bluuebunny/crossref_metadata_2025 huggingface dataset:
Type 2 diabetes mediating the increased cardiovascular risk in patients with rheumatoid arthritis: a bidirectional mendelian randomisation approach
Authors: Fokina A , Fill J , Mehmeti D , Taylor H , Klappacher G
Published: October 2024

Background

Patients with rheumatoid arthritis (RA) are at increased risk of developing coronary artery disease (CAD) as is evident from epidemiological studies. This however is not a causative association, as we have shown by two-sample mendelian randomisation (MR) in previous work. Mediators linking RA to cardiovascular phenotypes have yet to be identified.

Purpose

The present study seeks to determine whether type 2 diabetes (DM II) is such a mediator conferring the increased cardiovascular risk of patients with RA.

Methods

The associations between the phenotypes RA, CAD and DM II were tested for causality with two-sample MR using genetic instruments from genome-wide association studies (GWAS) in largely non-overlapping cohorts. For RA, genetic instruments were obtained from 14,361 cases and 43,923 controls of European ancestry in the dataset by Okada, comprised of 18 studies (1). For the trait DM II, the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium was used (2). This GWAS covered 120,000 SNPs from the Metabochip array in mixed European and Pakistani Population (34,840 cases and 114,981 controls). Genetic instruments for CAD were obtained from the CARDIoGRAMplusC4D consortium with 60,801 cases and 123,504 controls from 48 studies (3). Several MR regression methods such as MR Egger regression and inverse-variance weighted meta-analysis and sensitivity tests for pleiotropy and heterogeneity were performed for each exposure-outcome pair.

Results

Genetic predisposition to RA was not significantly associated with higher risk of CAD (OR = 1,02 [0,99-1,05]), see figure. In contrast, DM II was significantly, albeit weakly related as outcome to genetically determined manifestation of RA as exposure (OR = 1,04 [1,01-1,08]) and, conversely, genetic instruments of DM II conferred an increased risk of developing CAD ((OR = 1,11 [1,05-1,17]).

Conclusions

Despite the high prevalence of CAD among RA patients in observational studies, cardiovascular outcomes are not casually linked with RA. Instead, DM II could serve as a mediator, based on its significant associations with both RA and CAD in two-sample MR.
Association of inflammation with left ventricular mass index in patients with rheumatoid arthritis
Authors: Linde A , Gerdts E , Fevang B T , Ulvik A , Ueland P M , Meyer K , Kringeland E , Midtbo H
Published: October 2024

Background

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease associated with cardiovascular organ damage.

Purpose

We explored the association of inflammatory markers with left ventricular (LV) mass index during 22 months of follow-up in patients with RA.

Methods

Eighty-three outpatients with RA (age 55±12 years, 71 % women) with indication for biological (b) or targeted synthetic (ts) disease modifying antirheumatic drug (DMARD) therapy were examined with echocardiography at baseline and after 22 months. LV mass was indexed for height in the allometric power of 2.7. Serum concentrations of the inflammatory markers, C-reactive protein (CRP), serum amyloid A (SAA) and calprotectin were measured by MALDI-TOF mass spectrometry.

Results

At baseline, 37% had hypertension, 6% diabetes, 21% obesity and 100% were using b/ts DMARDs. The inflammatory markers decreased during follow-up (all p<0.001), while the LV mass index did not change (33.1±8.1 g/m^2.7 vs. 33.5±7.3 g/m^2.7, p=0.57). The prevalence of hypertension, diabetes and obesity were unchanged at follow-up (p>0.05), but the percentage of patients using b/ts DMARDs had decreased to 83% (p<0.001). In multivariable analyses, higher CRP and SAA at baseline were associated with higher LV mass index at both baseline and follow-up independent of presence of obesity, hypertension, age, sex or treatment with b/ts DMARDs at follow-up (Table 1). Inflammatory markers at follow-up were not associated with LV mass index (Table 1), but use of b/ts DMARDs at follow-up were associated with lower LV mass index after adjusting for inflammatory markers, age, sex, presence of obesity and hypertension (Table 1).

