Type 1 Myocardial Infarction in Patients With Acute Ischemic Stroke.

Importance: Elevated values of high-sensitivity cardiac troponin (hs-cTn) are common in patients with acute ischemic stroke and are associated with poor prognosis. However, diagnostic and therapeutic implications in patients with ischemic stroke remain unclear. Objective: To identify factors indicative of myocardial infarction (MI) in patients with acute ischemic stroke and hs-cTn elevation. The primary hypothesis was that a dynamic change of hs-cTn values (>50% change) in patients with acute ischemic stroke indicates MI. Design, Setting, and Participants: This cross-sectional study was a prospective, observational study with blinded end-point assessment conducted across 26 sites in Germany. Patients were included if they had acute ischemic stroke within 72 hours and either (1) highly elevated hs-cTn values on admission (>52 ng/L) or (2) hs-cTn levels above the upper limit of normal and a greater than 20% change at repeated measurements. Patients were enrolled between August 2018 and October 2020 and had 1 year of follow-up. Statistical analysis was performed between April 2022 and August 2023. Exposure: Standardized electrocardiography, echocardiography, and coronary angiography. Main Outcome and Measures: Diagnosis of MI as adjudicated by an independent end-point committee based on the findings of electrocardiography, echocardiography, and coronary angiography. Results: In total, 254 patients were included. End points were adjudicated in 247 patients (median [IQR] age, 75 [66-82] years; 117 were female [47%] and 130 male [53%]). MI was present in 126 of 247 patients (51%) and classified as type 1 MI in 50 patients (20%). Dynamic change in hs-cTn value was not associated with MI in univariable (32% vs 38%; χ2 P = .30) or adjusted comparison (odds ratio, 1.05; 95% CI, 0.31-3.33). The baseline absolute hs-cTn value was independently associated with type 1 MI. The best cutoffs for predicting type 1 MI were at hs-cTn values 5 to 10 times the upper limit normal. Conclusions and Relevance: This study found that in patients with acute ischemic stroke, a dynamic change in hs-cTn values did not identify MI, underscoring that dynamic changes do not identify the underlying pathophysiological mechanism. In exploratory analyses, very high absolute hs-cTn values were associated with a diagnosis of type 1 MI. Further studies are needed how to best identify patients with stroke who should undergo coronary angiography.

Imaging of the brain-heart axis: prognostic value in a European setting.

BACKGROUND AND AIMS: Increasing data suggest that stress-related neural activity (SNA) is associated with subsequent major adverse cardiovascular events (MACE) and may represent a therapeutic target. Current evidence is exclusively based on populations from the U.S. and Asia where limited information about cardiovascular disease risk was available. This study sought to investigate whether SNA imaging has clinical value in a well-characterized cohort of cardiovascular patients in Europe. METHODS: In this single-centre study, a total of 963 patients (mean age 58.4 ± 16.1 years, 40.7% female) with known cardiovascular status, ranging from 'at-risk' to manifest disease, and without active cancer underwent 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography between 1 January 2005 and 31 August 2019. Stress-related neural activity was assessed with validated methods and relations between SNA and MACE (non-fatal stroke, non-fatal myocardial infarction, coronary revascularization, and cardiovascular death) or all-cause mortality by time-to-event analysis. RESULTS: Over a maximum follow-up of 17 years, 118 individuals (12.3%) experienced MACE, and 270 (28.0%) died. In univariate analyses, SNA significantly correlated with an increased risk of MACE (sub-distribution hazard ratio 1.52, 95% CI 1.05-2.19; P = .026) or death (hazard ratio 2.49, 95% CI 1.96-3.17; P < .001). In multivariable analyses, the association between SNA imaging and MACE was lost when details of the cardiovascular status were added to the models. Conversely, the relationship between SNA imaging and all-cause mortality persisted after multivariable adjustments. CONCLUSIONS: In a European patient cohort where cardiovascular status is known, SNA imaging is a robust and independent predictor of all-cause mortality, but its prognostic value for MACE is less evident. Further studies should define specific patient populations that might profit from SNA imaging.

Change in body weight of older adults before and during the COVID-19 pandemic: longitudinal results from the Berlin Aging Study II.

