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Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) represent a high-risk heart failure population with continued unmet therapeutic needs. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction, and first evidence regarding their safety and effectiveness in patients with ATTR-CM is arising. This study investigates the association between SGLT2i therapy and clinical outcomes in these patients. Methods: This is an analysis of a prospective registry conducted at a referral centre for hypertrophic cardiomyopathies including 116 patients with confirmed ATTR-CM. Fifty-one patients (44%) were treated with SGLT2i while 65 patients (56%) remained SGLT2i-naïve. Results: During a median follow-up of 2.6 (1.7-3.7) years, 38 patients (33%) died, of whom 11 patients (9%) received SGLT2i treatment and 27 patients (23%) were treatment-naïve. SGLT2i therapy was significantly associated with lower mortality (HR 0.457, 95%CI 0.227-0.922, p = 0.029). This association persisted after adjusting for age and sex (HR 0.479, 95%CI 0.235-0.977, p = 0.043) and after additional adjustment for eGFR, NT-proBNP, LVEF, and concomitant therapy with tafamidis (HR 0.328, 95%CI 0.141-0.760, p = 0.009). However, when potential immortal time bias was considered, this association lost statistical significance (HR 1.075, 95%CI 0.524-2.206, p = 0.843). No significant associations between SGLT2i therapy and worsening heart-failure hospitalization or cardiovascular mortality were observed. Conclusions: In crude analysis, SGLT2i therapy associates with better survival in patients with ATTR-CM. However, after adjustment for immortal time, this association becomes statistically insignificant. Hence, to draw final conclusions on the effectiveness of SGLT2i therapy in these patients, a randomized controlled trial is warranted.

Background: Empagliflozin administered after acute myocardial infarction proofed to improve cardiometabolic parameters and biomarkers, but the impact on cardiac function is still largely unknown. The aim of this post-hoc echocardiographic sub-analysis of the EMMY trial was to provide in-depth echocardiographic analysis on the effects of empagliflozin versus placebo on standard and novel echocardiographic structural and functional parameters after acute myocardial infarction., Methods: In this post-hoc analysis of the EMMY trial a subset of 313 patients (157 empagliflozin vs. 156 placebo) was enrolled for post-processing analysis of echocardiographic structural and functional parameters. On top of two-dimensional and Doppler parameters, myocardial deformation analyses were performed to assess ventricular and atrial strain values., Results: Left ventricular volumes showed significant differences in favor of empagliflozin over the course of the trial (change in left ventricular end-diastolic volume median [interquartile range] 8 [-3;19]% versus 13 [0;29]%, p = 0.048; left ventricular end-systolic volume -3 [-15;12]% versus 4 [-12;18]%, p = 0.044). This effect persisted after adjusting for baseline values, age, and sex. Left ventricular systolic and diastolic function overall improved over the course of the trial and parameters for diastolic function showed a distinct trend between groups but did not meet statistical significance in this cohort., Conclusion: In this post-hoc analysis among patients with acute myocardial infarction, treatment with empagliflozin resulted in a significant beneficial effect on left ventricular end-diastolic and end-systolic volume, without significantly improving left ventricular or right ventricular functional parameters compared to placebo after 26 weeks., Gov Registration: NCT03087773., (© 2024. The Author(s).)

Aims: Chronic heart failure is associated with a bone-catabolic state and increases the risk of osteoporosis and fractures. Prospective studies investigating the clinical relevance of bone disease in heart failure are lacking. We aimed to assess the prevalence and prognostic impact of osteoporosis and vertebral fractures (VFs) in chronic heart failure with reduced ejection fraction (HFrEF)., Methods and Results: Symptomatic outpatients with chronic heart failure and a previous diagnosis of overtly reduced left ventricular ejection fraction < 40% on stable, optimal HFrEF therapy and left ventricular ejection fraction < 50% at enrolment were included into a prospective single-centre study. Osteoporosis was determined with dual-energy X-ray absorptiometry and defined as a T-score ≤ 2.5 at any site. VFs were assessed using X-ray of both thoracic and lumbar spine applying the semiquantitative Genant score. We enrolled 205 patients (22% women), with a median age of 66 (IQR 58-74) years. Median left ventricular ejection fraction was 37 (IQR 30-43) % and median N-terminal pro B-type natriuretic peptide was 964 (IQR 363-2173) pg/mL. Osteoporosis, as defined by bone mineral density, and at least one VF were prevalent in 31 (15%) and 29 patients (14%). Osteoporosis or VF were present in 55 patients (27%) and 5 patients (2%) had both osteoporosis and a VF. During a median follow-up of 4.7 (IQR 4.0-5.3) years, 18 patients (9%) died due to cardiovascular (CV) cause, and 46 patients (22%) had a worsening heart failure (WHF) hospitalization. In multivariate Cox regression analyses, presence of VF independently predicted CV death (HR 2.82, 95% CI 1.04-7.65, P = 0.042), WHF hospitalizations (HR 2.39, 95% CI 1.18-4.82, P = 0.015), and a composite endpoint of CV death and WHF hospitalizations (HR 2.44, 95% CI 1.23-4.82, P = 0.011). Osteoporosis was not significantly associated with CV events., Conclusions: In a prospective study, bone disease affected every fourth patient with HFrEF, and patients with VF at baseline had a two-fold risk of subsequent CV death or WHF hospitalization. Prevalent bone disease, particularly VF, should be considered as a clinically relevant comorbidity in HFrEF., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In patients with stable chronic heart failure with a reduced ejection fraction (HFrEF), left ventricular ejection fraction (LVEF) provides limited prognostic value, especially in patients with moderately to severely reduced LVEF. Echocardiographic parameters of right ventricular function may be associated with adverse clinical events in these patients. Therefore, we analyzed 164 patients with HFrEF in a prospective single-center cohort study to evaluate whether the parameters of right ventricular function are associated with worsening heart failure (WHF) hospitalizations, cardiovascular and all-cause deaths and combined endpoints. Methods: Echocardiographic cine loops were analyzed using vendor-independent post-processing software. Multivariate Cox regression analyses were performed, which were then adjusted for clinical characteristics and left ventricular functional parameters. Results: In these models, higher tricuspid annular plane systolic excursion (TAPSE) was significantly associated with lower rates of WHF hospitalizations (HR 0.880, 95%CI 0.800-0.968, p = 0.008), a composite endpoint of WHF hospitalizations and cardiovascular death (HR 0.878, 95%CI 0.800-0.964, p = 0.006), and a composite endpoint of WHF hospitalization and all-cause death (HR 0.918, 95%CI 0.853-0.988, p = 0.023). These associations were more pronounced in patients with LVEF ≤ 35%. Conclusions: In conclusion, in patients with HFrEF, TAPSE is an independent prognosticator for adverse clinical outcomes, warranting further studies to elucidate whether incorporating TAPSE into established risk scores improves their diagnostic accuracy.