Conclusion

Higher levels of inflammatory markers at baseline were associated with greater LV mass index in RA patients. The use of immunosuppressive treatment throughout the study period was associated with lower LV mass index at follow-up, pointing to a role of chronic inflammation in LV hypertrophy.
Sex disparities in bystander defibrillation for out-of-hospital cardiac arrest
Authors: Paratz E , Nehme E , Heriot N , Sundararajan V , Page G , Fahy L , Rowe S , Anderson D , Stub D , La Gerche A , Nehme Z
Published: October 2024

Background

Previous studies have suggested that females experiencing out-of-hospital cardiac arrest (OHCA) receive lower rates of both bystander cardiopulmonary resuscitation (CPR) and defibrillation compared to males. Whether this disparity has improved over time is unknown.

Purpose

To investigate rates of bystander CPR and defibrillation in a sex-disaggregated manner over the last two decades.

Methods

A state-wide OHCA registry in Victoria, Australia collected data over twenty years (2002-2021) regarding rates of bystander interventions in OHCA. Characteristics and outcomes of each OHCA were compared with logistic regression according to sex and time (defined in two-year periods).

Results

32,502 OHCAs were included (69.7% male). Both bystander CPR and defibrillation rates increased for females over time (p<0.0001). There was no sex disparity in receipt of bystander CPR after adjustment for baseline differences. Females were less likely than males to receive bystander defibrillation, with sex disparity increasing from 2010 onwards (adjOR 0.26 (95%CI 0.09-0.80) in 2020-21 for females compared to males).

Conclusion

Initiatives to increase bystander CPR and defibrillation have resulted in higher overall rates of bystander interventions in the last two decades and no significant sex differences in provision of bystander CPR. However, females receive less bystander defibrillation than males, and sex disparity is increasing. Strategies to promote bystander defibrillation in females experiencing OHCA with a shockable rhythm should be a priority.
Long-term survival after coronary artery bypass grafting comparing bilateral versus single internal mammary artery in a women cohort
Authors: Sousa I , Cerqueira R , Diaz S , Ferreira A F , Amorim M J , Pinho P , Lourenco A P , Barros A S , Saraiva F , Leite-Moreira A
Published: October 2024

Introduction

Although neutral results from the ART randomized controlled trial, observational studies have been supporting better survival after bilateral internal mammary artery (BIMA) vs single internal mammary artery (SIMA) coronary artery bypass grafting (CABG). However, for some specific subgroups, like women patients, more doubts remain about BIMA benefits.

Aim

To compare long-term survival and early results in women after SIMA vs BIMA.

Methods

Longitudinal, retrospective, single-center study including consecutive women with at least 2 left-coronary system (LCS) vessel disease who underwent primary isolated CABG with at least 1 internal mammary artery (IMA) conduit and a minimum of 2 conduits targeting the LCS, between 2004-2014. Emergent or salvage surgeries, on-pump beating-heart, BIMA in which 1 IMA targeted the right coronary artery territory were excluded. The primary outcome was all-causes mortality (checked on February 2023). Time-to-event outcomes were studied using Kaplan-Meier Curves, Log-Rank test and multivariable Cox Regression. Median follow-up was 11 years, maximum of 19 years.

