarding interactions between the heart and other organ systems, the clinical evidence, underlying mechanisms, potential available or yet-to-establish animal models to study such interactions and finally discuss potential new drug interventions to be developed in the future. Our working group suggests that more experimental research is required to understand the individual molecular mechanisms underlying heart failure and reinforces the urgency for tailored therapeutic interventions that target not only the heart but also other related affected organ systems to effectively treat heart failure as a clinical syndrome that affects and involves multiple organs.

Demonstrating the pharmacogenetic effects of angiotensin-converting enzyme inhibitors on long-term prognosis of diastolic heart failure.

The objective of this study was to evaluate the effects of angiotensin-converting enzyme (ACE) inhibitors and pharmacogenetic interaction on the survival of the patients with diastolic heart failure (DHF). A total of 285 subjects with DHF confirmed by echocardiography were recruited in the period between 1995 and 2003. Baseline characteristics (age, sex, prior history, medication, and echocardiographic findings) and genetic polymorphisms (ACE gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen (AGT) gene; and A1166C polymorphisms of the angiotensin II type I receptor (AT1R)) were collected and matched (by propensity score) in those who received and those who did not receive ACE inhibitors. The patients were followed up to 10 years. Kaplan-Meier curves and Cox regression models were used to demonstrate the survival trend. The 85 patients who received ACE inhibitors and the other 85 patients who did not were found to have comparable baseline characteristics and polymorphism distribution. Prescription of ACE inhibitors was associated with a significant decrease in overall mortality (hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.24-0.83; P=0.01), and a lower rate of cardiovascular events at 4000 days (HR, 0.53; 95% CI, 0.32-0.90; P=0.02). In addition, ACE I/D gene D allele was associated with higher overall mortality as compared with the I allele (HR, 2.04; P=0.003). This effect was diminished in those who received ACE inhibitors. The use of ACE inhibitor was associated with a significant decrease in long-term mortality and cardiovascular events in the patients with DHF. Genetic variants in the renin-angiotensin system genes were also associated, but their effects could be modified by the use of ACE inhibitors.

Heart failure with normal ejection fraction: consideration of mechanisms other than diastolic dysfunction.

More than half of patients with heart failure (HF) have a normal ejection fraction (EF). These patients are typically elderly, are predominantly female, and have a high incidence of multiple comorbid conditions associated with development of ventricular hypertrophy and/or interstitial fibrosis. Thus, the cause of HF has been attributed to diastolic dysfunction. However, the same comorbidities may also impact myocardial systolic, ventricular, vascular, renal, and extracardiovascular properties in ways that can also contribute to symptoms of HF by way of mechanisms not related to diastolic dysfunction. Accordingly, the descriptive term HF with normal EF has been suggested as an alternative to the mechanistic term diastolic HF. In this article, we review the current understanding of nondiastolic mechanisms that may contribute to the HF with normal EF syndrome to highlight potential pathways for research that may lead to new targets for therapy.