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ObjectiveClinical decision making in chronic heart failure (CHF) is based primarily on left ventricular ejection fraction (LVEF), and only secondarily on aetiology of the underlying disease. Our aim was to investigate the mediating role of LVEF in the relationship between aetiology and mortality.MethodsUsing data of 2056 Austrian patients with CHF (mean age 57.2 years; mean follow-up 8.8 years), effects of aetiology on LVEF and overall mortality were estimated using multivariable-adjusted linear and Cox regression models. In causal mediation analyses, we decomposed the total effect of aetiology on mortality into direct and indirect (mediated through LVEF) effects.ResultsFor the analysed aetiologies (dilated (DCM, n=1009) and hypertrophic (HCM, n=89) cardiomyopathy; ischaemic (IHD, n=529) and hypertensive (HHD, n=320) heart disease; cardiac amyloidosis (CA, n=109)), the effect of LVEF on mortality was similar (HR5%-points lower LVEF=1.07, 95% CI 1.04 to 1.10; pinteraction=0.718). HCM and CA were associated with significantly higher, and IHD and DCM with significantly lower LVEF compared with other aetiologies. Compared with respective other aetiologies, the corresponding total effect HRs for mortality were 0.77 (95% CI 0.67 to 0.89), 0.47 (95% CI 0.25 to 0.88), 1.40 (95% CI 1.21 to 1.62), 0.79 (95% CI 0.67 to 0.95) and 2.36 (95% CI 1.81 to 3.08) for DCM, HCM, IHD, HHD and CA, respectively. CA had the highest mortality despite a HRindirect effect of 0.74 (95% CI 0.65 to 0.83). For all other aetiologies, <20% of the total mortality effects were mediated through LVEF.ConclusionsThe direct effect of aetiology on mortality dominates the indirect effect through LVEF. Therefore, clarification of aetiology is as important as measurement of LVEF.

The premature aging disease Hutchinson–Gilford Syndrome (HGPS) is caused by defined mutations in the LMNA gene, resulting in the activation of a cryptic splice donor site, which leads to a defective truncated prelamin A protein called progerin. Notably, progerin expression has also been detected in non-mutated healthy individuals, and therefore, its involvement in the physiological aging process has been widely discussed. Since diabetes mellitus is associated with premature aging and increased cardiovascular mortality, we aimed to investigate the role of progerin expression in patients with diabetic retinopathy (DR). mRNA expression of progerin was analyzed in blood samples from 140 patients with DR who received anti-vascular endothelial growth factor (VEGF) therapy. Progerin mRNA levels were significantly lower in female compared to male patients (n = 42 vs. n = 98; 0.67 ± 0.19 vs. 0.89 ± 0.51, p = 0.006) and higher in patients with non-proliferative (NP)DR (n = 87 vs. n = 53; 0.9 ± 0.51 vs. 0.71 ± 0.29, p = 0.013) compared to those with proliferative (P)DR. Additionally, a positive correlation was found between progerin mRNA expression and the number of intravitreal anti-VEGF applications (n = 139, r = 0.21, p = 0.015), central macula thickness (CMT), (n = 137, r = 0.18, p = 0.036) and nicotine consumption (n = 105, r = 0.235, p = 0.002). The nuclear localization and significant upregulation of progerin mRNA and protein levels in dermal fibroblasts from HGPS donors emphasize its role in cellular aging mechanisms. Progerin mRNA levels were higher in patients with NPDR. CMT, number of intravitreal anti-VEGF therapy treatments, and cigarette consumption were positively related to progerin mRNA, suggesting an association with disease progression and premature aging.