Results

From 539 women selected for this study, BIMA CABG was performed in 30%. SIMA patient’s were older (mean age 68.95±8.39 vs 62.75±9.82 years, p<0.001), but the prevalence of cardiovascular risk factors were similar between groups (arterial hypertension, p=0.693; dyslipidemia, p=0.111; diabetes mellitus, p=0.462 and obesity, p=0.109). Peripheral artery disease (p=0.707), left ventricular dysfunction (p=0.727), cerebrovascular disease (p=0.730), active smoking habits (p=0.05) and chronic obstrutive pulmonary disease (p=0.537) were also similar. Severe chronic kidney disease (27% vs 14%, p<0.001) and Canadian Coronary Society - grade IV (74% vs 63%, p=0.011) were more frequent in SIMA group. In the univariable survival analysis, SIMA had worse survival results than BIMA (Log Rank test p<0.01). At 5-, 10- and 15- years of follow-up, cumulative survival for SIMA vs BIMA were 88% vs 90%, 68% vs 75%, 42% vs 58%, respectively. However, the multivariable Cox regression showed that BIMA was not associated with long-term survival (HR [95%CI]: 1.09 [0.75-1.59], p=0.6). Most of post-operative outcomes were similar between groups, with the exception of atrial fibrilation (25% vs 16%, p=0.031) and time to discharge (median days [min-max]: 7 [4-128] vs 7 [4-59]) that were higher in SIMA. No differences were found in immediate reexploration of thorax (sternal infection – 0.3% SIMA vs 1.2% BIMA, p=0.219; bleeding- 1.6% SIMA vs 0.6% BIMA, p=0.681). Redo CABG occurred in 1 SIMA and 1 BIMA women, at 41 and 84 months of follow-up, respectively.

Conclusion

In this study, revascularization with BIMA seems to be safe in women and provides similar results than SIMA. More studies in women are needed to establish the better approach for this specific subgroup.
Sex differences in cancer incidence amongst people with cardiovascular disease: a large British population study
Authors: Thuemmler R , Pana T A , Mamas M A , Myint P K
Published: October 2024

Background

Studies have shown that patients with cardiovascular disease (CVD) have an incremental risk of death due to noncardiac causes. This is especially attributable to cancer developments during long term follow up. The two diseases share pathophysiological mechanisms that extend beyond traditional risk factors. With well-established sex disparities in CVD, it becomes imperative to investigate whether similar sex-based differences exist in both the incidence of cancer and cancer-related mortality, in participants with CVD vs those without CVD.

Purpose

We aim to analyse the sex differences in incident cancer and cancer-related mortality between people with and without CVD.

Methods

Participants were drawn from a large British population based prospective cohort study and followed up for a median of 26.2 years. Participants were stratified by sex and whether they developed CVD over the study follow-up. The cumulative incidence of cancer, excluding non-melanoma skin cancers were calculated. Sex-specific lifetime risks were determined accounting for competing risks of death. Cause-specific hazard ratios were determined using Royston-Parmar models. Models were adjusted for ethnicity and time-updated covaries, including material deprivation, CV risk factors, lifestyle factors, comorbidities, and medication. Participants’ CVD status was time-updated over the study follow-up as this was diagnosed.

Results

Out of a total of 22, 534 participants, free of cancer at baseline, 53.7% were women. Mean (standard deviation) age was 58.6 (9.3) for women and 59.5 (9.3) for men, at baseline. Men were older and had more comorbidities. Hypertension and obesity were risk factors more prevalent amongst men, while women were more likely to be smokers at baseline. Participants with CVD had more comorbidities, were more likely to smoke, have higher HbA1cs and be obese than those without CVD. The adjusted lifetime risks of incident cancer in participants with CVD at age 75 were higher in men (13.9%) compared to women (10.1%). This translates into a cause-specific hazard ratio (cHR) (99% confidence interval) for incident cancer (men vs. women) of 1.41 (1.27 - 1.55). Similar findings were demonstrated in participants with no CVD (10.2% for men and 8.2% for women), corresponding to a cHR of 1.27 (1.15 - 1.40). Furthermore, men had a higher risk of cancer-related mortality compared to women in participants with CVD 1.54 (1.33 - 1.78), as well as among participants without CVD 1.34 (1.17 - 1.53).

