Heart Disease Research Articles

Cardiovascular health in women with turner's syndrome: a 3-year single centre audit

Abstract Background Turner’s syndrome (TS) is the most common genetic abnormality affecting females and is characterised by complete or partial absence of the X chromosome. Mortality is predominantly related to cardiovascular disease (1). Risk of life-threatening aortic dissection is 40 per 100,000 (2). Indexed aorta size (ASI) to body surface area (BSA) >20mm/m² is considered abnormal. An ASI of ≥25mm/m² is associated with increased risk of aortic dissection (3). Despite this there is a paucity of data in the literature regarding TS cardiovascular disease and providing evidence-based care can be challenging. Purpose Define cardiovascular disease, with focus upon aortopathy in our TS Cardiovascular Clinic (TCC). Methods Single centre retrospective medical record analysis of 248 women with TS (2021-2024) Results Patient baseline characteristics; mean age 37 years (range 18-75yrs), height 150cm (132-169cm), weight 62kg (37-130kg), BSA 1.55m² (1.19-2.17m²). 65 patients (29%) had bicuspid aortic valve (BAV), 19 (8%) and 5 (3%) had repaired and un-repaired aortic coarctation (CoA) respectively. 30 (13%) had other congenital heart disease, with most common was partial anomalous pulmonary venous connection (12 patients: 5%). 22/248 patients had previous aortic root surgery; 20 elective (mean ASI 29mm/m², range 26-33mm/m², mean age at time of surgery 42 years); 2 presented with aortic dissection (ASI 21mm/m²; pregnant, BAV & 24mm/m²; tri-leaflet aortic valve, TAV). Data was available for 221 unoperated patients (figure 1). The site of maximal dimension was observed at the sinus of Valsalva in 70% compared to 30% at the ascending aorta. 130 patients (59%) had maximal ASI of <20mm/m². Dimensions of 20-23mm/m² and 23-25mm/m² were seen in 64 (29%) and 18 (8%) patients respectively. 7 patients (3%) had a maximal ASI of >25mm/m². 4 patients (2%) had an absolute maximal dimension of 40mm with ASI of 23mm/m² for all four. 9/11 patients with dimension ≥25mm/m² or 40mm had a body mass index (BMI) >25kg/m². Review of medical history for patients at and above threshold for risk of aortic dissection revealed referral to or previous discussion in an Aortic multi-disciplinary meeting (MDT) with a plan for ongoing surveillance. 57 patients (35%) with TAV had significant aortopathy (mean age 46years, range 19-75years) compared with 33 (51%) with BAV (mean age 39yrs, range 22-72 years) (figure 2). Review of patients >55years of age demonstrated a very similar burden of aortopathy in both TAV (14%) and BAV (15%) populations. Conclusions A high burden of cardiovascular disease exists within our TS population. There is a very high prevalence of aortopathy, increasingly with age and both with and without the presence of a bicuspid aortic valve. More published data is needed to help better define those at risk.

Exploration of vitamin D hydroxy metabolites C3 epimers in cardiovascular patients: comparative cross-sectional study

Abstract Background Research on vitamin D deficiency has recently surged in popularity. This issue has been acknowledged as a widespread problem, often called a "pandemic", and approximately 90% of the Polish population suffers from vitamin D deficiency. The 3-epi-25(OH)D2 and 3-epi-25(OH)D3 metabolites are stereoisomers of 25(OH)D2 and 25(OH)D3 metabolites, and they may be accidentally measured when determining 25(OH)D levels and result in overestimating metabolite concentrations. Purpose Our study aims to identify vitamin D hydroxy metabolites (25-hydroxyvitamin D2, 25-hydroxyvitamin D3, and their epimers 3-epi-25-hydroxyvitamin D2 and 3-epi-25-hydroxyvitamin D3) in patients with cardiovascular disease and healthy volunteers. To our knowledge, no similar studies have been conducted on this topic. Method We included 27 adult patients with venous thrombosis (fourteen males and thirteen females, aged 64.11±14.84 years) and 35 healthy volunteers (thirty-three females and two males, aged 36.37±12.29 years). We used our validated UPLC-MS/MS method to measure the concentrations of 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D2, and 3-epi-25(OH)D3. Statistica 13.3 with Plus Kit 3.0 was used for the statistical assessment. Normal variables were represented as mean and standard deviation, and non-normal variables as the median and interquartile range. A P-value < 0.05 was considered statistically significant for all tests. Results Patients had significantly lower levels of epi-25(OH)D2 than the healthy control group (0.6 [0.4] ng/mL vs. 2.2 [1.3-4.3] ng/mL, p = 0.004). Similarly, they exhibited significantly lower levels of %epi-25(OH)D2 (8.6 [6-22.3] % vs. 39.4 [18.5] %, p = 0.035). Females had higher levels of 25(OH)D3 than males (26.5 [16.2-37.9] ng/mL vs. 18.8 [7.5] ng/mL, p = 0.04). They also exhibited higher levels of total 25(OH)D3 (30.3 [15.6] ng/mL vs. 19.4 [7.8] ng/mL, p = 0.016). Higher age (OR 1.12, 95% CI 1.07 to 1.18), being male (OR 17.77, 95% CI 3.54 to 89.3), and lower % 3-epi-25(OH)D2 (OR 0.92, 95% CI 0.84 to 0.998) were univariate predictors for patients with venous thrombosis. Conclusion: Demographic factors within a given population may affect the 25(OH)D3 concentration. The results indicate that vitamin D epimeric metabolites, particularly epi-25(OH)D2, and their percentage were different in patients compared to healthy volunteers. Additional studies involving a larger population are necessary to fully comprehend the relationship between these vitamin D epimeric metabolites and cardiovascular health

Additive effect of metabolic dysfunction-associated fatty liver disease on left ventricular function and global strain in type 2 diabetes mellitus patients: a 3.0 T CMR feature tracking study