Mutations in the LMNA gene are a common cause (6-8%) of dilated cardiomyopathy (DCM) leading to heart failure, a growing health care problem worldwide. The premature aging disease Hutchinson-Gilford syndrome (HGPS) is also caused by defined mutations in the LMNA gene resulting in activation of a cryptic splice donor site leading to a defective truncated prelamin A protein called progerin. Low levels of progerin are expressed in healthy individuals associated with ageing. Here, we aimed to address the role of progerin in dilated cardiomyopathy. mRNA expression of progerin was analyzed in heart tissue of DCM (n = 15) and non-failing hearts (n = 10) as control and in blood samples from patients with DCM (n = 56) and healthy controls (n = 10). Sequencing confirmed the expression of progerin mRNA in the human heart. Progerin mRNA levels derived from DCM hearts were significantly upregulated compared to controls (1.27 ± 0.42 vs. 0.81 ± 0.24; p = 0.005). In contrast, progerin mRNA levels in whole blood cells were not significantly different in DCM patients compared to controls. Linear regression analyses revealed that progerin mRNA in the heart is significantly negatively correlated to ejection fraction (r = -0.567, p = 0.003) and positively correlated to left ventricular enddiastolic diameter (r = 0.551, p = 0.004) but not with age of the heart per se. Progerin mRNA levels were not influenced by inflammation in DCM hearts. Immunohistochemistry and Immunofluorescence analysis confirmed increased expression of progerin protein in cell nuclei of DCM hearts associated with increased TUNEL+ apoptotic cells. Our data suggest that progerin is upregulated in human DCM hearts and strongly correlates with left ventricular remodeling. Progerin might be involved in progression of heart failure and myocardial aging.

Aims Iron is essential to maintain cellular energy metabolism in the myocardium. Impaired cellular iron availability negatively affects myocardial physiology and can aggravate heart failure (HF). Iron deficiency (ID) is frequently found in patients with acute and chronic HF (AHF, CHF) and associated with clinical outcome. The aim of this analysis was to assess the true ID prevalence in HF patients on the basis of different ID definitions. Methods We performed a retrospective analysis of 329 AHF and 613 CHF patients, recruited between 02/2021 and 05/2022 at the Innsbruck Medical University (47%/32% female, median age 81/64 years). ID was defined according to a general definition, gastroenterology and cardiology guidelines as ferritin <30 or <45 ng/mL or <100/ng/mL (absolute ID), ferritin 30–100 or 45–150 or 100–299 ng/mL plus TSAT <20% (combined ID), and ferritin >100 or >150 or ≥300 ng/mL plus TSAT <20% (functional ID). Results ID prevalence was significantly higher in AHF compared with CHF patients: general definition (74.8% vs. 32.6%, P < 0.001), gastroenterology guidelines (75.7% vs. 34.7%, P < 0.001), cardiology guidelines (79.9% vs. 47.3%, P < 0.001). We found distinctive differences in prevalence of ID types between the three definitions. Absolute ID prevalence was highest when applying cardiology compared with gastroenterology guidelines and general definition (AHF: 44.7% vs. 20.4% vs. 7.0%; CHF: 34.1% vs. 13.4% vs. 7.2%), while frequency of combined ID was almost equally distributed. Functional ID prevalence was highest when applying general definition compared with gastroenterology and cardiology guidelines (AHF: 34.7% vs. 23.4% vs. 11.6%; CHF: 13.1% vs. 9.0% vs. 3.4%). Out of 494 patients classified as having absolute or combined ID according to the cardiology guidelines, only 252 patients received the same classification while 107 and 135 patients were classified having no and functional ID when applying the general definition. Conclusions We show that ID prevalence is higher in AHF versus CHF patients in a continuous cohort of HF patients managed at the same institution over the same period of time. There were distinctive differences in detection of ID and the type of ID when applying several recommended definitions thus affecting sensitivity and specificity for absolute and functional ID detection. This may result in exclusion of patients, which may benefit from iron supplementation and inclusion of those who may not respond or even anticipate site effects. Our study calls for the urgent need of prospective trials for redefinition of ID and identification of biomarkers associated with therapeutic response to optimize patient outcomes.