Conclusion

Our study showed an association between CVD and the lifetime cancer risk in both sexes after extensive adjustment. Furthermore, we show that men have a higher risk of cancer incidence and cancer-related mortality than women, regardless of comorbid CVD. However, these associations, were stronger in participants with CVD. It is vital to identify driving forces of such disparities to achieve health equity.
Mitochondrial Oxidative Stress and Cardiac Dysfunction in TERT Knockout Mice
Authors: Zhou Z , Zhang Y , Zhao R , Liu D , Xie B , Zhang Q , Tse G , Wang F , Liu T
Published: October 2024

Background

Heart failure (HF) is a major cause of hospitalization in the elderly, with its incidence increasing due to aging and associated risk factors like hypertension, diabetes, and myocardial fibrosis. Aging-related myocardial fibrosis, characterized by alterations in the extracellular matrix and myocardial structure, impairs cardiac function. Mitochondrial oxidative stress plays a pivotal role in cardiac electrical and structural remodeling, necessitating a deeper understanding of its involvement in aging-related heart failure.

Purpose

The purpose of this study is to investigate the mechanisms of aging-related ventricular electrical and structural remodeling by constructing an aging mouse model. This research aims to provide potential therapeutic targets for heart failure associated with aging.

Methods

We developed a third-generation homozygous telomerase reverse transcriptase (TERT) knockout mouse model. Comparing third-generation homozygous TERT knockout mice (F3 group) with age-matched wild-type males (WT group). The study encompassed blood pressure measurement, electrocardiographic analysis, echocardiography, ELISA for cardiac biomarkers, ventricular tissue electrophysiology, fibrosis assessment through staining, transcriptomic profiling via RNA-seq, and electron microscopy of ventricular mitochondria.

Results

Compared to the WT group, the F3 group demonstrated increased P53 and P16 protein expression. Decreased LVEF and FS, along with increased interventricular septum thickness, left ventricular diameter, and left ventricular volume. Elevated serum NT-pro-BNP and troponin I (cTnI) levels, with prolonged QRS duration. Decreased left and right ventricular conduction velocity, accompanied by increased conduction dispersion. Notable elevation in COLI, TGFβ, and α-SMA gene transcription and protein expression in ventricular tissue. Significant differences in mitochondrial oxidative stress signal pathways via RNA-seq analysis. Elevated serum MDA levels and decreased SOD levels, with up-regulated Mn-SOD gene transcription and protein expression, and down-regulated MFN2 and Drp1 gene transcription and protein expression in ventricular tissue. Electron microscopy revealed mitochondrial abnormalities such as loose arrangement, decreased number, swelling, vacuolation, and myofilament disintegration or breakage in the F3 group.

Conclusion

Third-generation TERT-/- senescent mice exhibit notable cardiac impairments, including electrical remodeling, structural changes, and mitochondrial dysfunction. These findings suggest a potential link between mitochondrial oxidative stress and aging-related heart failure, indicating novel therapeutic opportunities targeting mitochondrial dysfunction for managing such conditions.
The Mutscore metapredictor: a new application of artificial intelligence in cardiogenetics
Authors: Porretta A , Fressart V , Denjoy I , Morgat C , Surget E , Messali A , Algalarrondo V , Vedrenne G , Pruvot E , Quinodoz M , Rivolta C , Leenhardt A , Extramiana F
Published: October 2024

Introduction

The rapid development of high-throughput next generation sequencing has shifted the limits of genetic knowledge from variant sequencing to variant interpretation. The current standards recommend that sequence variants are interpreted according to a comprehensive analysis including, among others, computational data. The two major types of in-silico predictive tools encompass those predicting the theoretical variant effect on splicing and algorithms predicting the potential damage of missense variants. However, overall for missense variants, prediction accuracy is often limited and results are sometimes inconsistent between software programs.

Purpose

We aimed at testing the predictive performance of a new predictive algorithm (Mutscore) for missense variants based on a machine learning approach, in our cohort of families referred for hereditary cardiac diseases.

Methods

We retrospectively reviewed DNA sequencing results from 230 families (from 01.07.2014 till 01.07.2023) addressed to our center for channelopathy or hereditary cardiomyopathy. Missense variants were identified and evaluated according to the current standards of the American College of Medical Genetics and Genomics. Variants were analysed with the commonly used in-silico tools CADD, Polyphen, Alpha-missense and Revel. We further applied the Mutscore, a new metapredictor integrating 16 existing predictive tools to data on variant topographical location.

