Cardio-Hepatic Interaction in Cardiac Amyloidosis.

Background: Congestion is associated with poor prognosis in cardiac amyloidosis (CA). The cardio-hepatic interaction and the prognostic impact of secondary liver affection by cardiac congestion in CA are poorly understood and require further characterisation. Methods: Participants of the amyloidosis cohort study AmyKoS at the Interdisciplinary Amyloidosis Centre of Northern Bavaria with proven transthyretin (ATTR-CA) and light chain CA (AL-CA) underwent serial work-up including laboratory tests, echocardiography, and in-depth hepatic assessment by vibration-controlled transient elastography (VCTE) and 13C-methacetin breath test. Results: In total, 74 patients with AL-CA (n = 17), ATTR-CA (n = 26) and the controls (n = 31) were analysed. ATTR-CA patients showed decreased microsomal liver function expressed by maximal percentage of dose rate (PDRpeak) related to hepatic congestion. Reduced PDRpeak in AL-CA could result from altered pharmacokinetics due to changed hepatic blood flow. Liver stiffness as a combined surrogate of chronic liver damage and congestion was identified as a predictor of all-cause mortality. Statistical modelling of the cardio-hepatic interaction revealed septum thickness, NT-proBNP and PDRpeak as predictors of liver stiffness in both CA subtypes; dilatation of liver veins and the fibrosis score FIB-4 were only significant for ATTR-CA. Conclusions: Non-invasive methods allow us to characterise CA-associated hepatic pathophysiology. Liver stiffness might be promising for risk stratification in CA.

Activated rate-response is associated with increased mortality risk in cardiac device carriers with acute heart failure.

AIMS: This study investigated whether an activated R-mode in patients carrying a cardiac implantable electronic device (CIED) is associated with worse prognosis during and after an episode of acutely decompensated heart failure (AHF). METHODS: Six hundred and twenty-three patients participating in an ongoing prospective cohort study that phenotypes and follows patients admitted for AHF were studied. We compared CIED carriers with activated R-mode stimulation (CIED-R) to CIED carriers not in R-mode (CIED-0) and patients without CIEDs (no-CIED). The independent impact of R-mode activation on 12-month all-cause death was examined using uni- and multivariable Cox proportional hazards regression taking into account potential confounders, and hazard ratios (HR) with their 95% confidence intervals (CI) were reported. RESULTS: Mean heart rate on admission was lower in CIED-R (n = 37, 16% women) vs. CIED-0 (n = 64, 23% women) or no-CIED (n = 511, 43% women): 70 bpm vs. 80 bpm or 82 bpm; both p<0.001. In-hospital mortality was similar across groups, but age- and sex-adjusted all-cause 12-month mortality risk was differentially affected by R-mode activation; CIED-R vs. CIED-0: HR 2.44, 95%CI 1.25-4.74; CIED-R vs. no-CIED: HR 2.61, 95%CI 1.59-4.29. These effects persisted after multivariable adjustment for potential confounders. Within CIED-R, mortality risk was similar in patients with pacemakers vs. ICDs and in subgroups with left ventricular ejection fraction (LVEF) <50% vs. ≥50%. CONCLUSION: In patients admitted with AHF, R-mode stimulation was associated with a significantly increased 12-month mortality risk. Our findings shed new light on "admission heart rate" as a potentially treatable target in AHF. Our data are compatible with the concept that chronotropic incompetence contributes to an adverse outcome in these patients and may not be adequately treated through accelerometer-based R-mode stimulation.

Determinants and reference values of the 6-min walk distance in the general population-results of the population-based STAAB cohort study.