Abstract Purpose Type 2 diabetes mellitus (T2DM) represents the most prevalent form of diabetes, exerting a significant influence on cardiovascular health. Concurrently, metabolic dysfunction-associated fatty liver disease (MAFLD) is closely linked to heightened cardiac dysfunction risk. Our study aimed to explore the additive effect of MAFLD on left ventricular (LV) deformation among T2DM patients, utilizing cardiac magnetic resonance (CMR) feature tracking technology. Methods This study retrospectively included 270 patients with T2DM, comprising 110 individuals with MAFLD and 160 without, alongside 80 age- and sex-matched healthy controls, all of whom underwent CMR examination. Parameters derived from CMR encompass those related to LV function and global strain metrics. LV global strain parameters include global radial peak strain (GRPS), longitudinal peak strain (GLPS), and circumferential peak strain (GCPS), peak systolic strain rate (PSSR), and peak diastolic strain rate (PDSR), measured across radial, circumferential, and longitudinal directions. Intergroup analysis, employing the Mann-Whitney U test, was utilized to compare LV function and global strain parameters. Results The LV function parameters, including LV end-diastolic volume (LVEDV), LVEDV index, LV end-systolic volume (LVESV), LVESVI, LV mass, and LV mass index, displayed a progressive augmentation from controls through T2DM patients without MAFLD, to those with MAFLD. In parallel, LVEF showed a declining trajectory across these groups. In contrast, LVSV and LVSVI were comparable among the three groups. In a similar vein, when examining global strain parameters derived from CMR, a significant and progressive deterioration is observed across the groups. GRPS, GCPS and GLPS, along with PSSR and PDSR in radial, circumferential, and longitudinal directions, manifest a pronounced decline moving from control subjects to T2DM patients without MAFLD, and further deteriorating in those with T2DM and MAFLD (All p-values < 0.05). To assess the effect of MAFLD severity on global peak strain, patients with T2DM and MAFLD were stratified into two groups: a mild MAFLD group (N=77) and a moderate to severe MAFLD group (N=33). Although there was a noticeable decline in GRPS, GCPS and GLPS, as well as in PSSR and PDSR across the three groups—from those without MAFLD to those with mild and then moderate to severe MAFLD—the observed differences did not reach statistical significance. The absence of statistical significance is likely due to the small sample sizes of the groups categorized by severity of MAFLD. Conclusions This study revealed that MAFLD has additive worsening effects on LV function and LV global strains in T2DM patients evaluated by CMR. Besides, moderate to severe MAFLD, compared to mild MAFLD, exhibits worse global strain parameters. Early detection and intervention of MAFLD might improve the prognosis of T2DM patients.

Health Promotion and the case of social prescription of laughter

Abstract Introduction The use of laughter to change lifestyle and promote active and successful ageing is an area of interest within the scope of health promotion. The positive effects of laughter practices occur throughout the life cycle. That is why “laughing” has been identified and indicated as a human activity of social prescription promoting healthy lifestyles. This communication aims to (1) identify the benefits for health, health promotion, well-being, and healthy lifestyle of using laughter activities and practices, (2) identify “laughing” as a social prescription activity that promotes a healthy lifestyle. Methods This work is structured in a narrative review of the literature and the authors’ lived experience as professionals in the well-being area. Results Studies show that laughing and using laughter-inducing approaches have immediate effects on the person who experiences them (e.g. increased general well-being, reduced cortisol levels) with benefits for the immune system and cardiovascular health. Daily practices that are structured and systematic interventions that induce laughter were revealed to have lasting and durable effects. Studies also highlighted the effectiveness of laughter and its important role in improving communication in healthcare professional-patient encounters. Discussion Several behaviors are associated with well-being, happiness and positive affect, but the one that is accessible to all people and with the most immediate effects is laughter. Daily practices, structured and systematic interventions that induce laughter are part of non-pharmacological approaches that promote health and well-being. The principles underlying laughter practices are aligned with the Sustainable Development Goals, namely goal 3 (Health), goal 4 (Education) and goal 16 (Peace).

Hypnotic use and the risk of cardiovascular diseases in insomnia patients

Abstract Background Insomnia, commonly treated with hypnotic agents, is an independent risk factor of cardiovascular diseases. Previous research demonstrated the detrimental effect of hypnotics on the prognosis of cardiovascular patients. Purpose We aimed to examine the association between hypnotic agents and cardiovascular outcomes in general individuals with insomnia. Methods In a propensity score matched cohort of UK Biobank (UKB) participants with insomnia, Cox proportional hazard model was used to estimate the association between regular use of hypnotic agents and predetermined cardiovascular outcomes including incident coronary heart diseases (CHD), heart failure (HF), stroke, and cardiovascular death. Inverse probability of treatment weighting and competing risk models were further performed during sensitivity analysis. Drug-target Mendelian randomization (MR) analyses were employed for further evaluation of hypnotics-related genes and cardiovascular disease association. The genome-wide association data of CHD, HF, and stroke were there large-scale genome-wide association analyses. Tissue-specified expression quantitative trait loci (eQTL) data was derived from BrainSeq phase II. Results During a median follow-up of 14.3 years, the matched cohort documented a total of 1,019 CHD cases, 406 HF cases, 285 stroke cases, and 197 cardiovascular deaths. No significant association was detected between Z-meds and CHD, stroke, and cardiovascular mortality. Benzodiazepine use was significantly associated with the increased risk of CHD, HF, and cardiovascular mortality (Figure 1). The inverse probability of treatment weighting and competing risk models didn’t alter the above associations. Moreover, drug-target MR analyses corroborated the safety of Z-meds in the general population regarding cardiovascular health. However, GABRG1—a drug target for benzodiazepines—was associated with heightened risks for heart failure, and ischemic stroke (Figure 2). Conclusions Our findings suggested the heterogeneous associations between different categories of hypnotics and incident cardiovascular events in individuals with insomnia. Z-meds are safe regarding the risk of cardiovascular outcomes in the UKB population with insomnia.Figure 1Figure 2

Twelve-months treatment with dapagliflozin improves endothelial glycocalyx and cardiovascular function in patients with type 1 diabetes mellitus