Background: Arterial hypertension (HTN) is associated with excess mortality in hypertrophic cardiomyopathy (HCM), but underlying mechanisms are largely elusive. The objective of this study was to investigate the association between HTN and markers of left ventricular (LV) dysfunction and low-grade systemic inflammation in a HCM cohort., Methods: This was a single-center cross-sectional case-control study comparing echocardiographic and plasma-derived indices of LV dysfunction and low-grade systemic inflammation between 30 adult patients with HCM and HTN (HTN+) and 30 sex- and age-matched HCM patients without HTN (HTN-). Echocardiographic measures were assessed using post-processing analyses by blinded investigators., Results: Mean age of the study population was 55.1 ± 10.4 years, 30% were women. Echocardiographic measures of systolic and diastolic dysfunction, including speckle-tracking derived parameters, did not differ between HTN+ and HTN-. Moreover, levels of N-terminal pro B-type natriuretic peptide were balanced between cases and controls. Compared with HTN-, HTN+ patients exhibited a higher white blood cell count [8.1 ± 1.8 10 9 /l vs. 6.4 ± 1.6 10 9 /l; p < 0.001] as well as higher plasma levels of interleukin-6 [2.8 pg/ml (2.0, 5.4) vs. 2.1 pg/ml (1.5, 3.4); p = 0.008] and high-sensitivity C-reactive protein [2.6 mg/l (1.4, 6.5) vs. 1.1 mg/l (0.9, 2.4); p = 0.004]., Conclusion: This study demonstrates that HTN is associated with indices of low-grade systemic inflammation among HCM patients. Moreover, this analysis indicates that the adverse impact of HTN in HCM patients is a consequence of systemic effects rather than alterations of cardiac function, as measures of LV systolic and diastolic dysfunction did not differ between HTN+ and HTN-., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

(1) Background : Mechanical circulatory support (MCS) in myocardial infarction-associated cardiogenic shock is subject to debate. This analysis aims to elucidate the impact of MCS's timing on patient outcomes, based on data from the PREPARE CS registry. (2) Methods : The PREPARE CS prospective registry includes patients who experienced cardiogenic shock (SCAI classes C-E) and were subsequently referred for cardiac catheterization. Our present analysis included a subset of this registry, in whom MCS was used and who underwent coronary intervention due to myocardial infarction. Patients were categorized into an Upfront group and a Procedural group, depending on the timing of MCS's introduction in relation to their PCI. The endpoint was in-hospital mortality. (3) Results : In total, 71 patients were included. MCS was begun prior to PCI in 33 (46%) patients (Upfront), whereas 38 (54%) received MCS during or after the initiation of PCI (Procedural). The groups' baseline characteristics and hemodynamic parameters were comparable. The Upfront group had a higher utilization of the Impella ® device compared to extracorporeal membrane oxygenation (67% vs. 33%), while the Procedural group exhibited a balanced use of both (50% vs. 50%). Most patients suffered from multi-vessel disease in both groups (82% vs. 84%, respectively; p = 0.99), and most patients required a complex PCI procedure; the latter was more prevalent in the Upfront group (94% vs. 71%, respectively; p = 0.02). Their rates of complete revascularization were comparable (52% vs. 34%, respectively; p = 0.16). Procedural CPR was significantly more frequent in the Procedural group (45% vs. 79%, p < 0.05); however, in-hospital mortality was similar (61% vs. 79%, respectively; p = 0.12). (4) Conclusions : The upfront implantation of MCS in myocardial infarction-associated CS did not provide an in-hospital survival benefit.

Imtroduction: The high-risk population of patients with cardiovascular (CV) disease or risk factors (RF) suffering from COVID-19 is heterogeneous. Several predictors for impaired prognosis have been identified. However, with machine learning (ML) approaches, certain phenotypes may be confined to classify the affected population and to predict outcome. This study aimed to phenotype patients using unsupervised ML technique within the International Postgraduate Course Heart Failure Registry for patients hospitalized with COVID-19 and Cardiovascular disease and/or RF (PCHF-COVICAV)., Material and Methods: Patients from the eight centres with follow-up data available from the PCHF-COVICAV registry were included in this ML analysis (K-medoids algorithm)., Results: Out of 617 patients included into the prospective part of the registry, 458 [median age: 76 (IQR:65-84) years, 55% male] were analyzed and 46 baseline variables, including demographics, clinical status, comorbidities and biochemical characteristics were incorporated into the ML. Three clusters were extracted by this ML method. Cluster 1 (n = 181) represents mainly women with the least number of overall comorbidities and cardiovascular RF. Cluster 2 (n = 227) is characterized mainly by men with non-CV conditions and less severe symptoms of infection. Cluster 3 (n=50) mainly represents men with the highest prevalence of cardiac comorbidities and RF, more extensive inflammation and organ dysfunction with the highest 6-month all-cause mortality risk., Conclusions: The ML process has identified three important clinical clusters from hospitalized COVID-19 CV and/or RF patients. The cluster of males with severe CV disease, particularly HF, and multiple RF presenting with increased inflammation had a particularly poor outcome.