AIMS: The 6-min walk test is an inexpensive, safe, and easy tool to assess functional capacity in patients with cardiopulmonary diseases including heart failure (HF). There is a lack of reference values, which are a prerequisite for the interpretation of test results in patients. Furthermore, determinants independent of the respective disease need to be considered when interpreting the 6-min walk distance (6MWD). METHODS: The prospective Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigates a representative sample of residents of the City of Würzburg, Germany, aged 30 to 79 years, without a history of HF. Participants underwent detailed clinical and echocardiographic phenotyping as well as a standardized assessment of the 6MWD using a 15-m hallway. RESULTS: In a sample of 2762 participants (51% women, mean age 58 ± 11 years), we identified age and height, but not sex, as determinants of the 6MWD. While a worse metabolic profile showed a negative association with the 6MWD, a better systolic and diastolic function showed a positive association with 6MWD. From a subgroup of 681 individuals without any cardiovascular risk factors (60% women, mean age 52 ± 10 years), we computed age- and height-specific reference percentiles. CONCLUSION: In a representative sample of the general population free from HF, we identified determinants of the 6MWD implying objective physical fitness associated with metabolic health as well as with cardiac structure and function. Furthermore, we derived reference percentiles applicable when using a 15-m hallway.

Prevalence of anti-beta-1 antibody 6 months after hospitalization for acute heart failure predicts adverse outcome.

AIMS: Agonistic antibodies against neurohumoral receptors can induce cardio-noxious effects by altering the baseline receptor activity. To estimate the prevalence of autoantibodies directed against the beta-1 receptor (b1-AAB) in patients admitted to the hospital for acute heart failure (HF) at (i) baseline and (ii) after 6 months of follow-up (F6) and (iii) after another 12 months of follow-up (i.e. 18 months after index hospitalization), to estimate their prognostic impact on clinical outcome (death or first hospitalization for HF). METHODS AND RESULTS: In 47 patients, b1-AAB were serially determined in serum samples collected at index hospitalization and at 6 months of follow-up (F6) with a flow cytometry-based assay: median age 71 years (quartiles 60, 80), 23 (49%) women, 24 (51%) HF with preserved ejection fraction. Beta1-AAB were detected in three subjects at index hospitalization (6%), and in eight subjects at F6 (17%). There were no differences apparent between patients with and without b1-AAB at F6 with regard to age, sex, type, duration, or main cause of HF. During the 12 month period following F6 (i.e. up to month 18), eight events occurred. Event-free survival was associated with prevalence of b1-AAB at F6. Compared with patients without b1-AAB at F6, age-adjusted Cox regression indicated a higher event risk in patients harbouring b1-AAB, with a hazard ratio of 8.96 (95% confidence interval 1.81-44.50, P = 0.007). CONCLUSIONS: Our results suggest a possible adverse prognostic relevance of b1-AAB in patients with acute HF, but this observation needs to be confirmed in larger patient collectives.

Rho-kinase inhibitors protect against neonatal hyperoxia-induced airway hyperreactivity in a rat pup model: Role of prostaglandin F2α.

BACKGROUND: Oxygen therapy in preterm neonates is associated with airway hyperreactivity. The role of Rho/Rho-kinase smooth muscle signaling in hyperoxia-induced airway hyperreactivity remains understudied. We hypothesized that inhibition of Rho-kinase will attenuate airway hyperreactivity induced by neonatal hyperoxia. METHODS: Newborn rats were raised in hyperoxia (>95% O2 ) or ambient air (AA) for 7 days. Subgroups were injected with a Rho-kinase inhibitor: Y-27632 (10 mg·kg-1 ·day-1 ) or fasudil (10 mg·kg-1 ·day-1 ), or a FP receptor antagonist - AS604872 (30 mg·kg-1 ·day-1 ). After exposures, tracheal cylinders were prepared for in vitro wire myography. Contraction to methacholine or PGF2α was measured in the presence or absence of tissue-bath Y-27632, fasudil, or AS604872. Lung PGF2α levels, Rho-kinase protein level and Rho-kinase 1 activity were measured by ELISA. RESULTS: Tracheal smooth muscle contraction was significantly greater in hyperoxic compared to AA groups. Both, Y-27632 and fasudil significantly decreased contractility to MCh or PGF2α in hyperoxic groups versus hyperoxic controls (p < 0.001), but did not alter AA group responses. Inhibition of FP receptors attenuated responses to PGF2α . Hyperoxia significantly increased lung PGF2α compared to AA (p < 0.01), but Rho-kinase inhibition did not influence PGF2α level. Rho-kinase protein level (p < 0.001) and activity (p < 0.01), were increased by hyperoxia, but blockade of FP receptor reduced the Rho-kinase 1 activity (p < 0.05) under hyperoxic condition. CONCLUSIONS: This study demonstrates an active role of Rho/Rho-kinase signaling on hyperoxia-induced airway hyperreactivity. These findings suggest that Rho-kinase inhibitors might serve as an effective therapy for hyperoxia-induced airway hyperreactivity.