OBJECTIVES: Change in body weight during the COVID-19 pandemic as an unintended side effect of lockdown measures has been predominantly reported for younger and middle-aged adults. However, information on older adults for which weight loss is known to result in adverse outcomes, is scarce. In this study we describe the body weight change in older adults before, during, and after the COVID-19 lockdown measures and explore putative associated factors with a focus on the period that includes the first six months of the COVID-19 containment measures. DESIGN: Prospective cohort study with three follow-up examinations over the course of 10 years. SETTING AND PARTICIPANTS: In this study, we analyzed the longitudinal weight change of 472 participants of the Berlin Aging Study II (mean age of 67.5 years at baseline). MEASUREMENTS: Body weight was assessed at four time points. Additionally, differences between subgroups characterized by socio-economic, cognitive, and psychosocial variables as well as morbidity burden, biological age markers (epigenetic clocks, telomere length), and frailty were compared. RESULTS: On average, women and men lost 0.87% (n = 227) and 0.5% (n = 245) of their body weight per year in the study period covering the first six months of the COVID-19 pandemic. Weight loss among men was particularly pronounced among groups characterized by change in physical activity due to COVID-19 lockdown, low positive affect, premature epigenetic age (7-CpG clock), diagnosed metabolic syndrome, and a more masculine gender score (all variables: p < 0.05, n = 245). CONCLUSION: During the COVID-19 pandemic, older participants lost weight with a 2.5-times (women) and 2-times (men) higher rate than what is expected in this age.

Impact of sex and gender on post-COVID-19 syndrome, Switzerland, 2020.

BackgroundWomen are overrepresented among individuals with post-acute sequelae of SARS-CoV-2 infection (PASC). Biological (sex) as well as sociocultural (gender) differences between women and men might account for this imbalance, yet their impact on PASC is unknown.AimWe assessed the impact of sex and gender on PASC in a Swiss population.MethodOur multicentre prospective cohort study included 2,856 (46% women, mean age 44.2 ± 16.8 years) outpatients and hospitalised patients with PCR-confirmed SARS-CoV-2 infection.ResultsAmong those who remained outpatients during their first infection, women reported persisting symptoms more often than men (40.5% vs 25.5% of men; p < 0.001). This sex difference was absent in hospitalised patients. In a crude analysis, both female biological sex (RR = 1.59; 95% CI: 1.41-1.79; p < 0.001) and a score summarising gendered sociocultural variables (RR = 1.05; 95% CI: 1.03-1.07; p < 0.001) were significantly associated with PASC. Following multivariable adjustment, biological female sex (RR = 0.96; 95% CI: 0.74-1.25; p = 0.763) was outperformed by feminine gender-related factors such as a higher stress level (RR = 1.04; 95% CI: 1.01-1.06; p = 0.003), lower education (RR = 1.16; 95% CI: 1.03-1.30; p = 0.011), being female and living alone (RR = 1.91; 95% CI: 1.29-2.83; p = 0.001) or being male and earning the highest income in the household (RR = 0.76; 95% CI: 0.60-0.97; p = 0.030).ConclusionSpecific sociocultural parameters that differ in prevalence between women and men, or imply a unique risk for women, are predictors of PASC and may explain, at least in part, the higher incidence of PASC in women. Once patients are hospitalised during acute infection, sex differences in PASC are no longer evident.

Socio-economic factors determine maternal and neonatal outcomes in women with peripartum cardiomyopathy: A study of the ESC EORP PPCM registry.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a global disease with substantial morbidity and mortality. The aim of this study was to analyze to what extent socioeconomic factors were associated with maternal and neonatal outcomes. METHODS: In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global PPCM registry, under the auspices of the ESC EORP Programme. We investigated the characteristics and outcomes of women with PPCM and their babies according to individual and country-level sociodemographic factors (Gini index coefficient [GINI index], health expenditure [HE] and human developmental index [HDI]). RESULTS: 739 women from 49 countries (Europe [33%], Africa [29%], Asia-Pacific [15%], Middle East [22%]) were enrolled. Low HDI was associated with greater left ventricular (LV) dilatation at time of diagnosis. However, baseline LV ejection fraction did not differ according to sociodemographic factors. Countries with low HE prescribed guideline-directed heart failure therapy less frequently. Six-month mortality was higher in countries with low HE; and LV non-recovery in those with low HDI, low HE and lower levels of education. Maternal outcome (death, re-hospitalization, or persistent LV dysfunction) was independently associated with income. Neonatal death was significantly more common in countries with low HE and low HDI, but was not influenced by maternal income or education attainment. CONCLUSIONS: Maternal and neonatal outcomes depend on country-specific socioeconomic characteristics. Attempts should therefore be made to allocate adequate resources to health and education, to improve maternal and fetal outcomes in PPCM.