Abstract Background Individuals diagnosed with type 1 diabetes mellitus (T1DM) exhibit indications of vascular and endothelial dysfunction earlier in comparison to healthy individuals. Evidence shows that SGLT-2 inhibitors (SGLT-2i) have a beneficial impact on cardiovascular health in individuals with type 2 diabetes mellitus (T2DM). We investigated the effects of dapagliflozin on endothelial and cardiovascular function in patients with T1DM. Methods We recruited in total 40 patients with T1DM and pour glycemic control who were treated with insulin and received dapagliflozin (n=20) or intensification of insulin treatment (n=20) (control group). We measured at baseline and at twelve months post-treatment the: a) Carotid-femoral pulse wave velocity (PWV-Complior; ALAM Medical) b) Central systolic blood pressure (cSBP) c) Perfused boundary region (PBR) of the sublingual arterial microvessels (marker of endothelial glycocalyx thickness) and d) Left ventricular global longitudinal strain (GLS) using speckle-tracking echocardiography. Results At baseline, patients among the two groups had similar age, sex, HbA1c and markers of endothelial and cardiovascular function (p>0.05). After 12 months of treatment, patients who received dapagliflozin displayed an improvement in PBR5–25 (−16%, p<0.05), in PWV (−9.3%, p<0.05), in cSBP (−6%, p<0.05) and in GLS (+4%, P<0.05) compared to baseline. However, no statistically significant changes in PBR5–25, in PWV, in cSBP and in GLS were observed after intensification of insulin treatment (PBR5–25: +0.4%, PWV: -1%, cSBP: −2%, GLS: −1% at 4 months, P>0.05), despite a similar HbA1c reduction (Table 1). Changes of PBR after one year treatment with dapagliflozin correlated with a concomitant reduction of PWV and cSBP (P<0.05). Conclusions Twelve months treatment with dapagliflozin improves endothelial glycocalyx and cardiovascular function in patients with T1DM, independently of glycemic control.

The utility of cardiac rehabilitation in improving endothelium-dependent vascular function in very elderly patients

Abstract Background Endothelial function is crucial for cardiovascular health and diseases. Cardiac rehabilitation has been reported to be useful in enhancing physical performance, quality of life, and endothelial function. The aging of patients with cardiovascular diseases is further progressing, and it is unclear whether cardiac rehabilitation improves physical function and endothelial function in very elderly patients with cardiovascular diseases. Purpose The purpose of this study is to investigate whether outpatient cardiac rehabilitation for individuals aged 80 and above improves physical function, quality of life (QOL), and vascular endothelial function. Methods Forty nine patients aged over 80 years with cardiovascular diseases participated in an outpatient cardiac rehabilitation program. Cardiac rehabilitation was conducted for 1 hour per session, 1-2 times per week for 3-4 months. Cardiopulmonary exercise testing (CPX) was conducted for the evaluation of physical function. QOL was assessed with Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. The reactive hyperemia index (RHI) was measured using EndoPAT2000 in each patient to assess endothelial function. An RHI ≤ 1.67 was defined as endothelial dysfunction. Results The mean ± standard deviation of age was 84 ± 4 years, with 16 (33%) being male. Peak oxygen uptake improved significantly (from 14.1 ± 4.0 to 15.4 ± 3.9 mL/kg/min, P=0.002), as did short physical performance battery scores (from 10.1 ± 2.7 to 10.7 ± 2.0, P=0.004), mini-mental state examination scores (from 27.7 ± 2.2 to 28.2 ± 2.0, P=0.004), Japanese version of the Cardiovascular Health Study criteria (from 2.3 ± 1.3 to 1.5 ± 1.2, P<0.0001), and KCCQ scores (from 76.8 ± 18.4 to 81.4 ± 20.4, P=0.02) after the cardiac rehabilitation program. Endothelial function also improved (LogRHI 0.48 ± 0.39 to 0.57 ± 0.30, P=0.027), and the prevalence of endothelial dysfunction decreased from 54% to 36% after the cardiac rehabilitation program. Conclusion Even in the very elderly patients, outpatient cardiac rehabilitation is beneficial for improving physical function, quality of life, and endothelial function.

Efficacy of diet with low glycemic index on coronary artery disease

Abstract Background Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide, with dietary factors playing a significant role in its pathogenesis. The glycemic index (GI) of foods has been implicated in cardiovascular health, with low GI diets hypothesized to reduce the risk of CAD and improve outcomes [1]. However, the efficacy of low glycemic index diets in patients with established CAD remains uncertain. Objective This study aimed to assess the efficacy of a low glycemic index diet on coronary artery disease by evaluating changes in cardiovascular biomarkers and major adverse cardiovascular events (MACE) using Kaplan-Meier analysis and Cox regression models. Material and Methods A randomized controlled trial was conducted involving 156 patients with established coronary artery disease (Aged 43-75 years, mean age 62.4±12.7 years, male=57%). Participants were randomized to either a low glycemic index diet group or a control group receiving standard dietary advice. Changes in cardiovascular biomarkers, including lipid profiles, inflammatory markers, and glycemic control parameters, were assessed at baseline and follow-up visits. Major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular death, were recorded over a median follow-up period of 6.2±2.4 years. Kaplan-Meier analysis and Cox regression models were used to evaluate the association between adherence to a low glycemic index diet and MACE. Results Preliminary analysis demonstrated significant improvements in cardiovascular biomarkers, including reductions in LDL cholesterol, triglycerides, and inflammatory markers, in the low glycemic index diet group compared to the control group (p < 0.05). Kaplan-Meier analysis revealed a lower incidence of MACE in patients adherent to the low glycemic index diet compared to non-adherent patients (log-rank p < 0.05). Cox regression analysis confirmed the independent association between adherence to a low glycemic index diet and reduced risk of MACE after adjusting for confounding factors (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.95; p < 0.001). Conclusion Our findings suggest that a low glycemic index diet may be efficacious in reducing cardiovascular risk and improving outcomes in patients with coronary artery disease. Adherence to a low glycemic index diet was associated with favorable changes in cardiovascular biomarkers and a reduced risk of major adverse cardiovascular events. Further research is warranted to confirm these findings and elucidate the mechanisms underlying the cardioprotective effects of low glycemic index diets.