Pivotal outcome trials targeting heart failure with preserved (HFpEF) and mildly-reduced ejection fraction (HFmrEF) may have excluded patients at highest risk of poor outcomes. We aimed to assess eligibility for HFpEF/HFmrEF outcome trials in an unselected heart failure cohort and its association with all-cause mortality. Among 32.028 patients presenting to a tertiary care center emergency unit for any reason between August 2018 and July 2019, we identified 407 admissions with evident HFpEF and HFmrEF. Eligibility criteria for pivotal trials CHARM-Preserved, I-PRESERVE, TOPCAT, PARAGON-HF, EMPEROR-Preserved and DELIVER were assessed by chart review. The proportions of admissions fulfilling HFpEF/HFmrEF trial eligibility criteria were 88% for CHARM-Preserved, 40% for I-PRESERVE, 35% for TOPCAT, 28% for PARAGON-HF, 51% for EMPEROR-Preserved, and 49% for DELIVER. During a median follow-up of 1.9 years, death-from-any-cause occurred in 121 cases (30%). Twenty-four-month overall survival estimates for non-eligible and eligible admissions were 53% vs. 76% for CHARM-Preserved (HR=2.32, 95% CI: 1.47-3.67, p<0.001), 62% vs. 87% for I-PRESERVE (HR=2.97, 1.85-4.77, p<0.001), 67% vs. 84% for TOPCAT (HR=2.04, 1.29-3.24, p = 0.002), 68% vs. 85% for PARAGONHF (HR=2.28, 1.33-3.90, p = 0.003), 64% vs. 81% for EMPEROR-Preserved (HR=1.90, 1.27-2.84, p = 0.002), and 65% vs. 80% for DELIVER (HR=1.71, 1.14-2.57, p = 0.010). Exclusion criteria independently predicting death were eGFR <20 ml/min/1.73 m 2 , COPD with home oxygen therapy, and severe valvular heart disease. Conclusively, in a contemporary HFpEF/HFmrEF cohort, non-eligibility for outcome trials predicted for strongly increased mortality. HFpEF/HFmrEF patients at highest mortality risk were likely underrepresented in previous outcome trials and their treatment remains an unmet medical need., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cardiogenic shock (CS) exhibits high (~50%) in-hospital mortality. The recently published Extracorporeal life Support in Cardiogenic Shock (ECLS-SHOCK) trial demonstrated the neutral effects of the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) on all-cause death, as well as on all secondary outcomes in subjects presenting with myocardial-infarction (MI)-related CS. Here, we compared ECLS-SHOCK eligibility criteria with a real-world cohort of CS patients., Methods and Results: ECLS-SHOCK eligibility criteria were applied to a prospective single-center CS registry (the PREPARE CS registry) consisting of 557 patients who were consecutively admitted to the catheterization laboratory (cath lab) of the Medical University of Graz, Austria, due to CS (SCAI C-E). Overall use of mechanical circulatory support (MCS) in this cohort was 19%. Sixty-nine percent of the entire cohort had MI-related CS, 38% of whom would have met ECLS-SHOCK eligibility criteria, thus representing only 27% of the PREPARE CS registry. Exclusion from the ECLS-SHOCK trial was based on patients with initial lactate values below 3 mmol/L (n = 168; 43.6%), aged over 80 years (n = 65; 16.9%), and with a duration of cardiopulmonary resuscitation (CPR) exceeding 45 min (n = 22; 5.7%). The 30-day mortality of patients of the PREPARE CS registry who met the ECLS-SHOCK eligibility criteria was 57.0%, compared to 48.4% of patients in the ECLS-SHOCK trial. The patients' baseline characteristics, however, differed considerably with respect to type of infarction, age, and gender., Conclusions: In a real-world cohort of patients with MI-related CS, only 38% of patients met the eligibility criteria of the ECLS-SHOCK trial. Thus, the impact of the use of VA-ECMO on outcome parameters in MI-related CS, as observed in the ECLS-SHOCK trial, may differ in a more heterogeneous real-world CS population of the PREPARE CS registry.

Background: Percutaneous closure of patent foramen ovale (PFO) is conventionally performed under continuous transesophageal echocardiographic (TEE) guidance. We aimed to evaluate whether a simplified procedural approach, including pure fluoroscopy-guidance and final TEE control, as well as an aimed 'next-day-discharge' is comparable with the conventional TEE-guided procedure in terms of periprocedural and intermediate-term outcomes., Methods: All patients who underwent a PFO closure at our center between 2010 and 2022 were retrospectively included. Prior to June 2019 cases were performed with continuous TEE guidance (TEE-guided group). Since June 2019, only pure fluoroscopy-guided PFO closures have been performed with TEE insertion and control just prior to device release (fluoroscopy-guided group). We analyzed procedural aspects, as well as long term clinical and echocardiographic outcomes., Results: In total 291 patients were included in the analysis: 197 in the TEE-guided group and 94 in the fluoroscopy-guided group. Fluoroscopy-guided procedures were markedly shorter (48 ± 20 min vs. 25 ± 9 min; p < .01). There was no difference in procedural complications, including death, major bleeding, device dislodgement, stroke or clinically relevant peripheral embolization between the two groups (.5% vs. 0%; p = .99). Hospital stay was also shorter with the simplified approach (2.5 ± 1.6 vs. 3.5 ± 1.2 days; p < .01), allowing 85% same-day discharges during the last 12 months of observation period. At 6 ± 3 months echocardiographic follow-up a residual leakage was described in 8% of the TEE-guided cases and 2% of the fluoroscopy-guided cases (p = .08)., Conclusion: While a complete TEE-free PFO closure might have potential procedural risks, our approach of pure fluoroscopy-guided with a brisk final TEE check seems to be advantageous in terms of procedural aspects with no sign of any acute or intermediate-term hazard and it could offer an equitable compromise between the two worlds: a complete TEE procedure and a procedure without any TEE., (© 2023 The Authors. Echocardiography published by Wiley Periodicals LLC.)