Sex differences and estrogen effects in cardiac mitochondria in human aortic stenosis and in the mouse heart.

Introduction: Sex differences in the adaptation to pressure overload have been described in humans, as well as animal models, and have been related to sex-specific expression of mitochondrial genes. We therefore tested whether sex differences in cardiac mitochondrial respiration exist in humans with aortic stenosis (AS). We also examined whether these potential differences may be at least partially due to sex hormones by testing if mitochondrial respiration is affected by estrogen (17ß-estradiol (E2)). Methods: Consecutive patients undergoing transapical aortic valve implantation (TAVI) (women, n = 7; men, n = 10) were included. Cardiac biopsies were obtained during TAVI and used directly for mitochondrial function measurements. Male and female C57BL/6J mice (n = 8/group) underwent sham surgery or gonadectomy (GDX) at the age of 2 months. After 14 days, mice were treated once with intraperitoneally injected vehicle (placebo), 17ß-estradiol (E2), estrogen receptor alpha (ERα) agonist [propyl pyrazole triol (PPT)], or ER beta (ERß) agonist (BAY-1214257). Thereafter, mitochondrial measurements were performed directly in cardiac skinned fibers from isolated left ventricles and musculus solei. Results: Mitochondrial State-3 respiration was higher in female than that in male human heart biopsies (15.0 ± 2.30 vs. 10.3 ± 2.05 nmol/mL/min/mg, p< 0.05). In the mouse model, mitochondrial State-3 respiration decreased significantly after GDX in female (27.6 ± 1.55 vs. 21.4 ± 1.71 nmol/mL/min/mg; p< 0.05) and male hearts (30.7 ± 1,48 vs. 23.7 ± 2,23 nmol/mL/min/mg; p< 0.05). In ovariectomized female mice, E2 and ERß-agonist treatment restored the State-3 respiration to intact placebo level, whereas ERα-agonist treatment did not modulate State-3 respiration. The treatment with E2, ERα-, or ERß-agonist did not modulate the State-3 respiration in GDX male mice. Conclusion: We identified sex differences in mitochondrial respiration in the diseased human heart. This is in alignment with known sex differences in the gene expression and proteome level at the functional level. E2 and ERß affect cardiac mitochondrial function in the mouse model, suggesting that they may also contribute to the sex differences in the human heart. Their roles should be further investigated.

Impact of body mass index on worsening of diastolic function and impairment of left atrial strain in the general female urban population: a subanalysis of the Berlin female risk evaluation echocardiography follow-up study.

Background: The association of body mass index (BMI) with diastolic dysfunction (DD) is well described in the literature. However, there is conflicting evidence and long-term follow-up data regarding effects of BMI on preclinical DD and left atrial (LA) function are scarce, highlighting the importance of early detection tools, such as myocardial strain. Purpose: The aim of our study was to prospectively analyze the impact of clinical and demographic parameters, especially of BMI, on worsening of diastolic function and left atrial strain (LAS) in an urban population of women with a low prevalence of cardiovascular risk factors. Methods and Results: An extensive clinical and echocardiographic assessment comprising the analysis of phasic LAS using two-dimensional speckle-tracking echocardiography (2D STE) was performed in 258 participants of the Berlin Female Risk Evaluation (BEFRI) trial between October 2019 and December 2020 after a mean follow-up period of 6.8 years. We compared clinical and echocardiographic parameters stratifying women by BMI < or ≥25 kg/m2, and we analyzed the impact of demographic characteristics on the worsening of DD and LA mechanics in the longer-term follow-up using univariate and multivariate regression analyses. 248 women were suitable for echocardiographic analysis of LAS using 2D STE. After a mean follow-up time of 6.8 years, LA reservoir strain (LASr) and LA conduit strain (LAScd) were significantly reduced in participants with a BMI ≥25 kg/m2 compared with women with a BMI <25 kg/m2 at baseline (30 ± 8% vs. 38 ± 9%, p < 0.0001; -14 ± 7% vs. -22 ± 8%, p < 0.0001). 28% of the overweighted women presented a deterioration of diastolic function at the time of follow-up in contrast with only 7% of the group with a BMI <25 kg/m2 (p < 0.0001). BMI remained significantly associated with LAS reductions after adjustment for other risk factors in multivariate regression analyses. Conclusion: Overweight and obesity are related to impaired LAS and to a worsening of diastolic function after a long-term follow-up in a cohort of randomly selected women.