Prediction of cardiovascular outcomes by subtle changes in the peripheral immune cell landscape - insights from the LURIC single cell RNA-sequencing study (LuRNA)

Abstract Background and Aims Atherosclerosis and its clinical sequelae, myocardial infarction and stroke, represent the main causes of death worldwide. Although preclinical evidence has suggested the existence of an inflammatory response driving disease, the extend of cellular alterations in human atherosclerosis remains enigmatic. Here, we employ single cell RNA-sequencing (scRNA-seq) on peripheral blood mononucleated cells (PBMCs) in a well-defined cardiovascular risk cohort from the "Ludwigshafen Risk and Cardiovascular Health (LURIC) trial" to define changes in the immune cell landscape in atherosclerotic patients. Methods and Results Of 3317 patients enrolled in the LURIC trial between 1997 and 2000, we selected individuals with stable coronary-artery disease (CAD) (n=31) and healthy patients (no CAD) (n=16) by propensity score matching, adjusted for CRP, NTproBNP, Troponin T, LDL-C, and Cystatin-C, in a case-control design. scRNA-seq was performed by droplet sequencing on PBMCs stored in liquid nitrogen. Individual data sets were integrated and changes between healthy individuals and patients with CAD were evaluated on numeric and transcriptional level. Single cell transcriptomes were annotated using an established CITE-seq reference atlas. While bulk RNA-sequencing of PBMC preparations revealed only minor changes between both conditions, we identified several leukocyte populations on a single cell level with specific transcriptomes that were differentially regulated between both conditions. Interestingly, we found that several subsets of Natural Killer (NK) cells, T cells with an enrichment of proliferation-associated pathways, and a population resembling hematopoietic stem cells were more frequent in patients with CAD, while naïve phenotypes of B and T cells were overrepresented in the absence of CAD. Consistently, most T and B cell populations in patients with CAD were enriched in pathways associated with cell activation, immune receptor signalling, and differentiation. In addition, we detected restricted repertoires of T cell receptor sequences in several adaptive immune cell subtypes from patients with CAD, suggestive of increased cellular clonality and antigen-specificity. Finally, in a comparison of cellular frequencies with cardiovascular outcomes over more than 15 years, several immune cell subsets and cell-type specific transcriptional programs predicted cardiovascular death in this case-control scenario in multi-variate adjusted regression analysis. Notably, addition of scRNA-seq derived parameters was superior to traditional risk prediction with clinical characteristics and soluble biomarkers alone. Conclusion Employing scRNAseq, we demonstrate that atherosclerosis is associated with a profound change in the circulating immune cell landscape even in the absence of measurable differences in inflammatory biomarkers. These findings propose the usage of scRNAseq for the discovery of outcome-relevant cellular biomarkers in the future.

Investigating lifestyle determinants of carotid intima-media thickness: cross-sectional insights from the UK biobank cohort

Abstract Background/Introduction Carotid intima-media thickness (CIMT) is recognised as a crucial marker for cardiovascular disease (CVD) risk, inherently associated with vascular ageing and influenced by biomarkers such as elevated levels of HbA1c, dyslipidaemia, and hypertension. The significance of CIMT lies in its potential to act as a surrogate marker for CVD risk, bridging a gap in understanding the progression of vascular health. Purpose This study aims to investigate the correlation between CIMT and a composite biomarker score to enhance risk assessment and guide the prevention and treatment strategies for CVD. By examining this relationship, the study seeks to underline the importance of CIMT progression as an indicative marker for cardiovascular health. Methods A subset of participants from the UK Biobank, with valid CIMT measurements taken in 2014, was selected for this analysis. CIMT was measured through ultrasound techniques and considered the primary outcome variable, treated as continuous in the analysis. A linear regression model was used to examine the correlation between CIMT and lifestyle risk factors, with a focus on the moderating effects of sex. Results The study included 29,292 UK Biobank participants (48% female, mean age 64 years), with a mean CIMT of 687.11µm (SD 124.28). Significant predictors of CIMT were age (β=6.05) and male gender (β=13.02). Lifestyle factors such as body weight (β=0.84) and high physical activity (β=10.66) were positively correlated with CIMT. Current smokers showed a stronger association with CIMT (β=14.47) compared to former smokers (β=9.21). In females, age (β=6.07), body weight (β=0.71), CRBI score (β=9.95), and previous smoking (β=6.64) positively correlated with CIMT, while high CRP levels were negatively associated (β=-0.61). In males, significant factors included age (β=6.04), body weight (β=0.95), CRBI score (β=10.79), and smoking history, with previous smokers showing a stronger effect (β=11.67) and high physical activity notably associated with increased CIMT (β=18.73). Conclusion(s) The study's findings highlight the impact of lifestyle choices on vascular health, demonstrating that active living, maintaining a healthy weight, and abstaining from smoking can positively affect CIMT and thereby reduce CVD risk. The results confirm the importance of weight management for arterial health across all demographics and highlight the role of abnormal biomarker levels in increasing CIMT. This study contributes to a deeper understanding of the factors affecting CIMT and, by extension, cardiovascular health, advocating for targeted lifestyle interventions to mitigate CVD risk.

Prevecardio: a single-visit population screening model for detection and prevention of 10-year cardiovascular risk

Abstract Introduction Cardiovascular diseases (CVDs) are a major contributor to global mortality. The early detection of cardiovascular risk factors, coupled with timely intervention strategies, is essential for CVD prevention. PreveCardio was developed as an innovative, single-visit population screening model designed to facilitate the early identification and management of cardiovascular risk factors within a population of 1 million in a European capital city region totaling 6 million inhabitants. Purpose This study aimed to ascertain the prevalence of cardiovascular risk factors within the general population and to evaluate the effectiveness of the PreveCardio model in estimating 10-year cardiovascular risks and promoting preventive interventions. Methods In this cross-sectional prevalence study, individuals aged 50 to 75 from a health network were randomly selected and invited to participate in a comprehensive health check. The 30-minute screening consisted of lifestyle evaluations, anthropometric measurements, and blood tests for lipid profiles and glycated haemoglobin. The methodology was designed to provide participants with immediate feedback on their results, cardiovascular health and practical guidance for risk management. Results From the 8,492 individuals solicited, 3,546 took part in the screening: 56,83% were female, mean age 61,17 ± 7,33 y.o. Picture 1 shows the population's percentages with various modifiable cardiovascular risk factors, including 20% with active smoking, 30% with sedentarism, 16% with risky alcohol consumption, 49% with non-adherence to the Mediterranean diet, 40% with overweight, and 30% with obesity. The screening revealed new diagnoses of LDL-hypercholesterolemia in 47% participants, high levels of blood pressure in hypertension range in 49%, prediabetes in 30% and diabetes in 2% (Picture 2). After use SCORE2 and SCORE-OP risk prediction algorithms, PreveCardio is estimated to potentially prevent between 39 to 202 fatal and non-fatal cardiovascular events over 10 years. Predictive modelling based on PreveCardio data projected that expanding the screening across the capital region could prevent at least 26,260 cardiovascular events over 10 years. Conclusion(s) PreveCardio has established itself as a viable and effective model for the early detection of cardiovascular risk factors in a general population. It holds significant promise for public health impact by potentially reducing the incidence of CVD through comprehensive screening and proactive intervention.