We aimed to ascertain the real-world diagnostic accuracy of bone scintigraphy in combination with free light chain (FLC) assessment for transthyretin (ATTR) cardiac amyloidosis (CA) using the histopathological diagnosis derived from endomyocardial biopsy (EMB) as a reference standard. We retrospectively analyzed 102 patients (22% women) with suspected CA from seven Austrian amyloidosis referral centers. The inclusion criteria comprised the available results of bone scintigraphy, FLC assessment, and EMB with histopathological analysis. ATTR and AL were diagnosed in 60 and 21 patients (59%, 21%), respectively, and concomitant AL and ATTR was identified in one patient. The specificity and positive predictive value (PPV) of Perugini score ≥ 2 for ATTR CA were 95% and 96%. AL was diagnosed in three out of 31 patients (10%) who had evidence of monoclonal proteins and a Perugini score ≥ 2. When excluding all patients with detectable monoclonal proteins (n = 62) from analyses, the PPV of Perugini score ≥ 2 for ATTR CA was 100% and the NPV of Perugini score < 2 for ATTR CA was 79%. Conclusively, ATTR CA can be diagnosed non-invasively in the case of a Perugini score ≥ 2 and an unremarkable FLC assessment. However, tissue biopsy is mandatory in suspected CA in any other constellation of non-invasive diagnostic work-up.

Background: As a preventive procedure, minimizing periprocedural risk is crucially important during left atrial appendage closure (LAAC). Methods: We included consecutive patients receiving LAAC at nine centres and assessed the relationship between baseline characteristics and the acute procedural outcome. Major procedural complications were defined as all complications requiring immediate invasive intervention or causing irreversible damage. Logistic regression was performed and included age and left-ventricular function. Furthermore, the association between acute complications and long-term outcomes was evaluated. Results: A total of 405 consecutive patients with a median age of 75 years (37% female) were included. 47% had a history of stroke. Median CHA2DS2-VASc score was 4 (interquartile range, 3−5) and the median HAS-BLED score was 3 (2−4). Major procedural complications occurred in 7% of cases. Low haemoglobin (OR 0.8, 95% CI 0.65−0.99 per g/dL, p = 0.040) and end-stage kidney disease (OR 13.0, CI 2.5−68.5, p = 0.002) remained significant in multivariate analysis. Anaemia (haemoglobin < 12 and < 13 g/dL in female and male patients) increased the risk of complications 2.2-fold. Conclusions: The major complication rate was low in this high-risk patient population undergoing LAAC. End-stage kidney disease and low baseline haemoglobin were independently associated with a higher major complication rate.