Determinants of myocardial work indices in women.

OBJECTIVE: By incorporating myocardial deformation and afterload, novel echocardiographic myocardial work indices appear to be advantageous compared to load-dependent left ventricular (LV) deformation analyses. As such, these indices may provide a more accurate and, above all, load-independent estimation of LV function in patients with chronically increased afterload. To date however, data on the relation of these indices to clinical and conventional echocardiographic parameters are scarce. PURPOSE: Our aim was to evaluate the relationship between myocardial work indices and age, body mass index (BMI), NTproBNP, the clinical history of arterial hypertension and diastolic dysfunction as well as selected conventional echocardiographic parameters in women. METHODS: We analyzed echocardiographic data of women included in the Berlin Female Risk Evaluation (BEFRI) trial. Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW) and Global Work Efficiency (GWE) were calculated using commercially available software based on noninvasive pressure-strain loops. The impact of selected clinical and echocardiographic characteristics on myocardial work parameters was investigated by uni- and multivariate regression analyses. RESULTS: A total of 224 women were included in the final analysis. 155 of them were normotensive and 69 had a history of arterial hypertension. Diastolic dysfunction was more prevalent in subjects with arterial hypertension. Study participants with arterial hypertension showed higher GWI and GCW whereas GWW and GWE did not significantly differ between groups. GCW and GWW were lower and GWE higher in the presence of normal diastolic function. In multivariate regression analyses, arterial hypertension, LV GLS, and interventricular septal thickness were significantly associated with GWI. GCW showed significant associations with the clinical history of arterial hypertension, LV GLS, age and IVRT. Similarly, LV GLS, IVRT and mitral inflow E wave deceleration time were identified to be significant determinants of GWW and GWE. CONCLUSION: Our data confirm that, in a randomly selected sample of the general urban female population, myocardial work parameters are predominantly determined by LV GLS. In addition, the presence of arterial hypertension was identified to be a significant determinant of GWI and GCW, but not for GWW and GWE. Finally, a prolonged LV relaxation time was significantly associated with GWW and GWE, suggesting more wasted myocardial work and lower GWE values with increasing LV relaxation time.

Cardiovascular health-related quality of life in cancer: a prospective study comparing the ESC HeartQoL and EORTC QLQ-C30 questionnaire.

AIMS: Health-related quality of life (HRQoL) is highly relevant in cancer and often assessed with the EORTC QLQ-C30. Cardiovascular HRQoL in cancer can be measured with the ESC HeartQoL questionnaire. We compared these instruments and examined their prognostic value. METHODS AND RESULTS: Summary scores for EORTC QLQ-C30 (0-100 points) and ESC HeartQoL (0-3 points) questionnaires were prospectively assessed in 290 patients with mostly advanced cancer (stage 3/4: 81%, 1-year mortality: 36%) and 50 healthy controls (similar age and sex). Additionally, physical function and activity assessments were performed. Both questionnaires demonstrated reduced HRQoL in patients with cancer versus controls (EORTC QLQ-C30: 67 ± 20 vs. 91 ± 11, p < 0.001; ESC HeartQoL: 1.8 ± 0.8 vs. 2.7 ± 0.4, p < 0.001). The instruments were strongly correlated with each other (summary scores [r = 0.76], physical [r = 0.81], and emotional subscales [r = 0.75, all p < 0.001]) and independently associated with all-cause mortality (best cut-offs: EORTC QLQ-C30 <82.69: hazard ratio [HR] 2.33, p = 0.004; ESC HeartQoL <1.50: HR 1.85, p = 0.004 - adjusted for sex, age, left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin T, cancer stage/type), with no differences in the strength of the association by sex (p-interaction > 0.9). Combining both questionnaires identified three risk groups with highest mortality in patients below both cut-offs (vs. patients above both cut-offs: HR 3.60, p < 0.001). Patients with results below both cut-offs, showed higher NT-proBNP and reduced physical function and activity. CONCLUSIONS: The EORTC QLQ-C30 and ESC HeartQoL - assessing cancer and cardiovascular HRQoL - are both associated with increased mortality in cancer patients, with even greater stratification by combing both. Reduced HRQoL scores were associated with elevated cardiovascular biomarkers and decreased functional status.