Predicting atrial fibrillation from ECG characteristics

Abstract Background/Introduction Atrial fibrillation (AF) is the most common cardiac arrythmia, and demographic shifts in age continues to increase the prevalence of atrial fibrillation on a global scale. With manifestations of short and intermittent duration, identifying and diagnosing AF often proves to be a challenge. As a consequence, patients who develop AF are at risk of experiencing stroke and other cardiac diseases such as heart failure (HF) before appropriate treatment is initialized. Despite the potential benefits of early AF detection, risk profiling based on electrocardiographic (ECG) findings is currently lacking. Several smaller studies have identified ECG characteristics associated with increased risk of AF, but these characteristics have not been individually evaluated in large-scale nationwide cohorts, and no evidence exists on the additive effect of these ECG characteristics. Purpose We aimed to evaluate the risk of new-onset AF, HF, and stroke according to five ECG characteristics previously linked to AF, in order to identify potential predictors of AF. Methods We used national registers and the Danish Nationwide ECG Cohort to include patients with ECG measurements taken between 2010 and 2022. Patients were grouped according to how many of the following ECG characteristics were present in their baseline ECG: Elevated heart rate (>80), prolonged PR-interval (≥196 ms for women and ≥204 ms for men), biphasic P-waves (positive and negative amplitude within same p-wave), abnormal P terminal force (≥ 6000 mV×ms), and prolonged P-wave duration(≥120 ms). Patients were followed for 2 years to evaluate the risk of atrial fibrillation, heart failure (HF), and stroke, according to baseline ECG characteristics. Results We included 1,505,474 patients of whom 594,702 had exactly one ECG characteristic, 197,367 had two characteristics, 44,983 had three characteristics, 6,390 had four characteristics, and 451 had all five characteristics on their baseline ECG. The risk of developing AF or HF increased with the number of ECG characteristics present on the baseline ECG. Patients with two ECG characteristics had a 2-fold increased risk of AF or HF compared to patients with no ECG characteristics (HR: 2.11 95%CI: 2.05-2.16). Patients with two or more ECG characteristics present on their baseline ECG exceeded a 5% 2-year absolute risk of developing either AF or HF. Among patients with only one ECG characteristic on their baseline ECG, elevated heart rate and prolonged PR interval were the factors most associated with an increased risk of AF compared to patients with none of the ECG characteristics on their baseline ECG. Conclusions The absolute and relative risk of atrial fibrillation, heart failure, and stroke increased with the number of ECG characteristics present on the baseline ECG. We suggest that the ECG characteristics evaluated in this study could be used in screening scenarios for atrial fibrillation to identify high risk patients.Absolute and relative 2-year risksRisk acc. to specific ECG characteristic

Chromatin remodeling by the histone methyltransferase SETD2 drives cardiometabolic heart failure with preserved ejection fraction

Abstract Background Cardiometabolic heart failure with preserved ejection fraction (cHFpEF) is highly prevalent and associates with a poor outcome. Pathological gene expression in heart failure is accompanied by changes in active histone marks without major alterations in DNA methylation. Histone 3 trimethylation at lysine 36 (H3k36me3) - a chromatin signature induced by the histone methyltransferase SETD2 – has shown a strong correlation with changes in gene expression in the human failing heart; however its role in cardiac disease is poorly understood. The present study investigates the role of SETD2/ H3k36me3 in cHFpEF. Purpose To investigate the role of chromatin remodelling in obese HFpEF (obHFpEF). Methods Mice with cardiomyocyte-specific deletion of SETD2 (c-SETD2-/-) were generated and subjected to high fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Cardiac function and exercise tolerance were assessed by echocardiography and Treadmill exhaustion test, respectively. ChIP-Seq datasets were employed to determine the biological pathways regulated by H3k36me3, whereas chromatin immunoprecipitation assays (ChIP) were performed to investigate SETD2/H3k36me3 enrichment on gene promoters. SETD2 gain- and loss-of-function experiments were performed in cultured cardiomyocytes (CMs) exposed to metabolic stress (palmitic acid). SETD2/H3k36me3 axis was also investigated in left ventricular (LV) myocardial specimens from patients with cHFpEF and control donors. Moreover, pharmacological inhibition of SETD2 was performed in skinned CMs from cHFpEF patients. Results Bioinformatic analysis of ChIP-Seq data in mouse CMs showed a strong involvement of SETD2/H3k36me3 in lipid-related pathways. Specifically, SETD2 and H3k36me3 were upregulated in cHFpEF vs. control mouse hearts and were highly enriched on the promoter of sterol regulatory element-binding transcription factor 1 (SREBP1) gene. SETD2 activation in cHFpEF led to SREBP1 upregulation, myocardial triglyceride accumulation and lipotoxic damage. In cHFpEF mice, cardiomyocyte-specific deletion of SETD2 prevented hypertrophic remodeling, diastolic dysfunction and lung congestion while improving exercise tolerance. Mechanistically, SETD2 deletion blunted H3K36me3 enrichment on SREBP1 promoter thus preventing SREBP1-driven lipid accumulation and leading to a significant rewiring of the cardiac lipidome. These findings were associated with restoration of autophagic flux in the cHFpEF myocardium. In CMs exposed to palmitic acid, SETD2 depletion prevented SREBP1 upregulation, whereas SETD2 overexpression recapitulated lipotoxic damage. Finally, SETD2 was upregulated in LV myocardial samples from cHFpEF patients and its pharmacological inhibition attenuated CM stiffness. Conclusions SETD2 is a new molecular target implicated in the pathophysiology of cHFpEF.