Aims Amyloid cardiomyopathy is an underappreciated cause of morbidity and mortality. Recent evidence suggests that ATTR wild‐type cardiomyopathy (ATTRwt‐CM) is probably much more common than widely appreciated. So far, no data are available on comparison of mortality from ATTRwt‐CM and other heart failure aetiologies. Methods and results This was a retrospective, observational, cohort study of 2251 patients and their data collected prospectively from May 2000 to June 2018. Long‐term mortality was the main outcome measure. Underlying cardiomyopathies were classified as amyloid CM (6.1%) [ATTRwt 3.0%; light‐chain amyloidosis (AL) 3.1%], dilated CM (dCMP) (46.4%), ischaemic heart disease (IHD) (24.4%), hypertensive heart disease (HHD) (14.6%), hypertrophic CM (HCM) (5.1%), and valvular heart disease (VHD) (3.4%). Median duration of follow‐up was 7.1 years (interquartile range 3.4–11.3). Five‐year overall survival in the whole cohort was 80.1%. In multivariate analysis, individuals with amyloid CM were 3.74 times [95% confidence interval (CI) 2.72–5.14; P < 0.001] more likely to die of any reason than were individuals with dCMP. Mortality was higher in AL‐CM compared with ATTRwt‐CM [hazard ratio (HR) 2.88; 95% CI 1.48–5.58; P = 0.002]. Mortality rates in patients with ATTRwt‐CM were higher than in patients with dCMP (HR 1.96; 95% CI 1.24–3.22; P = 0.007), HCM (HR 2.94; 95% CI 1.28–6.67; P = 0.011), HHD (HR 2.08; 95% CI 1.27–3.45; P = 0.004), VHD (HR 2.38; 95% CI 1.30–4.35; P = 0.005), or left ventricular ejection fraction ≥ 40% (HR 1.99; 95% CI 1.12–3.52; P = 0.018). Conclusions Our study demonstrates that amyloid CM is independently associated with poor survival among patients with various causes of heart failure. ATTRwt‐CM had a better long‐term prognosis than did AL‐CM, but was associated with higher mortality than were dCMP, HCM, HHD, VHD, and heart failure with preserved or mid‐range ejection fraction.

Obesity is a well-described risk factor resulting in premature aging of the cardiovascular system ultimately limiting longevity. Premature cardiac death and aging is the hallmark of Hutchinson–Gilford syndrome (HGPS), a disease caused by defined mutations in the lamin A gene leading to a shortened prelamin A protein known as progerin. Since small amounts of progerin are expressed in healthy individuals we aimed to investigate the association of Body-Mass-Index (BMI) with respect to expression of progerin mRNA in blood samples of patient with known cardiovascular disease. In this cross-sectional retrospective analysis, 111 patients were consecutively included of which 46 were normal (BMI < 25 kg/m2) and 65 overweight (BMI ≥ 25.0 kg/m2). Blood samples were analyzed for quantitative expression of progerin mRNA. Progerin as well as high-sensitive C-Reactive Protein (hs-CRP) levels were significantly upregulated in the overweight group. Linear regression analyses showed a significant positive correlation of BMI and progerin mRNA (n = 111; r = 0.265, p = 0.005), as well as for hs-CRP (n = 110; r = 0.300, p = 0.001) and for Hb1Ac (n = 110; r = 0.336, p = 0.0003). Our data suggest that BMI strongly correlates with progerin mRNA expression and inflammation. Progerin might contribute to well described accelerated biologic aging in obese individuals.

Abstract Background Eosinophilic myocarditis (EM) is a rare disease with different clinical pictures and disease courses. Little literature is available on the various courses of the disease. Case summary A previously healthy 44-year-old male patient presented with acute heart failure and developed complete atrioventricular (AV) block requiring pacing. Acute heart failure was managed with inotropic support, non-invasive ventilation, and implantation of a permanent AV-sequential pacemaker. Cardiac magnetic resonance imaging was suggestive of myocarditis and endomyocardial biopsy diagnosed EM histologically. Endomyocardial biopsy was essential for definite aetiologic assignment, thus dispelling initial reservations about immunosuppressive therapy. Final treatment strategy consisted of steroids and Azathioprine. Discussion Endomyocardial biopsy is essential to establish diagnosis and targeted treatment in EM, which can rapidly lead to life-threatening conditions. Left ventricular function recovered within 2 weeks in response to immunosuppression and the patient was consistently well during follow-up. Despite the otherwise good response to immunosuppression, complete AV block continued over time.