Sex and age differences in AMPK phosphorylation, mitochondrial homeostasis, and inflammation in hearts from inflammatory cardiomyopathy patients.

Linked to exacerbated inflammation, myocarditis is a cardiovascular disease, which may lead to dilated cardiomyopathy. Although sex and age differences in the development of chronic myocarditis have been postulated, underlying cellular mechanisms remain poorly understood. In the current study, we aimed to investigate sex and age differences in mitochondrial homeostasis, inflammation, and cellular senescence. Cardiac tissue samples from younger and older patients with inflammatory dilated cardiomyopathy (DCMI) were used. The expression of Sirt1, phosphorylated AMPK, PGC-1α, Sirt3, acetylated SOD2, catalase, and several mitochondrial genes was analyzed to assess mitochondrial homeostasis. The expression of NF-κB, TLR4, and interleukins was used to examine the inflammatory state in the heart. Finally, several senescence markers and telomere length were investigated. Cardiac AMPK expression and phosphorylation were significantly elevated in male DCMI patients, whereas Sirt1 expression remained unchanged in all groups investigated. AMPK upregulation was accompanied by a preserved expression of all mitochondrial proteins/genes investigated in older male DCMI patients, whereas the expression of TOM40, TIM23, and the mitochondrial oxidative phosphorylation genes was significantly reduced in older female patients. Mitochondrial homeostasis in older male patients was further supported by the reduced acetylation of mitochondrial proteins as indicated by acetylated SOD2. The inflammatory markers NF-κB and TLR4 were downregulated in older male DCMI patients, whereas the expression of IL-18 was increased in older female patients. This was accompanied by progressed senescence in older DCMI hearts. In conclusion, older women experience more dramatic immunometabolic disorders on the cellular level than older men.

Diabetes type 2 in the Berlin Aging Study II: Cross-sectional and longitudinal data on prevalence, incidence and severity over on average seven years of follow-up.

AIMS: Aim of the current study was to describe the prevalence, incidence, and severity of diabetes mellitus type 2 (T2D) in a cohort of older men and women aged 60 years and above over the course of on average 7 years, since longitudinal data on this topic are scarce for this age group in Germany. METHODS: Baseline data of 1671 participants of the Berlin Aging Study II (BASE-II; 68.8 ± 3.7 years) and follow-up data assessed 7.4 ± 1.5 years later were analysed. The BASE-II is an exploratory, observational study on cross-sectional and longitudinal data of an older population. T2D was diagnosed based on self-report, antidiabetic medication use and laboratory parameters. T2D severity was determined by the diabetes complications severity index (DCSI). Prognostic capacity of laboratory parameters was evaluated. RESULTS: The proportion of participants with T2D increased from 12.9% (37.3% women) at baseline to 17.1% (41.1% women) with 74 incident cases and 22.2% not being aware of the disease at follow-up. The incidence rate is 10.7 new T2D diagnoses per 1000 person-years. More than half of the 41 newly identified incident T2D cases were diagnosed solely by the 2 h-plasma glucose test (OGTT) and diagnosis based on OGTT as the only criterion among incident cases was found more frequently in women (p = 0.028). T2D severity expressed by the DCSI significantly increased from baseline to follow-up (mean DCSI 1.1 ± 1.2 vs. 2.0 ± 1.8; range 0-5 vs. 0-6). Cardiovascular complications had the highest impact (43.2% at baseline and 67.6% at follow-up). CONCLUSIONS: A comprehensive picture of T2D with respect to prevalence, incidence, and severity in older people of the Berlin Aging Study II is provided.

Phasic left atrial strain to predict worsening of diastolic function: Results from the prospective Berlin Female Risk Evaluation follow-up trial.