Aims: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF., Methods and Results: The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by -0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred., Conclusion: The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period., Competing Interests: Conflict of interest: E.G. received grants/contracts from Bayer, MSD, United Therapeutics and OMT; consulting fees from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics; payments/honoraria from Bayer, Janssen and MSD; support for attending meetings and/or travel from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics. E.G. participated on data monitoring/advisory boards for Janssen, United Therapeutics, and Acceleron. I.P. has received honoraria for lectures from Orion, AOP Orphan and Amomed. D.B. received financial support for the present manuscript in form of an unrestricted research grant by Bayer (all payments were made to the Medical University of Vienna); research grants by Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi (all payments were made to the Medical University of Vienna); and payments/honoraria from Bayer AG, Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi, Astra Zeneca, Boehringer Ingelheim, Zoll, Janssen, AOP Orphan, and MSD. All other authors declare that there is no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Purpose: Accumulating evidence points towards a close relationship between cardiovascular, endocrine and metabolic diseases. The BioPersMed Study (Biomarkers of Personalised Medicine) is a single-centre prospective observational cohort study with repetitive examination of participants in 2-year intervals. The aim is to evaluate the predictive impact of various traditional and novel biomarkers of cardiovascular, endocrine and metabolic pathways in asymptomatic individuals at risk for cardiovascular and/or metabolic disease., Participants: Between 2010 and 2016, we recruited 1022 regional individuals into the study. Subjects aged 45 years or older presenting with at least one traditional cardiovascular risk factor or manifest type 2 diabetes mellitus (T2DM) were enrolled. The mean age of the participants was 57±8 years, 55% were female, 18% had T2DM, 33% suffered from arterial hypertension, 15% were smokers, 42% had hyperlipidaemia, and only 26% were at low cardiovascular risk according to the Framingham 'Systematic COronary Risk Evaluation'., Findings to Date: Study procedures during screening and follow-up visits included a physical examination and comprehensive cardiovascular, endocrine, metabolic, ocular and laboratory workup with biobanking of blood and urine samples. The variety of assessed biomarkers allows a full phenotyping of individuals at cardiovascular and metabolic risk. Preliminary data from the cohort and relevant biomarker analyses were already used as control population for genomic studies in local and international research cooperation., Future Plans: Participants will undergo comprehensive cardiovascular, endocrine and metabolic examinations for the next decades and clinical outcomes will be adjudicated prospectively., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: We assessed the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations., Methods and Results: International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID-19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF-COVICAV). The primary endpoint was in-hospital mortality. Of 1974 patients hospitalized with COVID-19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62-81] years, 58% male), with HF being present in 256 [20%] patients. Overall in-hospital mortality was 25% (n = 323/1282 deaths). In-hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non-HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44-2.59], P < 0.001). After adjusting, HF remained associated with in-hospital mortality (OR 1.45 [95% confidence interval: 1.01-2.06], P = 0.041). Importantly, 186 of 1282 [15%] patients had an acute HF event during hospitalization (76 [40%] with de novo HF), which was associated with higher in-hospital mortality (89 [48%] vs. 220 [23%]) than in patients without HF event (OR 3.10 [2.24-4.29], P < 0.001)., Conclusions: Hospitalized COVID-19 patients with HF are at increased risk for in-hospital death. In-hospital worsening of HF or acute HF de novo are common and associated with a further increase in in-hospital mortality., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Accumulating evidence suggests that individuals with sarcomeric hypertrophic cardiomyopathy (HCM) carrying MYH7 mutations may have a worse prognosis than MYBPC3 mutation carriers. Myocardial deformation analysis is superior to standard echocardiography in detecting subtle myocardial dysfunction and scar formation, but studies evaluating the association with HCM genotype are scarce. We therefore aimed to compare myocardial strain parameters between MYBPC3 and MYH7 mutation carriers with proven HCM. Participants of the prospective Graz HCM Registry carrying at least one causative mutation in MYBPC3 ( n = 39) or MYH7 ( n = 18) were enrolled. MYBPC3 mutation carriers were older, predominantly male and more often treated with an implantable cardioverter-defibrillator (39% vs. 0%; p = 0.002). Using analyses of covariance, there were no significant differences between MYBPC3 and MYH7 mutation carriers with regard to left ventricular global longitudinal strain (estimated marginal means ± standard deviation: -16.9 ± 0.6% vs. -17.3 ± 0.9%; p = 0.807) and right ventricular 6-segments endocardial strain (-24.3 ± 1.0% vs. 26.3 ± 1.5%; p = 0.285). Our study suggests, that myocardial deformation analysis may not be helpful in concluding on the underlying HCM genotype, and vice versa.

The prevalence and significance of cardiac amyloidosis have been considerably underestimated in the past; however, the number of patients diagnosed with cardiac amyloidosis has increased significantly recently due to growing awareness of the disease, improved diagnostic capabilities and demographic trends. Specific therapies that improve patient prognosis have become available for certain types of cardiac amyloidosis. Thus, the earliest possible referral of patients with suspicion of cardiac amyloidosis to an experienced center is crucial to ensure rapid diagnosis, early initiation of treatment, and structured patient care. This requires intensive collaboration across several disciplines, and between resident physicians and specialized centers. The aim of this consensus statement is to provide guidance for the rapid and efficient diagnosis and treatment of light-chain amyloidosis and transthyretin amyloidosis, which are the most common forms of cardiac amyloidosis.

Background: Complete real-world data on the indications and outcomes of left atrial appendage closure (LAAC) outside of clinical trials are rare. In this study, we stratified patients undergoing LAAC by indication groups., Methods: This analysis of the national multicentre Austrian LAAC Registry comprised all patients that underwent LAAC up until 2018 at the currently active centres in Austria. The baseline characteristics, procedural details and outcomes between the following indication groups were compared: bleeding as an indication for LAAC ("bleeding" group) vs. thromboembolism despite oral anticoagulation (OAC; "thromboembolism" group) vs. an intolerance to OAC for reasons other than the above ("other" group)., Results: The analysis included 186 patients, with 59.7% in the "bleeding" group, 8.1% in the "thromboembolism" group and 32.2% in the "other" group. The CHADS 2 score was the highest in the "thromboembolism" group and the HAS-BLED score was the highest in the "bleeding" group. The procedural outcomes were similar between groups (implantation success, 97.3%), with major complications occurring in 7.0% of patients. One-year survival free from stroke, bleeding or LAAC-associated hospitalisation was 83.9%, 90.0% and 81.4% in the "bleeding", "thromboembolism" and "other" groups, respectively ( p = 0.891)., Conclusions: In routine clinical practice, LAAC was used in a heterogeneous patient population with atrial fibrillation (AF) and contraindication, inefficacy or intolerance to OAC. The long-term outcome was favourable in all groups.

Background: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin ( TTR ) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory. This study aimed to assess the prevalence and phenotypic spectrum of hATTR in Austria., Methods: Within the period of 2014-2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the TTR gene., Results: We identified 43 cases from 22 families carrying 10 different TTR missense mutations and confirmed two mutational hot spots at c.323A>G (p.His108Arg) and c.337G>C (p.Val113Leu). Two further patients with late onset ATTR carried TTR variants of unknown significance. The majority of patients initially presented with heart failure symptoms that were subsequently accompanied by progressive polyneuropathy in most cases. A total of 55% had a history of carpal tunnel syndrome before the onset of other organ manifestations., Conclusions: Our study underlined the relevance of hATTR in the pathogenesis of amyloid-driven cardiomyopathy and axonal polyneuropathy and indicated considerable genetic heterogeneity of this disease in the Austrian population. The estimated prevalence of hATTR in Austria based on this study is 1:200,000 but a potentially higher number of unknown cases must be taken into account. With respect to new therapeutic approaches, we strongly propose genetic testing of the TTR gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy.

Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors are established antidiabetic drugs with proven cardiovascular benefit. Although growing evidence suggests beneficial effects on myocardial remodeling, fluid balance and cardiac function, the impact of empagliflozin initiated early after acute myocardial infarction (AMI) has not been investigated yet. Therefore, the impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction (EMMY) trial was designed to investigate the efficacy and safety of empagliflozin in diabetic and non-diabetic patients after severe AMI., Methods: Within a multicenter, randomized, double-blind, placebo-controlled, phase 3b trial we will enroll patients with AMI and characteristics suggestive of severe myocardial necrosis are randomized in a 1:1 ratio to empagliflozin (10 mg once daily) or matching placebo. The primary endpoint is the impact of empagliflozin on changes in NT-proBNP within 6 months after AMI. Secondary endpoints include changes in echocardiographic parameters, levels of ketone body concentrations, HbA1c levels and body weight, respectively. Hospitalization rate due to heart failure or other causes, the duration of hospital stay and all-cause mortality will be assessed as exploratory secondary endpoints., Discussion: The EMMY trial will test empagliflozin in patients with AMI regardless of their diabetic status. The EMMY trial may therefore underpin the concept of SGLT2 inhibition to improve cardiac remodeling, pre-and afterload reduction and cardiac metabolism regardless of its antidiabetic effects. Results will provide the rationale for the conduct of a cardiovascular outcome trial to test the effect of empagliflozin in patients with AMI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Deposition of amyloidogenic proteins leading to the formation of amyloid fibrils in the myocardium causes cardiac amyloidosis. Although any form of systemic amyloidosis can affect the heart, light-chain (AL) or transthyretin amyloidosis (ATTR) account for the majority of diagnosed cardiac amyloid deposition. The extent of cardiac disease independently predicts mortality. Thus, the reversal of arrest of adverse cardiac remodeling is the target of current therapies. Here, we provide a condensed overview on the pathophysiology of AL and ATTR cardiac amyloidoses and describe treatments that are currently used or investigated in clinical or preclinical trials. We also briefly discuss acquired amyloid deposition in cardiovascular disease other than AL or ATTR., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Dual antiplatelet therapy is the standard of care for patients with myocardial infarction (MI), who have been resuscitated and treated with therapeutic hypothermia (TH). We compare the antiplatelet effect and bleeding risk of intravenous cangrelor to oral P2Y12-inhibitors in patients with MI receiving TH in a prospective comparison of two matched patient cohorts. Twenty-five patients within the CANGRELOR cohort were compared to 17 patients receiving oral P2Y12-inhibitors. CANGRELOR group (NCT03445546) and the ORAL P2Y12 Group (NCT02914795) were registered at clinicaltrials.gov. Platelet function testing was performed using light-transmittance aggregometry and monitored for 4 days. P2Y12-inhibition was stronger in CANGRELOR compared to ORAL P2Y12 (adenosine diphosphate (ADP) (area under the curve (AUC)) 26.0 (5.9⁻71.6) vs. 160.9 (47.1⁻193.7)) at day 1. This difference decreased over the following days as more patients were switched from CANGRELOR to oral P2Y12-inhibitor treatment. There was no difference in the effect of aspirin between the two groups. We did not observe significant differences with respect to thrombolysis in myocardial infarction (TIMI) or Bleeding Academic Research Consortium (BARC) classified bleedings, number of blood transfusions or drop in haemoglobin B (Hb) or hematocrit (Hct) over time. Cangrelor treatment is not only feasible and effective in resuscitated patients, but also inhibited platelet function more effectively than orally administered P2Y12-inhibitors without an increased event rate for bleeding.

Background: Primary hyperparathyroidism (pHPT) is associated with low-grade inflammation, left ventricular hypertrophy and increased cardiovascular mortality, but the association between inflammatory markers and parameters of adverse cardiac remodeling is unknown. We investigated the relationship between C-reactive protein (CRP), the essential amino acid tryptophan and its pro-inflammatory derivatives kynurenine and quinolinic acid (QUIN) with echocardiographic parameters., Methods: Cross-sectional baseline data from the "Eplerenone in Primary Hyperparathyroidism" trial were analyzed. Patients with any acute illness were excluded. We assessed associations between CRP, serum levels of tryptophan, kynurenine and QUIN and left ventricular mass index (LVMI), left atrial volume index (LAVI) and E/e'., Results: Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%. Multivariate linear regression analyses with LVMI, LAVI and E/e' as respective dependent variables, and C-reactive protein and tryptophan, kynurenine and QUIN as respective independent variables were performed. Analyses were adjusted for age, sex, blood pressure, parathyroid hormone, calcium and other cardiovascular risk factors. LVMI was independently associated with CRP (adjusted β-coefficient=0.193, p=0.030) and QUIN (β=0.270, p=0.007), but not kynurenine. LAVI was related with CRP (β=0.315, p<0.001), kynurenine (β=0.256, p=0.005) and QUIN (β=0.213, p=0.044). E/e' was related with kynurenine (β=0.221, p=0.022) and QUIN (β=0.292, p=0.006). Tryptophan was not associated with any of the remodeling parameters. [Correction added after online publication (22 April 2017: The sentence "Among 136 subjects with pHPT (79% females), 100 (73%) had left ventricular hypertrophy." was corrected to "Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%."] Conclusions: Cardiac remodeling is common in pHPT and is associated with low-grade inflammation and activation of the tryptophan-kynurenine pathway. The potential role of kynurenine and QUIN as cardiovascular risk factors may be further investigated in future studies.