Impact of QRS complex fragmentation on all-cause mortality before and after cardiac resynchronization therapy

Abstract Introduction Cardiac resynchronization therapy (CRT) have demonstrated to reduce all-cause mortality in selected patients with HFrEF. However, there is still a high rate of non-responders, so risk stratification is crucial. Fragmentation of the QRS complex (QRSf) has been suggested as a valuable prognostic factor in different cardiac diseases, but the evidence in patients undergoing CRT is controversial and limited. Purpose To evaluate if changes in QRSf status before and after CRT implantation has a prognostic role in patients undergoing CRT in terms all-cause mortality. Methods Consecutive patients undergoing CRT were prospectively included from October 2009 to December 2022. Demographic clinical, electrocardiographic and echocardiographic variables were recorded. Prospective follow-up variables were collected from electronic clinical records and telephone interview. QRSf complex was defined by the presence of different RSR′ patterns including additional R-waves (R′) and notches of the R-wave and S-wave in two contiguous leads corresponding to a main coronary artery territory in a 12-lead electrocardiogram performed before and after CRT. Results A total of 244 patients (mean age 71.8 ± 9.8 years, 79.5% male) were included. The etiology of LV systolic disfunction was ischemic in 50.0%. Mean LVEF before implantation was 25 ± 9%. A CRT-D was implanted in 176 patients (72.2%). The mean width of the paced QRS was 141 ± 23 ms. At baseline, 150 patients had a QRSf. After CRT implantation, 69 (28.4%) patients experimented a change in QRSf status: 29 patients (11.9%) without prior QRSf developed QRSf, whereas 40 patients (16.5%) resolved QRSf after CRT. Median follow-up time was 36.0 months (interquartile range 18.2-75.7). During the follow-up period, 90 patients died. In the multivariate Cox regression survival analysis, the presence of QRSf before the implantation with or without paced QRSf after CRT were independently associated with all-cause mortality (HR 4.43; 95% CI 1.53-12.80 and HR 3.69; 95% CI 1.16-11.80 respectively). Those without QRSf prior implantation who developed QRSf after CRT did not present significantly higher risk of all-cause mortality. Univariate and multivariate Cox regression analyses for all-cause mortality are presented in Table 1. Figure 1 presents Kaplan-Meier curves for all-cause mortality according to QRSf status before and after CRT implantation. Conclusions According to our results, preimplantation QRSf is an independent predictor of all-cause mortality regardless the resolution or maintenance of QRSf after CRT in patients with HFrEF undergoing CRT. Therefore, patients with QRSf before CRT implantation regardless the paced QRSf status, should be followed more strictly because they are at higher mortality risk.Table 1.Cox Regression Analyses

Cardiac amyloidosis: a texture issue. a proof of concept study on quantification of granular sparkling in patients with transthyretin-related cardiac amyloidosis using radiomics and granulometry

Abstract Background Granular sparkling is a well-known echocardiographic feature found in patients with transthyretin-related cardiac amyloidosis (ATTR-CA). However, there is no objective technique for quantifying this feature, which therefore remains a qualitative, elusive and ultimately unreliable imaging characteristic. Recent evidence suggests that radiomics and, in particular, ultrasonomics could play an important role in the non-invasive tissue characterization of cardiomyopathies through the study of specific myocardial texture features. Purpose The aim of this study is to statistically and geometrically characterize granular sparkling as a volume-independent texture property of the myocardium in patients with ATTR-CA. Methods We retrospectively collected echocardiogram video-clips in parasternal long axis (PLAX) and 4-chamber (4CH) views of 229 patients with ATTR-CA, and 224 age- and gender-matched hypertensive patients without any known cardiac disease. From each video-clip, one end-diastole frame was extracted and annotated by an expert to identify a region-of-interest (ROI) within the interventricular septum. Left ventricle chamber masks were also extracted, and used as a brightness reference to enforce invariance w.r.t. the settings of the specific ultrasound system (Fig. 1). Because many established radiomic textural features are heavily volume-confounded, we analyzed the ROI texture by extracting a subset of volume-invariant radiomic features (i.e. ROI-independent), as well as morphological granulometry features. We then fitted a logistic regression classifier to discriminate between ATTR-CA and controls based on the computed textural features. Results 94 radiomic features were identified, of which 73 were volume-invariant. The texture-based classifier predicted the diagnosis with a cross-validated accuracy of 91%, a specificity of 90% and a sensitivity of 92% by utilizing 73 volume-invariant radiomic features on both PLAX and 4CH views (Fig. 2). The addition of granulometry and the further addition of 11 volume-confounded features and 9 shape features to the model did not significantly enhance its discriminative performance (Fig. 2). The top 10 volume-invariant discriminative features were largely consistent in PLAX and 4CH views (Fig. 2), with variables descriptive of greater heterogeneity (such as glszm_ZoneEntropy and glszm_RunEnNtropy) and a higher spatial rate of change (such as ngtdm_Complexity) in the texture of ATTR-CA frames as compared to control frames. Conclusions Our results confirm the ability of radiomics in detecting subtle differences in the myocardial texture of echocardiographic images between patients with ATTR-CA and hypertensive controls. High levels of accuracy are obtained with a purely texture-based, volume-independent set of features. These findings suggest that the diagnosis of ATTR-CA could be simplified and made earlier using a statistical model based on the extraction of radiomic features.Figure 1Figure 2

Could piano music therapy alleviate high sinus rhythm in subjects with controlled hypertension?