Results

Among our 230 families, we detected 252 missense variants (class I-II 2.4%, class III 62.3%, class IV and V 15.9% and 19.4% respectively). We observed a significant positive correlation (r = 0.59, p=0.000) between the Mutscore and the interpretation of variants according to standards. The Mutscore had a better predictive performance than Polyphen (AUC 0.83 vs 0.67, p=0.007), Alpha-missense (AUC 0.87 vs 0.79, p=0.047) and CADD (AUC 0.87 vs 0.70, p=0.0001). Compared to Revel, the Mutscore had a comparable predictive performance (0.89 vs 0.87, p=NS), but a better sensitivity (75% vs 66%) at the maximum tolerated false positive rate of 10%. Figure 1. Focusing on variants of uncertain significance (VUS), we applied Mutscore cut-off values which were identified to reclassify variants in our previous study (1). Importantly, the Mutscore reclassified 45% of VUS into likely benign/pathogenic variants. Figure 2.

Conclusions

The Mutscore, through its metaprediction approach integrating data on variant topographical location, improves the accuracy of pathogenicity prediction as compared to three out of four algorithms commonly used in clinical practice, and seems to represent a valuable tool contributing to VUS disambiguation.
Cardiovascular outcomes in pregnant women with congenital heart disease
Authors: Kanigalpula S P R , Ali Z , Mufarrih S A , Pothuru S
Published: October 2024

Background

Individuals with congenital heart disease (CHD) are at increased risk of cardiovascular complications. There is limited available data on burden of acute cardiovascular complications in pregnant women with CHD.

Purpose

To study the acute cardiovascular complications in pregnant women with CHD.

Methods

We conducted a retrospective observational analysis using the Nationwide Inpatient Sample (NIS) database. Using ICD-9 and ICD-10-CM codes, we identified pregnant women aged 18 years or older with and without CHD hospitalized between January 1st, 2010, and December 31st, 2019. The outcomes of the study were peripartum cardiomyopathy, hypertensive disorders of pregnancy (gestational hypertension, pre-eclampsia, and eclampsia), acute myocardial infarction, cardiac arrhythmias, cardiac arrest, stroke or transient ischemia, and in hospital mortality.

Results

During the study period, there were a total of 41,114,105 hospitalizations for pregnancy. Of these, 43,131 (0.1%) had CHD. The mean age of the population was 28 years in both CHD and non-CHD groups. The majority were white patients, followed by black patients and then Asians in both groups. There was a higher proportion of white patients in the CHD group compared to the non-CHD group. Comorbidities including diabetes mellitus, chronic pulmonary disease, chronic kidney disease, hyperlipidemia, smoking, depression, and drug abuse were higher in the CHD group compared to the non-CHD group (Table 1). Pregnant women with CHD had a significantly higher incidence of peripartum cardiomyopathy (1905 vs 89 per 100,000 pregnancy hospitalizations; p<0.001), hypertensive disorders of pregnancy (9332 vs 7802 per 100,000 pregnancy hospitalizations ; p<0.001), acute coronary syndrome (253 vs 12 per 100,000 pregnancy hospitalizations; p<0.001), cardiac arrhythmias (3480 vs 176 per 100,000 pregnancy hospitalizations; p<0.001), cardiac arrest (127 vs 6 per 100,000 pregnancy hospitalizations; p<0.001), stroke or transient ischemic attack (1648 vs 32 per 100,000 pregnancy hospitalizations; p<0.001), and venous thromboembolism (816 vs 124 per 100,000 pregnancy hospitalizations; p<0.001) (Table 2). Similarly, pregnant women with CHD had significantly higher in hospital mortality compared to pregnant women with no CHD (116 vs 11 per 100,000 pregnancy hospitalizations; p<0.001).