Purpose: The predictive value of maximum left atrial volume index (LAVI), phasic left atrial strain (LAS) and other standard echocardiographic parameters assessing left ventricular (LV) diastolic function to discriminate a future worsening of diastolic function (DD) in patients at risk is unclear. We aimed to prospectively assess and compare the clinical impact of these parameters in a randomly selected study sample of the general urban female population. Methods and results: A comprehensive clinical and echocardiographic evaluation was performed in 256 participants of the Berlin Female Risk Evaluation (BEFRI) trial after a mean follow up time of 6.8 years. After an assessment of participants' current DD status, the predictive impact of an impaired LAS on the course of DD was assessed and compared with LAVI and other DD parameters using receiver operating characteristic (ROC) curve and multivariate logistic regression analyses. Subjects with no DD (DD0) who showed a decline of diastolic function by the time of follow-up showed a reduced LA reservoir (LASr) and conduit strain (LAScd) compared to subjects who remained in the healthy range (LASr 28.0% ± 7.0 vs. 41.9% ± 8.5; LAScd -13.2% ± 5.1 vs. -25.4% ± 9.1; p < 0.001). With an area under the curve (AUC) of 0.88 (95%CI 0.82-0.94) and 0.84 (95%CI 0.79-0.89), LASr and LAScd exhibited the highest discriminative value in predicting worsening of diastolic function, whereas LAVI was only of limited prognostic value [AUC 0.63 (95%CI 0.54-0.73)]. In logistic regression analyses, LAS remained a significant predictor for a decline of diastolic function after controlling for clinical and standard echocardiographic DD parameters, indicating its incremental predictive value. Conclusion: The analysis of phasic LAS may be useful to predict worsening of LV diastolic function in DD0 patients at risk for a future DD development.GRAPHICAL ABSTRACT.

DNA methylation age acceleration is associated with risk of diabetes complications.

BACKGROUND: Patients with Type 2 diabetes mellitus (T2D) are at risk for micro- and macrovascular complications. Implementable risk scores are needed to improve targeted prevention for patients that are particularly susceptible to complications. The epigenetic clock estimates an individual's biological age using DNA methylation profiles. METHODS: In this study, we examined older adults of the Berlin Aging Study II that were reexamined on average 7.4 years after baseline assessment as part of the GendAge study. DNA methylation age (DNAmA) and its deviation from chronological age DNAmA acceleration (DNAmAA) were calculated with the 7-CpG clock (available at both timepoints, n = 1,071), Horvath's clock, Hannum's clock, PhenoAge and GrimAge (available at follow-up only, n = 1,067). T2D associated complications were assessed with the Diabetes Complications Severity Index (DCSI). RESULTS: We report on a statistically significant association between oral glucose tolerance test results and Hannum and PhenoAge DNAmAA. PhenoAge was also associated with fasting glucose. In contrast, we found no cross-sectional association after covariate adjustment between DNAmAA and a diagnosis of T2D. However, longitudinal analyses showed that every additional year of 7-CpG DNAmAA at baseline increased the odds for developing one or more additional complications or worsening of an already existing complication during the follow-up period by 11% in male participants with T2D. This association persisted after covariate adjustment (OR = 1.11, p = 0.045, n = 56). CONCLUSION: Although our results remain to be independently validated, this study shows promising evidence of utility of the 7-CpG clock in identifying patients with diabetes who are at high risk for developing complications.

Deterioration of vision, kidney function and cardiovascular function are just a few examples of diabetes-related complications. However, not all patients develop these complications, and it is desirable to detect patients that have a high risk for the complications early. In this study, we examine markers, which are based on reversible modifications of the DNA, in the context of diabetes and its complications. We found that one of these biomarkers is able to predict the development of diabetes complications over a period of about seven years in our dataset. If these results can be confirmed in other studies, our findings might help physicians to identify patients with diabetes that have an increased risk for developing complications in the future.

Disease- and sex-specific differences in patients with heart valve disease: a proteome study.

Pressure overload in patients with aortic valve stenosis and volume overload in mitral valve regurgitation trigger specific forms of cardiac remodeling; however, little is known about similarities and differences in myocardial proteome regulation. We performed proteome profiling of 75 human left ventricular myocardial biopsies (aortic stenosis = 41, mitral regurgitation = 17, and controls = 17) using high-resolution tandem mass spectrometry next to clinical and hemodynamic parameter acquisition. In patients of both disease groups, proteins related to ECM and cytoskeleton were more abundant, whereas those related to energy metabolism and proteostasis were less abundant compared with controls. In addition, disease group-specific and sex-specific differences have been observed. Male patients with aortic stenosis showed more proteins related to fibrosis and less to energy metabolism, whereas female patients showed strong reduction in proteostasis-related proteins. Clinical imaging was in line with proteomic findings, showing elevation of fibrosis in both patient groups and sex differences. Disease- and sex-specific proteomic profiles provide insight into cardiac remodeling in patients with heart valve disease and might help improve the understanding of molecular mechanisms and the development of individualized treatment strategies.