Observational studies suggested a link between bone disease and left ventricular (LV) dysfunction that may be pronounced in hyperparathyroid conditions. We therefore aimed to test the hypothesis that circulating markers of bone turnover correlate with LV function in a cohort of patients with primary hyperparathyroidism (pHPT). Cross-sectional data of 155 subjects with pHPT were analyzed who participated in the "Eplerenone in Primary Hyperparathyroidism" (EPATH) Trial. Multivariate linear regression analyses with LV ejection fraction (LVEF, systolic function) or peak early transmitral filling velocity (e', diastolic function) as dependent variables and N-terminal propeptide of procollagen type 1 (P1NP), osteocalcin (OC), bone-specific alkaline phosphatase (BALP), or beta-crosslaps (CTX) as the respective independent variable were performed. Analyses were additionally adjusted for plasma parathyroid hormone, plasma calcium, age, sex, HbA1c, body mass index, mean 24-hours systolic blood pressure, smoking status, estimated glomerular filtration rate, antihypertensive treatment, osteoporosis treatment, 25-hydroxy vitamin D and N-terminal pro-brain B-type natriuretic peptide. Independent relationships were observed between P1NP and LVEF (adjusted β-coefficient = 0.201, P = 0.035) and e' (β = 0.188, P = 0.042), respectively. OC (β = 0.192, P = 0.039) and BALP (β = 0.198, P = 0.030) were each independently related with e'. CTX showed no correlations with LVEF or e'. In conclusion, high bone formation markers were independently and paradoxically related with better LV diastolic and, partly, better systolic function, in the setting of pHPT. Potentially cardio-protective properties of stimulated bone formation in the context of hyperparathyroidism should be explored in future studies.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a rapidly growing class of drugs developed for treating type-2 diabetes mellitus. Patients with diabetes carry an up to 5-fold greater mortality risk compared to non-diabetic patients, mainly as a result of cardiovascular diseases. Although beneficial cardiovascular effects have been reported, exact mechanisms of GLP-1R-agonist action in the heart, especially in human myocardium, are poorly understood. The effects of GLP-1R-agonists (exenatide, GLP-1(7-36)NH2, PF-06446009, PF-06446667) on cardiac contractility were tested in non-failing atrial and ventricular trabeculae from 72 patients. The GLP-1(7-36)NH2 metabolite, GLP-1(9-36)NH2, was also examined. In electrically stimulated trabeculae, the effects of compounds on isometric force were measured in the absence and presence of pharmacological inhibitors of signal transduction pathways. The role of β-arrestin signaling was examined using a β-arrestin partial agonist, PF-06446667. Expression levels were tested by immunoblots. Translocation of GLP-1R downstream molecular targets, Epac2, GLUT-1 and GLUT-4, were assessed by fluorescence microscopy. All tested GLP-1R-agonists significantly increased developed force in human atrial trabeculae, whereas GLP-1(9-36)NH2 had no effect. Exendin(9-39)NH2, a GLP-1R-antagonist, and H-89 blunted the inotropic effect of exenatide. In addition, exenatide increased PKA-dependent phosphorylation of phospholamban (PLB), GLUT-1 and Epac2 translocation, but not GLUT-4 translocation. Exenatide failed to enhance contractility in ventricular myocardium. Quantitative real-time PCR (qRT-PCR) revealed a significant higher GLP-1R expression in the atrium compared to ventricle. Exenatide increased contractility in a dose-dependent manner via GLP-1R/cAMP/PKA pathway and induced GLUT-1 and Epac2 translocation in human atrial myocardium, but had no effect in ventricular myocardium. Therapeutic use of GLP-1R-agonists may therefore impart beneficial effects on myocardial function and remodelling., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: Guidelines have been published for improving management of chronic heart failure (CHF). We examined the association between improved guideline adherence and risk for all-cause death in patients with stable systolic HF., Methods: Data on ambulatory patients (2006-2010) with CHF and reduced ejection fraction (HF-REF) from the Austrian Heart Failure Registry (HIR Austria) were analysed. One-year clinical data and long-term follow-up data until all-cause death or data censoring were available for 1014 patients (age 65 [55-73], male 75%, NYHA class I 14%, NYHA II 56%, NYHA III/IV 30%). A guideline adherence indicator (GAI [0-100%]) was calculated for each patient at baseline and after 12 ± 3 months that considered indications and contraindications for ACE-I/ARB, beta blockers, and MRA. Patients were considered ΔGAI-positive if GAI improved to or remained at high levels (≥ 80%). ΔGAI50+ positivity was ascribed to patients achieving a dose of ≥ 50% of suggested target dose., Results: Improvements in GAI and GAI50+ were associated with significant improvements in NYHA class and NT-proBNP (1728 [740-3636] to 970 [405-2348]) (p<0.001). Improvements in GAI50+, but not GAI, were independently predictive of lower mortality risk (HR 0.55 [95% CI 0.34-0.87; p=0.01]) after adjustment for a large variety of baseline parameters and hospitalisation for heart failure during follow-up., Conclusions: Improvement in guideline adherence with particular emphasis on dose escalation is associated with a decrease in long-term mortality in ambulatory HF-REF subjects surviving one year after registration., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

High aldosterone levels are considered to play a key role in arterial hypertension. Data on the relationship between the aldosterone to active renin ratio (AARR), a quantity of aldosterone excess, and ambulatory blood pressure (BP) monitoring (ABPM) during the night are, however, sparse. Hypertensive patients were recruited from local outpatient clinics who underwent 24-hour urine collection and in parallel ABPM. Plasma aldosterone and renin concentrations were measured by radioimmunoassay. A total of 211 patients (age, 60.2±10.2 years; 51.9% female) with a mean systolic/diastolic ABPM value of 128.7±12.8/77.1±9.2 mm Hg were evaluated. In backwards linear regression analyses adjusted for age, sex, body mass index, smoking, glomerular filtration rate, hemoglobin A1c , N-terminal prohormone of brain natriuretic peptide, urinary sodium/potassium ratio, and ongoing antihypertensive medication, AARR was significantly associated with nocturnal systolic (ß-coefficient: 0.177; P=.017) and diastolic BP (ß-coefficient: 0.162; P=.027). In patients with arterial hypertension, a significant association between AARR and nighttime BP even after adjustment for a broad panel of confounders was found., (©2014 Wiley Periodicals, Inc.)