Impact of cardiovascular risk factors on myocardial work-insights from the STAAB cohort study.

Myocardial work is a new echocardiography-based diagnostic tool, which allows to quantify left ventricular performance based on pressure-strain loops, and has been validated against invasively derived pressure-volume measurements. Myocardial work is described by its components (global constructive work [GCW], global wasted work [GWW]) and indices (global work index [GWI], global work efficiency [GWE]). Applying this innovative concept, we characterized the prevalence and severity of subclinical left ventricular compromise in the general population and estimated its association with cardiovascular (CV) risk factors. Within the Characteristics and Course of Heart Failure STAges A/B and Determinants of Progression (STAAB) cohort study we comprehensively phenotyped a representative sample of the population of Würzburg, Germany, aged 30-79 years. Indices of myocardial work were determined in 1929 individuals (49.3% female, mean age 54 ± 12 years). In multivariable analysis, hypertension was associated with a mild increase in GCW, but a profound increase in GWW, resulting in higher GWI and lower GWE. All other CV risk factors were associated with lower GCW and GWI, but not with GWW. The association of hypertension and obesity with GWI was stronger in women. We conclude that traditional CV risk factors impact selectively and gender-specifically on left ventricular myocardial performance, independent of systolic blood pressure. Quantifying active systolic and diastolic compromise by derivation of myocardial work advances our understanding of pathophysiological processes in health and cardiac disease.

Establishing a cardiac training group for patients with heart failure: the "HIP-in-Würzburg" study.

BACKGROUND: Exercise training in heart failure (HF) is recommended but not routinely offered, because of logistic and safety-related reasons. In 2020, the German Society for Prevention&Rehabilitation and the German Society for Cardiology requested establishing dedicated "HF training groups." Here, we aimed to implement and evaluate the feasibility and safety of one of the first HF training groups in Germany. METHODS: Twelve patients (three women) with symptomatic HF (NYHA class II/III) and an ejection fraction ≤ 45% participated and were offered weekly, physician-supervised exercise training for 1 year. Patients received a wrist-worn pedometer (M430 Polar) and underwent the following assessments at baseline and after 4, 8 and 12 months: cardiopulmonary exercise test, 6-min walk test, echocardiography (blinded reading), and quality of life assessment (Kansas City Cardiomyopathy Questionnaire, KCCQ). RESULTS: All patients (median age [quartiles] 64 [49; 64] years) completed the study and participated in 76% of the offered 36 training sessions. The pedometer was worn ≥ 1000 min per day over 86% of the time. No cardiovascular events occurred during training. Across 12 months, NT-proBNP dropped from 986 pg/ml [455; 1937] to 483 pg/ml [247; 2322], and LVEF increased from 36% [29;41] to 41% [32;46]%, (p for trend = 0.01). We observed no changes in exercise capacity except for a subtle increase in peak VO2% predicted, from 66.5 [49; 77] to 67 [52; 78]; p for trend = 0.03. The physical function and social limitation domains of the KCCQ improved from 60 [54; 82] to 71 [58; 95, and from 63 [39; 83] to 78 [64; 92]; p for trend = 0.04 and = 0.01, respectively. Positive trends were further seen for the clinical and overall summary scores. CONCLUSION: This pilot study showed that the implementation of a supervised HF-exercise program is feasible, safe, and has the potential to improve both quality of life and surrogate markers of HF severity. This first exercise experiment should facilitate the design of risk-adopted training programs for patients with HF.

Sex-specific bimodal clustering of left ventricular ejection fraction in patients with acute heart failure.