High-Sensitivity Cardiac Troponin T and Cognitive Decline in Older Adults: Results of the Berlin Aging Study II.

INTRODUCTION: There is evidence of an association between markers of cardiac injury and cognition in patients with cardiovascular disease. We hypothesized that levels of high-sensitivity cardiac troponin T (hs-cTnT) are associated with cognitive performance and cognitive decline in a population of predominantly healthy older adults. METHODS: We included 1,226 predominantly healthy adults ≥60 years from the Berlin Aging Study II. Participants were recruited from the general population of the Berlin metropolitan area from 2009 to 2014. At baseline, participants underwent measurement of hs-cTnT and cognitive testing using the extended Consortium to Establish a Registry for Alzheimer's Disease (CERAD-Plus) battery. In addition, the Digit Symbol Substitution Test (DSST) was performed at baseline and at follow-up (7.3 ± 1.4 years after the baseline visit). The CERAD test results were summarized into four cognitive domains (processing speed, executive function, visuo-construction, and memory). After summing-up the respective raw scores, we calculated standardized z scores. We performed unadjusted and adjusted linear regression models to assess links between hs-cTnT and cognitive domains. We used linear mixed models to analyze associations between hs-cTnT and cognitive decline according to changes in DSST scores over time. RESULTS: The mean age of study participants at baseline was 68.5 (±3.6) years, 49% were female, and median hs-cTnT levels were 6 ng/L (IQR 4-8 ng/L). We detected no significant association between hs-cTnT and different cognitive domains at baseline after adjustment for age, sex, education, and cardiovascular risk factors. Hs-cTnT was associated with cognitive decline, which remained statistically significant after full adjustment (adjusted beta-coefficient -0.82 (-1.28 to -0.36), p = 0.001). After stratification for sex, the association with hs-cTnT remained statistically significant in men but not in women. CONCLUSION: Higher hs-cTnT levels in older men are associated with cognitive decline measured with the DSST.

Sex hormones in SARS-CoV-2 susceptibility: key players or confounders?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a clear sex disparity in clinical outcomes. Hence, the interaction between sex hormones, virus entry receptors and immune responses has attracted major interest as a target for the prevention and treatment of SARS-CoV-2 infections. This Review summarizes the current understanding of the roles of androgens, oestrogens and progesterone in the regulation of virus entry receptors and disease progression of coronavirus disease 2019 (COVID-19) as well as their therapeutic value. Although many experimental and clinical studies have analysed potential mechanisms by which female sex hormones might provide protection against SARS-CoV-2 infectivity, there is currently no clear evidence for a sex-specific expression of virus entry receptors. In addition, reports describing an influence of oestrogen, progesterone and androgens on the course of COVID-19 vary widely. Current data also do not support the administration of oestradiol in COVID-19. The conflicting evidence and lack of consensus results from a paucity of mechanistic studies and clinical trials reporting sex-disaggregated data. Further, the influence of variables beyond biological factors (sex), such as sociocultural factors (gender), on COVID-19 manifestations has not been investigated. Future research will have to fill this knowledge gap as the influence of sex and gender on COVID-19 will be essential to understanding and managing the long-term consequences of this pandemic.

Longitudinal effects of a common UMOD variant on kidney function, blood pressure, cognitive and physical function in older women and men.