Abstract Background/Introduction With a millenary tradition, music is rediscovered nowadays, as adjuvant therapy. The number of beats per minute (bpm) is the common factor of cardiology – representing heart rate (HR), and music – reprezentative for tempo. Purpose Our goal was the HR modulation in patients (pts) with moderate tachycardia using three piano kits: K1 – Adagio by Albinoni, K2 – Piano Concerto nr. 21 by Mozart, second part; and K3 – Liebestraum by Liszt. Methods During 1st January – 31st December 2023, we identified by ambulatory screening 288 pts adequate for our goal. As exclusion criterion, we considered any type of rhythm or conduction dysturbances. All selected pts were controlled with antihypertensive agents not altering HR, usually thiazide/thiazide-like diuretics and/or ACEis/ARBs. The study group consisted in 144 hypertensive pts controlled at least six months, without any other cardiac diseases. The control group consisted in 144 pts with normal cardiologic examination. Both groups were demographically balanced. The HR at admission was between 84 and 120 bpm, the pts being stratified in three bpm subcategories. All pts have done three visits consisting in: physical examination, ECG, lab markers, TTE for V1 at initiation and EoS at six months, and respectively, physical exam and ECG for V2 at 3 months. Results (in bpm): Inside the group with HR 84-96 treated with K1, the Controlled HTN group (CHG) and the Normal Cardiac group (NCG) alleviated HR from 85,8 +/- 12,6 to 82,6 +/- 12,2; and from 85,7 +/- 12,6 to 80,8 +/- 11,9, respectively. For pts inside the interval 97-108 treated with K1, the CHG group and the NCG alleviated HR from 94,3 +/- 14,1 to 90,9 +/- 13,7 and, respectively, from 94,4 +/- 14,1 to 89,7 +/- 13,6. In pts from HR spectrum 97-108 treated with K2, the CHG and the NCG alleviated HR from 98,4 +/- 14,6 to 95,7 +/- 14,1; and from 98,5 +/- 14,6 to 94,1 +/- 13,8; respectively. Inside the group with HR spectrum 109-120 treated with K1, the CHG and the NCG alleviated HR from 97,1 +/- 14,3 to 94,8 +/- 13,9; and, respectively, from 97,0 +/- 14,3 to 93,9 +/- 13,7. For pts inside the interval 109-120 treated with K2, the CHG and the NCG alleviated HR from 101,7 +/- 14,6 to 99,3 +/- 14,2; and from 101,8 +/- 14,6 to 97,3 +/- 14,1; respectively. In pts from HR spectrum 109-120 treated with K3, the CHG and the NCG alleviated HR from 106,1 +/- 14,7 to 103,8 +/- 14,6; and from 106,5 +/- 14,4 to 103,6 +/- 14,4; respectively. Conclusions The effect of piano music on HR seems favorable in controlled hypertensive pts without major comorbidities, probably by interfering the sympathetic vegetative nervous system. In this regard, it could be used as adjuvant in optimizing this cardiac parameter. However, a multicentered randomized clinical study will be needed.

QRS complex fragmentation status before and after cardiac resynchronization therapy predicts hospitalizations for heart failure

Abstract Introduction Cardiac resynchronization therapy (CRT) reduces mortality and hospitalization for heart failure (HF) in selected patients with HF with reduced ejection fraction (HFrEF). However, there is a significant percentage of non-responders who are readmitted for HF after implantation. Several biomarkers and electrocardiographic findings have been suggested as prognostic markers in this group of patients. Fragmentation of the QRS complex (QRSf) has been associated with worse prognosis in several cardiac diseases, but evidence in patients undergoing CRT remains to be limited. Purpose To evaluate if the changes in QRSf status before and after CRT implantation have a prognostic role in patients undergoing CRT in terms of hospitalization for HF. Methods Consecutive patients undergoing CRT were prospectively included from October 2009 to December 2022. Demographic clinical, electrocardiographic and echocardiographic variables were recorded. Prospective follow-up variables were collected from electronic clinical records and telephone interview. QRSf complex was defined by the presence of different RSR′ patterns including an additional R-waves (R′) and notches of the R-wave and S-wave in two contiguous leads corresponding to a main coronary artery territory in a 12-lead surface electrocardiogram performed before and after CRT. Results A total of 244 patients (mean age 72 ± 10 years, 80% male) were included. The etiology of the LV systolic dysfunction was ischemic in 50.0%. Mean LVEF before implantation was 25 ± 9% and mean paced QRS width was 141 ± 23 ms. CRT-D was implanted in 176 patients (72.2%). At baseline, 150 patients had a QRSf. After CRT implantation, 69 (28.4%) patients experimented a change in QRSf status: 29 patients (11.9%) without prior QRSf developed QRSf, whereas 40 patients (16.5%) resolved QRSf after CRT. Median follow-up time was 36.0 months (interquartile range 18.2-75.7). At follow-up, 90 patients died and 91 presented at least one hospitalization for HF. Multivariate Cox regression survival analysis showed that development of QRSf after CRT implantation (HR 8.87; 95% CI 1.85-42.50) and the presence of QRSf before implantation with or without paced QRSf after CRT (HR 8.21; 95% CI 1.75-38.50 and HR 16.70; 95% CI 3.88-71.80 respectively) were independently associated with hospitalizations for HF. Univariate and multivariate Cox regression analyses for HF hospitalization are presented in Table 1. Figure 1 presents Kaplan-Meier curves for QRSf status and hospitalizations for HF. Conclusions According to our results, QRSf status before and after CRT have a significant prognostic role in terms of hospitalization for HF after CRT, especially in those who develop QRSf after CRT and those with baseline QRSf regardless QRSf status after CRT. The worse prognosis was observed in those with QRSf before and after CRT. Therefore, these patients should be followed more strictly because they are at higher risk of decompensation.Table 1.Cox Regression Analyses

Prognostic implication of right ventricular - pulmonary arterial coupling in patients with non-valvular atrial fibrillation

Abstract Background The clinical importance of right ventricular (RV) - pulmonary arterial (PA) coupling has been reported in various cardiac diseases such as right heart failure, pulmonary hypertension, and valvular dysfunction. However, there is limited data on patients with non-valvular atrial fibrillation (AF). We aim to investigate whether RV-PA uncoupling affects the clinical outcome in patients with non-valvular AF. Methods A total of 807 consecutive patients with non-valvular AF who underwent echocardiography (mean age 70 ± 12 years, 39% female) were included. We excluded patients with significant (at least moderate degree) valvular diseases, left ventricular ejection fraction (LVEF) <50%, cardiac implantable electronic devices, previous cardiac surgery, and poor echocardiographic image for RV analysis. RV-PA coupling was assessed by the ratio of RV global longitudinal strain (GLS) to PA systolic pressure (PASP), and decreased RV-PA coupling was defined as less than 0.52 %/mmHg based on on the receiver operating characteristic analysis. The primary outcome was the composite of all-cause death and hospitalization for heart failure. Results Over a mean of 4.7 ± 3.5 years of follow-up, 178 (22%) patients had experienced primary outcomes. Among them, 107 (13%) patients were hospitalized for HF and 90 (11%) patients died. Patients with decreased RV-PA coupling were older (73 ± 11 vs. 68 ± 12 years, p<0.001), had a higher prevalence of females (51 vs. 33%, p<0.001) and diabetes (33 vs. 23%, p=0.003), lower left ventricular ejection fraction (60 ± 5 vs. 61 ± 5%, p=0.011), higher E/e’ (14 ± 5 vs. 11 ± 4, p<0.001), larger left atrial volume index (78 ± 37 vs. 62 ± 22 ml/m2, p<0.001) and larger RV end-systolic area (11 ± 4 vs. 10 ± 3 cm2/m2, p=0.001) compared to those with preserved RV-PA coupling. In multivariate Cox regression analysis, decreased RV-PA coupling was associated with worse clinical outcomes even after adjusting for age, diabetes, E/e’, and RV end-systolic area (Hazard ratio [HR] 1.50, 95% Confidence interval [CI] 1.09 – 2.07, p=0.014) (Figure 1). Conclusions In patients with non-valvular AF, RV-PA coupling was associated with clinical outcome, suggesting that it may provide additional information for predicting future cardiovascular risk in this population.