AIMS: There is an ongoing discussion whether the categorization of patients with heart failure according to left ventricular ejection fraction (LVEF) is scientifically justified and clinically relevant. Major efforts are directed towards the identification of appropriate cut-off values to correctly allocate heart failure-specific pharmacotherapy. Alternatively, an LVEF continuum without definite subgroups is discussed. This study aimed to evaluate the natural distribution of LVEF in patients presenting with acutely decompensated heart failure and to identify potential subgroups of LVEF in male and female patients. METHODS AND RESULTS: We identified 470 patients (mean age 75 ± 11 years, n = 137 female) hospitalized for acute heart failure in whom LVEF could be quantified by Simpson's method in an in-hospital echocardiogram. Non-parametric modelling revealed a bimodal shape of the LVEF distribution. Parametric modelling identified two clusters suggesting two LVEF peaks with mean (variance) of 61% (9%) and 31% (10%), respectively. Sub-differentiation by sex revealed a sex-specific bimodal clustering of LVEF. The respective threshold differentiating between 'high' and 'low' LVEF was 45% in men and 52% in women. CONCLUSIONS: In patients presenting with acute heart failure, LVEF clustered in two subgroups and exhibited profound sex-specific distributional differences. These findings might enrich the scientific process to identify distinct subgroups of heart failure patients, which might each benefit from respectively tailored (pharmaco)therapies.

Dynamics of Left Ventricular Myocardial Work in Patients Hospitalized for Acute Heart Failure.

BACKGROUND: The left ventricular ejection fraction (LVEF) is the most commonly used measure describing pumping efficiency, but it is heavily dependent on loading conditions and therefore not well-suited to study pathophysiologic changes. The novel concept of echocardiography-derived myocardial work (MyW) overcomes this disadvantage as it is based on LV pressure-strain loops. We tracked the in-hospital changes of indices of MyW in patients admitted for acute heart failure (AHF) in relation to their recompensation status and explored the prognostic utility of MyW indices METHODS AND RESULTS: We studied 126 patients admitted for AHF (mean 73 ± 12 years, 37% female, 40% with a reduced LVEF [<40%]), providing pairs of echocardiograms obtained both on hospital admission and prior to discharge. The following MyW indices were derived: global constructive and wasted work (GCW, GWW), global work index (GWI), and global work efficiency. In patients with HF with reduced ejection fraction with decreasing N-terminal prohormone B-natriuretic peptide levels during hospitalization, the GCW and GWI improved significantly, whereas the GWW remained unchanged. In patients with HF with preserved ejection fraction, the GCW and GWI were unchanged; however, in patients with no decrease or eventual increase in N-terminal prohormone B-natriuretic peptide, we observed an increase in GWW. In all patients with AHF, higher values of GWW were associated with a higher risk of death or rehospitalization within 6 months after discharge (per 10-point increment hazard ratio 1.035, 95% confidence interval 1.005-1.065). CONCLUSIONS: Our results suggest differential myocardial responses to decompensation and recompensation, depending on the HF phenotype in patients presenting with AHF. The GWW predicted the 6-month prognosis in these patients, regardless of LVEF. Future studies in larger cohorts need to confirm our results and identify determinants of short-term and longer term changes in MyW.

Left Ventricular Remodeling and Myocardial Work: Results From the Population-Based STAAB Cohort Study.

Introduction: Left ventricular (LV) dilatation and LV hypertrophy are acknowledged precursors of myocardial dysfunction and ultimately of heart failure, but the implications of abnormal LV geometry on myocardial function are not well-understood. Non-invasive LV myocardial work (MyW) assessment based on echocardiography-derived pressure-strain loops offers the opportunity to study detailed myocardial function in larger cohorts. We aimed to assess the relationship of LV geometry with MyW indices in general population free from heart failure. Methods and Results: We report cross-sectional baseline data from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of the general population of Würzburg, Germany, aged 30-79 years. MyW analysis was performed in 1,926 individuals who were in sinus rhythm and free from valvular disease (49.3% female, 54 ± 12 years). In multivariable regression, higher LV volume was associated with higher global wasted work (GWW) (+0.5 mmHg% per mL/m2, p < 0.001) and lower global work efficiency (GWE) (-0.02% per mL/m2, p < 0.01), while higher LV mass was associated with higher GWW (+0.45 mmHg% per g/m2, p < 0.001) and global constructive work (GCW) (+2.05 mmHg% per g/m2, p < 0.01) and lower GWE (-0.015% per g/m2, p < 0.001). This was dominated by the blood pressure level and also observed in participants with normal LV geometry and concomitant hypertension. Conclusion: Abnormal LV geometric profiles were associated with a higher amount of wasted work, which translated into reduced work efficiency. The pattern of a disproportionate increase in GWW with higher LV mass might be an early sign of hypertensive heart disease.