Conclusion

Pregnant women with CHD are at significantly increased risk of acute cardiovascular complications compared to those without CHD. Our study underscores the importance of close monitoring and specialized care for this high-risk population during pregnancy and delivery. Further research is warranted to better understand the risks associated with these complications and to optimize management strategies for pregnant women with CHD.Baseline CharacteristicsOutcomes
Validation of the HCM Risk-SCD model in patients with hypertrophic cardiomyopathy and future perspectives
Authors: Pay L , Cetin T C , Dereli S D , Kadi H K , Yumurtas A C Y , Cinar T C , Hayiroglu M I H
Published: October 2024

Background/Introduction

The fact that hypertrophic cardiomyopathy (HCM) is associated with sudden cardiac death (SCD) due to malignant ventricular arrhythmias underlies its clinical importance (1). SCD in patients with HCM is often an unpredictable event, occurring without previous warning signs or symptoms, and is most common in the young middle-aged group (2). The greatest dilemma in the management of HCM patients is to identify the high-risk population for SCD. The HCM risk- SCD model provides a useful convenience in determining the risk of SCD in patients with HCM even though some patients with low-risk scores still remain at risk of SCD (3). These results have increased the interest in additional strategies to improve the existing risk model.

Purpose

Hence, the aim of our study was to assess the performance of HCM Risk-SCD in a large series of consecutive patients with HCM who had been followed up in a tertiary centre.

Methods

The study population consisted of 389 consecutive HCM patients who had been followed up between 2004 and 2021. Demographic and clinical characteristics estimated 5-year risk using the HCM Risk-SCD model were compiled and survival data were collected during follow-up. Patients were divided into 2 groups according to their long-term survival and HCM risk-SCD scores of these two groups were compared.

Results

The long-term mortality was observed in 47 patients out of 389 patients in the mean follow-up of 55.5 ± 12.7 months. The mean HCM Risk-SCD of surviving patients was significantly lower than that of non-survivors (1.8% vs. 3.0%, p<0.001). The HCM Risk-SCD score was above 6% in 9 (2.6%) survivors and 9 (19.1%) non-survivors (p<0.001). Considering the Kaplan-Meier curve based on the 6% HCM Risk-SCD score, patients at ≥6% risk also had a significantly higher long-term risk of death compared to those with <6% (log-rank test value: 33.72, p<0.001) (Figure 1). The ROC curve based on the HCM Risk-SCD score had 61% sensitivity and 61% specificity for risk for 2.0%, 38% sensitivity and 99% specificity for ≥4%, 17% sensitivity and 99% specificity for ≥6% (Figure 2).

Conclusion(s)

In conclusion, the current study demonstrates that the HCM risk-SCD model, while easily calculable and clinically useful, does not reliably identify a significant subset of patients with HCM who will potentially be at lifetime risk of SCD. Identifying patients with hypertrophic cardiomyopathy at high risk for SCD who deserve ICD therapy is a critical management priority. A new risk algorithm that can detect the SCD risk of HCM patients with higher sensitivity is needed.Figure 1Figure 2
Impact of chronic kidney disease on patients with Myocardial Infarction with Non Obstructive Coronary Arteries (MINOCA)
Authors: Gil Mancebo N , Mata Caballero R , Fraile Sanz A , Izquierdo Coronel B , Rodriguez Montes P , Martin Munoz M , Alvarez Bello M , Perela Alvarez C , Nieto Ibanez D , De La Serna Real De Asua M , Humanes Ybanez S , Olsen Rodriguez R , Espinosa Pascual M , Awamleh Garcia P , Alonso Martin J J
Published: October 2024

Background

Chronic kidney disease (CKD) in patients with myocardial infarction (MI) is associated with more advanced disease, a higher risk of complications and poorer prognosis, as well as increased mortality. The aim of this study is to assess the impact of CKD in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) and its influence on the prognosis of these patients.

Methods

it was an observational, prospective and analytic study. We analyzed all consecutive patients with MI who underwent coronary angiography admitted to our Hospital between 2016 and 2023; MINOCA patients were classified following the 2023 ESC Guidelines definition. The patients were divided into two groups depending on whether they had CKD or not. Median follow-up was 43 months [20-71].