Activation of the CXCL12/CXCR4/ACKR3 axis is known to aid myocardial repair through ischemia-triggered hypoxia-inducible factor-1α (HIF-1α). To enhance the upregulation of HIF-1α, we administered roxadustat, a novel prolyl hydroxylase inhibitor (PHI) clinically approved by the European Medicines Agency 2021 for the treatment of renal anemia, with the purpose of improving LV function and attenuating ischemic cardiomyopathy. Methods: We evaluated roxadustat’s impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI. Results: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling. Conclusions: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.

ObjectivesTo evaluate right ventricle (RV) function by coronary computed tomography angiography (CTA) using a novel automated three-dimensional (3D) RV volume segmentation tool in comparison with clinical reference modalities.MethodsTwenty-six patients with severe end-stage heart failure [left ventricle (LV) ejection fraction (EF) <35%] referred to CTA were enrolled. A specific individually tailored biphasic contrast agent injection protocol was designed (80%/20% high/low flow) was designed. Measurement of RV function [EF, end-diastolic volume (EDV), end-systolic volume (ESV)] by CTA was compared with tricuspid annular plane systolic excursion (TAPSE) by transthoracic echocardiography (TTE) and right heart invasive catheterisation (IC).ResultsAutomated 3D RV volume segmentation was successful in 26 (100%) patients. Read-out time was 3 min 33 s (range, 1 min 50s–4 min 33s). RV EF by CTA was stronger correlated with right atrial pressure (RAP) by IC (r = -0.595; p = 0.006) but weaker with TAPSE (r = 0.366, p = 0.94). When comparing TAPSE with RAP by IC (r = -0.317, p = 0.231), a weak-to-moderate non-significant inverse correlation was found. Interobserver correlation was high with r = 0.96 (p < 0.001), r = 0.86 (p < 0.001) and r = 0.72 (p = 0.001) for RV EDV, ESV and EF, respectively. CT attenuation of the right atrium (RA) and right ventricle (RV) was 196.9 ± 75.3 and 217.5 ± 76.1 HU, respectively.ConclusionsMeasurement of RV function by CTA using a novel 3D volumetric segmentation tool is fast and reliable by applying a dedicated biphasic injection protocol. The RV EF from CTA is a closer surrogate of RAP than TAPSE by TTE.Key Points• Evaluation of RV function by cardiac CTA by using a novel 3D volume segmentation tool is fast and reliable.• A biphasic contrast agent injection protocol ensures homogenous RV contrast attenuation.• Cardiac CT is a valuable alternative modality to CMR for the evaluation of RV function.

Lamins are important filaments forming the inner nuclear membrane. Lamin A is processed by zinc metalloproteinase (ZMPSTE24). Failure to cleave a truncated form of prelamin A—also called progerin—causes Hutchinson–Gilford progeria syndrome a well-known premature aging disease. Minor levels of progerin are readily expressed in the blood of healthy individuals due to alternative splicing. Previously, we found an association of increased progerin mRNA with overweight and chronic inflammation (hs-CRP). Here, we aimed to elucidate correlations of ZMPSTE24, lamin A/C and progerin with the inflammatory marker hs-CRP. In this retrospective, cross-sectional study we analyzed blood samples from 110 heart failure patients for quantitative mRNA expression of ZMPSTE24, lamin A/C, progerin and hs-CRP protein. Spearman correlations and linear regression analyses including adjustments for age, gender and ejection fraction showed a significant positive correlation of lnprogerin with lnZMPSTE24 (n = 110; r = 0.33; p = 0.0004) and lnlamin A/C (n = 110; r = 0.82, p < 0.0001), whereas no association was observed between lnlamin A/C and lnZMPSTE24 expression. Further analyses showed a significant positive correlation of lnhs-CRP with lnZMPSTE24 (n = 110; r = 0.21; p = 0.01) and lnlamin A/C (n = 110; r = 0.24; p = 0.03). We conclude that chronic inflammation is associated with increased expression of ZMPSTE24 and lamin A/C mRNA. Both markers also positively correlate with increased expression of the premature aging marker progerin which may be linked to cardiovascular aging.