Currently, there are no clinically approved surgical glues that are nontoxic, bind strongly to tissue, and work well within wet and highly dynamic environments within the body. This is especially relevant to minimally invasive surgery that is increasingly performed to reduce postoperative complications, recovery times, and patient discomfort. We describe the engineering of a bioinspired elastic and biocompatible hydrophobic light-activated adhesive (HLAA) that achieves a strong level of adhesion to wet tissue and is not compromised by preexposure to blood. The HLAA provided an on-demand hemostatic seal, within seconds of light application, when applied to high-pressure large blood vessels and cardiac wall defects in pigs. HLAA-coated patches attached to the interventricular septum in a beating porcine heart and resisted supraphysiologic pressures by remaining attached for 24 hours, which is relevant to intracardiac interventions in humans. The HLAA could be used for many cardiovascular and surgical applications, with immediate application in repair of vascular defects and surgical hemostasis.

Background: In left ventricular (LV) pressure-overload hypertrophy, lack of adaptive capillary growth contributes to progression to failure. Remodeling of the hypertrophied myocardium requires proteolysis of the extracellular matrix (ECM) carried out by matrix metalloproteinases (MMPs). MMPs, specifically MMP-9, are known to cleave ECM components to generate angiogenesis inhibitors (angiostatin, endostatin, tumstatin). We hypothesize that MMP-9 releases antiangiogenic factors during compensated and decompensated hypertrophy, which results in lack of adaptive capillary growth., Methods: Newborn rabbits underwent aortic banding. Myocardial tissue from age-matched and banded animals at compensated (4 weeks) and decompensated hypertrophy (7 weeks), as identified by serial echocardiography, was analyzed by immunoblotting for angiostatin, endostatin, and tumstatin. MMP-9 activity was determined by zymography. A cell-permeable, potent, selective MMP-9 inhibitor was administered intrapericardially to animals with hypertrophied hearts and tissue was analyzed., Results: MMP-9 is activated in hypertrophied myocardium versus in control hearts (22 ± 2 versus 16 ± 1; p = 0.04), which results in significantly increased levels of angiostatin (115 ± 10 versus 86 ± 7; p = 0.02), endostatin (33 ± 1 versus 28 ± 1; p = 0.006), and tumstatin (35 ± 6 versus 17 ± 4; p = 0.04). Zymography confirms inhibition of MMP-9 (hypertrophy + MMP-9 inhibitor, 14 ± 0.6 versus hypertrophy + vehicle, 17 ± 1; p = 0.01) and angiostatin, endostatin, and tumstatin are down-regulated, accompanied by up-regulation of capillary density (hypertrophy + MMP-9 inhibitor, 2.99 ± 0.07 versus hypertrophy + vehicle, 2.7 ± 0.05; p = 0.002)., Conclusions: Up-regulation of angiogenesis inhibitors prevents adaptive capillary growth in pressure-overload hypertrophied myocardium. Therapeutic interventions aimed at inhibition of angiogenesis inhibitors are useful in maintaining capillary density and thereby preventing heart failure., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Aims: Inadequate capillary growth in pressure-overload hypertrophy impairs myocardial perfusion and substrate delivery, contributing to progression to failure. Capillary growth is tightly regulated by angiogenesis growth factors like vascular endothelial growth factor (VEGF) and endogenous inhibitors such as the splice variant of VEGF receptor-1, sVEGFR-1. We hypothesized that inadequate expression of VEGF and up-regulation of VEGFR-1 and its soluble splice variant, sVEGFR-1, restrict capillary growth in pressure-overload hypertrophy., Methods and Results: Neonatal New Zealand White rabbits underwent aortic banding. mRNA (qRT-PCR) and protein levels (immunoblotting) were determined in hypertrophied and control myocardium (7/group) for total VEGF, VEGFR-1, sVEGFR-1, VEGFR-2, and phospho-VEGFR-1 and -R-2. Free VEGF was determined by enzyme-linked immunoassay (ELISA) in hypertrophied myocardium, controls, and hypertrophied hearts following inhibition of sVEGFR-1 with placental growth factor (PlGF). VEGFR-1 and sVEGFR-1 mRNA (seven-fold up-regulation, P = 0.001) and protein levels were significantly up-regulated in hypertrophied hearts vs. controls (VEGFR-1: 44 ± 8 vs. 23 ± 1, P = 0.031; sVEGFR-1: 71 ± 13 vs. 31 ± 3, P = 0.016). There was no change in VEGF and VEGFR-2 mRNA or protein levels in hypertrophied compared with controls hearts. A significant decline in free, unbound VEGF was found in hypertrophied myocardium which was reversed following inhibition of sVEGFR-1 with PlGF, which was accompanied by phosphorylation of VEGFR-1 and VEGFR-2., Conclusion: Up-regulation of the soluble VEGFR-1 in pressure-loaded myocardium prevents capillary growth by trapping VEGF. Inhibition of sVEGFR-1 released sufficient VEGF to induce angiogenesis and preserved contractile function. These data suggest sVEGFR-1 as possible therapeutic targets to prevent heart failure.