Results

we included 136 patients with MINOCA, of whom 11 (8.1%) had CKD. Patients with impaired kidney function were older and mostly male. They also exhibited a higher prevalence of classic cardiovascular risk factors such as hypertension, diabetes, or dyslipidemia. However, there were fewer smokers in this group. We did not find significant differences in coronary artery anatomy (smooth or small plaques) between both groups. Additionally, the majority of patients in both groups had preserved left ventricular function. Despite that, patients with CKD typically had ST segment elevation in the ECG and higher myocardial injury biomarkers’ levels as well as NT-proBNP.

During hospitalization, patients without renal dysfunction had more complications (11.2% vs 0%, p=0.062) such as inotropic requirements, stroke or cardiogenic shock, but overall there were very few. In terms of treatment, it was fairly similar in both groups, although patients with kidney disease received diuretics significantly more often.

Throughout the follow up, there were no significant differences in MACE (major adverse cardiovascular events) between death (27.3% vs 7.4%, p=0.06), readmission (10% vs 10.8%, p=1) or MI (0% vs 3.4%, p=1), but patients with CKD suffered more frequently from stroke (40% vs 4.2%, p<0.01).

Conclusions

1) Patients with MINOCA and CKD are typically older and predominantly male with a high prevalence of cardiovascular comorbidities (hypertension, diabetes, dyslipidaemia).

2) The severity of MI appears to be slightly higher in this group, as evidenced by more ST-segment elevation upon admission and higher hs Troponine T levels. However, they experience fewer cardiovascular complications and maintain normal left ventricular function.

3) Although we found no significant differences in major adverse cardiovascular events (MACE), patients with CKD were more likely to suffer from stroke.Table 1Table 1
Developing p21-activated kinase 1 (PAK1) activators to treat hypertrophic cardiomyopathy (HCM)
Authors: He Y , Bae J , Wang Y J , Watkins H , Lei M
Published: October 2024

Despite significant progress in comprehending the genetic and metabolic underpinnings of cardiomyocyte dysfunction, there is still a pressing need for targeted treatments to address hypertrophy and progressive remodelling (e.g., fibrosis), seen in HCM1 . PAK1, a regulator of ion channels and myofilaments in cardiomyocytes, has shown promise in curbing pathological hypertrophy2 . Our hypothesis centres on the potential therapeutic benefits of pharmacologically activating PAK1 in managing hypertrophy and adverse remodelling in HCM. First, we conducted virtual screening and kinase assays to identify potent small molecule PAK1 activators, which significantly increased PAK1 activity by 3 to 5-fold, with an EC50 range between 0.5 and 2.5 μΜ. We then evaluated these compounds on cellular hypertrophy in an in vitro model using neonatal rat cardiomyocytes exposed to isoprenaline (ISO). Among those, JB2020A not only prevented ISO-induced hypertrophy, but also reversed pre-existing cellular hypertrophy induced by ISO 24 hours earlier. Subsequently, we assessed the therapeutic potential of JB2020A in a well-characterised HCM mouse model (i.e., Actc1E99K) 3 , known for its rapid disease progression. We initiated a six-week oral treatment regime at 4 weeks of age, dosing at 10 mg/kg per day. Echocardiography and fibrosis evaluation confirmed that JB2020A led to a significant reduction in cardiac hypertrophy and fibrosis with preserved contractile function. Western blotting analysis revealed increased PAK1 phosphorylation and activation in JB2020A-treated E99K hearts, along with a reduction in pro-apoptotic CHOP expression and an upregulation of protective endoplasmic reticulum (ER) response (e.g., ATF4 and Xbp1), indicating an amelioration of ER stress in HCM. These findings underscore the therapeutic potential of small molecule PAK1 activators as a novel approach for addressing hypertrophy and progressive remodelling in HCM.
Experimental evidence on colchicine's mode of action in human carotid artery plaques
Authors: Von Ehr A , Steenbuck I D , Haefele C , Vico T A , Wolf D , Tholen S , Schilling O , Czerny M , Westermann D , Hilgendorf I
Published: October 2024

Background and aims

Atherosclerosis driven by inflammation is a major cause of cardiovascular events. Recent clinical trials have demonstrated the therapeutic potential of anti-inflammatory treatments. Consequently, colchicine is recommended in current guidelines as a second-line therapy for secondary prevention, although the drug's mechanism of action is not fully understood.