Cardioprotective effects of nicorandil on mitochondrial apoptosis signaling in the failing heart of cardiac-specific Bcl-2-associated athanogene (BAG) 3 knockout mice

Abstract Background Bcl-2-associated athanogene (BAG) 3 is a known regulator of mitochondrial apoptotic cell death and autophagic protein degradation in the heart. Disruption of the BAG3 gene in a cardiac-specific manner can lead to cardiac failure in mice. However, therapeutic approaches for cardiac failure induced by BAG3 gene disruption remain poorly understood. Method and results We characterized mice with the ablated BAG3 gene using the Cre-recombinase-loxp site system in a cardiac-specific manner (BAG3f/f crossbred with cardiac specific Cre transgenic mice; BAG3 cKO) and examined the therapeutic effect of nicorandil, an antianginal drug, in BAG3 cKO mice. Cardiac BAG3 levels were markedly reduced in the cytoplasmic and mitochondrial fractions from the hearts of BAG3 cKO mice compared to BAG3f/f mice. BAG3cKO mice exhibited cardiac disease such as a reduction in fractional shortening detected by echocardiography, cardiac fibrosis at 6 months of age, and approximately 40% premature death by 6 months of age. Electron microscopy analysis confirmed cardiomyocyte loss and mitochondrial abnormalities in some areas of the heart section from BAG3cKO mice at 4.5 months of age. A marked decrease in the level of cytochrome C in the mitochondrial fraction and a slight increase in the cytoplasmic fraction, along with apoptotic cell death, were observed in hearts from BAG3 cKO mice at 4.5 months. Mitochondrial levels of anti-apoptotic factors, such as Bcl-2 and Bcl-xl, were reduced, while there was a marked increase in Bak1, an apoptotic inducible factor, in hearts from BAG3 cKO mice at 4.5 months of age. These results suggest that cardiac mitochondrial impairment and subsequent apoptotic cell death occurred in BAG3cKO mice. Nicorandil treatment (81 mg/L drinking water) initiated at 2 months of age prevented the reduction of fractional shortening, cardiac fibrosis, ultrastructural cardiac abnormalities, and premature death. Furthermore, nicorandil treatment prevented the decrease in mitochondrial cytochrome C and the increase in cytoplasmic cytochrome C in hearts from BAG3 cKO mice at 4.5 months of age. Nicorandil treatment also inhibited the elevation of mitochondrial Bak1 levels, reduction in Bcl-2 levels, and occurrence of apoptotic cell death in hearts from BAG3 cKO mice at 4.5 months of age. Conclusion Long-term treatment with nicorandil can inhibit cardiac disease induced by cardiac- specific BAG3 ablation through mitochondrial protection via the prevention of activation of mitochondrial apoptosis signaling.

Novel cardiovascular magnetic resonance imaging heterogeneity biomarkers to diagnose and predict cardiovascular disease: a UK Biobank CMR strain study

Abstract Background Myocardial strain evaluation on cardiovascular magnetic resonance imaging (CMR) shows significant promise to investigate cardiac function in vivo. There is concern that derived global longitudinal strain (GLS) and global circumferential strain (GCS) are less sensitive to early pathological cardiac remodelling, especially when regional. By quantifying contractile variability across the myocardium, the absolute longitudinal and circumferential strain coefficients of variation, |CoVLS| and |CoVCS| may facilitate earlier diagnosis and improved prognostication. Purpose We compared experimental heterogeneity biomarkers, |CoVLS| and |CoVCS|, to established global strain markers, GLS and GCS, to discriminate prevalent cardiovascular disease (CVD) and predict major adverse cardiovascular events (MACE). Methods Prevalent and incident CVD were defined among 44,955 participants from the UK Biobank (UKBB), who had feature-tracking (FT-CMR) derived strain markers. Prevalent CVD was the sum of established cardiovascular diagnoses at the time of baseline CMR, including hypertension, diabetes, atrial fibrillation, coronary artery disease, stroke and heart failure (HF). Incident CVD was newly identified MACE, including death from any cause, myocardial infarction, HF and stroke. Biomarkers were separately regressed against said endpoints, using ordinal logistic and Cox proportional hazards regression respectively. Statistical adjustment was performed for important baseline co-variables, including age, sex, ethnicity, smoking status, body mass index (BMI), low-density lipoprotein (LDL), left atrial volume, left ventricular mass and ejection fraction. Results Overall, 30,289 (67.4%) participants had no prevalent CVD, 10,362 (23.0%) had 1 CVD and 29 (0.06%) had ≥5 CVD. |CoVLS|, GLS, |CoVCS| and GCS were associated with a higher odds of prevalent CVD diagnoses (Figure 1). GLS had the greatest strength of association (OR 1.25, 95% CI 1.20-1.29), followed by |CoVCS| (OR 1.14, 95% CI 1.10-1.17). Over median 2.7 years (Q1-Q3 1.9-4.1 years), 966 (2.1%) participants experienced MACE, including 379 (0.8%) deaths, 263 (0.6%) MI, 246 (0.5%) HF, 237 (0.5%) stroke. |CoVLS|, |CoVCS| and GLS were comparable risk markers for MACE (Figure 2). The largest and smallest effect sizes were in predicting HF and death from any cause respectively. Conclusion Subclinical cardiac disease is often patchy, diffuse and regional; measures of heterogeneity may be more sensitive to these early pathological signals. We demonstrated that |CoVLS| and |CoVCS| are comparable to GLS and better than GCS in discriminating prevalent cardiac disease and predicting future cardiovascular events. These findings need to be replicated in other population studies and diseased cohorts.