Adaptive anti-myocardial immune response following hospitalization for acute heart failure.

AIMS: It has been hypothesized that cardiac decompensation accompanying acute heart failure (AHF) episodes generates a pro-inflammatory environment boosting an adaptive immune response against myocardial antigens, thus contributing to progression of heart failure (HF) and poor prognosis. We assessed the prevalence of anti-myocardial autoantibodies (AMyA) as biomarkers reflecting adaptive immune responses in patients admitted to the hospital for AHF, followed the change in AMyA titres for 6 months after discharge, and evaluated their prognostic utility. METHODS AND RESULTS: AMyA were determined in n = 47 patients, median age 71 (quartiles 60; 80) years, 23 (49%) female, and 24 (51%) with HF with preserved ejection fraction, from blood collected at baseline (time point of hospitalization) and at 6 month follow-up (visit F6). Patients were followed for 18 months (visit F18). The prevalence of AMyA increased from baseline (n = 21, 45%) to F6 (n = 36, 77%; P < 0.001). At F6, the prevalence of AMyA was higher in patients with HF with preserved ejection fraction (n = 21, 88%) compared with patients with reduced ejection fraction (n = 14, 61%; P = 0.036). During the subsequent 12 months after F6, that is up to F18, patients with newly developed AMyA at F6 had a higher risk for the combined endpoint of death or rehospitalization for HF (hazard ratio 4.79, 95% confidence interval 1.13-20.21; P = 0.033) compared with patients with persistent or without AMyA at F6. CONCLUSIONS: Our results support the hypothesis that AHF may induce patterns of adaptive immune responses. More studies in larger populations and well-defined patient subgroups are needed to further clarify the role of the adaptive immune system in HF progression.

Myocardial work - correlation patterns and reference values from the population-based STAAB cohort study.

BACKGROUND: Recently, myocardial work analysis as an echocardiographic tool to non-invasively determine LV work has been introduced and validated against invasive measurements. Based on systolic blood pressure and speckle-tracking derived longitudinal strain (GLS) during systole and isovolumic relaxation, it is considered less load-dependent than LV ejection fraction (LVEF) or GLS and to integrate information on LV active systolic and diastolic work. OBJECTIVES: We aimed to establish reference values for global constructive (GCW) and global wasted work (GWW) as well as of global work index (GWI) and global work efficiency (GWE) across a wide age range and to assess the association with standard echocardiography parameters to estimate the potential additional information provided by myocardial work (MyW). METHODS: The Characteristics and Course of Heart Failure STAges A/B and Determinants of Progression (STAAB) cohort study carefully characterized a representative sample of the population of the City of Würzburg, Germany, aged 30-79 years. We performed myocardial work analysis using the standardized, quality-controlled transthoracic echocardiograms of all individuals lacking any cardiovascular risk factor. RESULTS: Out of 4965 participants, 779 (49±10 years, 59% women) were eligible for the present analysis. Levels of GCW, GWW, and GWE were independent of sex and body mass index, and were stable until the age of 45 years. Thereafter, we observed an upward shift to further stable values of GCW and a linear increase of GWW with advancing age, resulting in lower GWE. Age-adjusted percentiles for GCW, GWW, GWI, and GWE were derived. Higher levels of blood pressure or LV mass were associated with higher GCW, GWI, and GWW, resulting in lower GWE; higher LVEF correlated with higher GCW and GWI, but lower GWW. Higher E/e´ correlated with higher GWW, higher e´ with lower GWW. CONCLUSIONS: Derived from a large sample of apparently healthy individuals from a population based-cohort, we provide age-adjusted reference values for myocardial work indices, applicable for either sex. Weak correlations with common echocardiographic parameters suggest MyW indices to potentially provide additional information, which has to be evaluated in diseased patient cohorts.