Genetic variants in UMOD associate with kidney function and hypertension. These phenotypes are also linked to sex-related differences and impairment in cognitive and physical function in older age. Here we evaluate longitudinal associations between a common UMOD rs4293393-A>G variant and changes in estimated glomerular filtration rate (eGFR), blood pressure (BP), cognitive and physical function parameters in older participants in the BASE-II after long-term follow-up as part of the GendAge study. Overall, 1010 older participants (mean age 75.7 ± 3.7 years, 51.6% women) were analyzed after follow-up (mean 7.4 years) both in cross-sectional analysis and in longitudinal analysis as compared to baseline. In cross-sectional analysis, heterozygous G-allele carriers exhibited significantly higher eGFR values (AA, 71.3 ml/min/1.73 m2, 95% CI, 70.3-72.3 vs. AG, 73.5 ml/min/1.73 m2, 95% CI, 72.1-74.9, P = 0.033). Male heterozygous G-allele carriers had lower odds of eGFR < 60 mL/min/1.73 m2 (OR 0.51, 95% CI, 0.28-0.95, P = 0.032) and in Timed Up and Go-Test ≥ 10 s (OR 0.50, 95% CI, 0.29-0.85, P = 0.011) whereas women were less likely to have hypertension (OR 0.58, CI, 0.37-0.91, P = 0.018). UMOD genotypes were not significantly associated with longitudinal changes in any investigated phenotype. Thus, while the impact of UMOD rs4293393 on kidney function is maintained in aging individuals, this variant has overall no impact on longitudinal changes in BP, kidney, cognitive or functional phenotypes. However, our results suggest a possible sex-specific modifying effect of UMOD on eGFR and physical function in men and hypertension prevalence in women.

Gender medicine: effects of sex and gender on cardiovascular disease manifestation and outcomes.

Despite a growing body of evidence, the distinct contributions of biological sex and the sociocultural dimension of gender to the manifestations and outcomes of ischaemic heart disease and heart failure remain unknown. The intertwining of sex-based differences in genetic and hormonal mechanisms with the complex dimension of gender and its different components and determinants that result in different disease phenotypes in women and men needs to be elucidated. The relative contribution of purely biological factors, such as genes and hormones, to cardiovascular phenotypes and outcomes is not yet fully understood. Increasing awareness of the effects of gender has led to efforts to measure gender in retrospective and prospective clinical studies and the development of gender scores. However, the synergistic or opposing effects of sex and gender on cardiovascular traits and on ischaemic heart disease and heart failure mechanisms have not yet been systematically described. Furthermore, specific considerations of sex-related and gender-related factors in gender dysphoria or in heart-brain interactions and their association with cardiovascular disease are still lacking. In this Review, we summarize contemporary evidence on the distinct effects of sex and gender as well as of their interactions on cardiovascular disease and how they favourably or unfavourably influence the pathogenesis, clinical manifestations and treatment responses in patients with ischaemic heart disease or heart failure.

Development and validation of a prognostic model for the early identification of COVID-19 patients at risk of developing common long COVID symptoms.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic demands reliable prognostic models for estimating the risk of long COVID. We developed and validated a prediction model to estimate the probability of known common long COVID symptoms at least 60 days after acute COVID-19. METHODS: The prognostic model was built based on data from a multicentre prospective Swiss cohort study. Included were adult patients diagnosed with COVID-19 between February and December 2020 and treated as outpatients, at ward or intensive/intermediate care unit. Perceived long-term health impairments, including reduced exercise tolerance/reduced resilience, shortness of breath and/or tiredness (REST), were assessed after a follow-up time between 60 and 425 days. The data set was split into a derivation and a geographical validation cohort. Predictors were selected out of twelve candidate predictors based on three methods, namely the augmented backward elimination (ABE) method, the adaptive best-subset selection (ABESS) method and model-based recursive partitioning (MBRP) approach. Model performance was assessed with the scaled Brier score, concordance c statistic and calibration plot. The final prognostic model was determined based on best model performance. RESULTS: In total, 2799 patients were included in the analysis, of which 1588 patients were in the derivation cohort and 1211 patients in the validation cohort. The REST prevalence was similar between the cohorts with 21.6% (n = 343) in the derivation cohort and 22.1% (n = 268) in the validation cohort. The same predictors were selected with the ABE and ABESS approach. The final prognostic model was based on the ABE and ABESS selected predictors. The corresponding scaled Brier score in the validation cohort was 18.74%, model discrimination was 0.78 (95% CI: 0.75 to 0.81), calibration slope was 0.92 (95% CI: 0.78 to 1.06) and calibration intercept was -0.06 (95% CI: -0.22 to 0.09). CONCLUSION: The proposed model was validated to identify COVID-19-infected patients at high risk for REST symptoms. Before implementing the prognostic model in daily clinical practice, the conduct of an impact study is recommended.