Methods

To this end, we performed a multiomic study of the effect of colchicine on human carotid plaques. Sections from endarterectomy specimens were exposed ex vivo to colchicine at concentrations of 2 ng/ml and 10 ng/ml for 24 hours and compared with untreated segments of the same plaque. Changes in gene expression were analyzed by RNA sequencing, and plaque secretomes were subjected to proteomic analysis by mass spectrometry. In situ cell proliferation was examined histologically.

Results

Our data suggest that colchicine primarily suppresses neutrophil and platelet degranulation, collagen degradation, and macrophage proliferation in atheromatous plaques in a dose-dependent manner, while stimulating myofibroblast activation.

Conclusion

Our study demonstrates multifactorial pathways by which colchicine, the first anti-inflammatory drug recommended by cardiovascular guidelines, acts on human atherosclerotic lesions. Targeting neutrophil and platelet degranulation, collagen degradation and macrophage proliferation could provide significant therapeutic benefit in atherosclerotic cardiovascular disease without the adverse side effects of colchicine.
Combined sodium-glucose-transporters inhibitors (SGLT2i) and glucagon-like-peptide receptor agonist (GLP1ra) compared with SGLT2i or GLP1ra alone improves survival: a Real-World Registry
Authors: Garcia Vega D , Cinza-Sanjurjo S , Eiras S , Gonzalez-Juanatey J R
Published: October 2024

Background

Prior clinical trials found diabetic patients, after being treated with SGLT2i (sodium-glucose-transporters inhibitors) and/or GLP1ra (glucagon-like-peptide receptor agonist), had lower rates of cardiovascular (CV) complications. But there is poor evidence of the additive benefits of combined therapy in the general population.

Purpose

This study sought to determine if the combined therapy reduced the major CV complications or all-cause of death in comparison with SGLT2i or GLP1ra alone in a health area.

Methods

This is a retrospective observational study of patients who were prescribed with an SGLT2i, GLP1ra or both between January 1st 2018 and 30th June 2022 from one healthcare area that includes primary care centres and hospitals. They were followed up until 31st October 2022. The primary outcomes were the combined incidence of hospitalisation or/and death for heart failure (HF), coronary artery disease (CAD), cerebrovascular accident (CVA) and all-cause mortality. Sex, age, glucose lowering drugs (GLD) (and duration), diabetes (and duration), arterial hypertension (HBP), dyslipidemia (DLP), CAD, HF, atrial fibrillation (AF) and CVA were included on a Cox regression analysis for determining the main predictors for each outcome.

Results

We have included 15.549 patients with/out CVD who were prescribed GLD from 2018. The population was represented by 97% with T2DM, 46% with obesity, 71% with HBP, 59% with DLP, 15% CAD, 10% with HF, 12% with AF and 6% with CVA (Figure 1). The mean follow-up was 33 (19) months. The Kaplan Meier analysis determined that the cumulative risk for CAD and CVA events was similar among the 3 different therapy groups. However, the combined therapy reduced the risk for HF events (HR: 0,771 [95% CI: 0,612-0,970]) or all-cause mortality (HR: 0,255 [95% CI: 0,325-0,414]) (Figure 2a, 2c). The multivariate Cox regression analysis showed that combined therapy, treatment duration and DLP were associated with a significant reduction in HF and all-cause mortality events; while age, sex (male), CAD, HF and AF increased them (Figure 2b, 2d).

Conclusions

Compared with SGLT2i or GLP1ra alone, combined therapy SGLT2i + GLP1ra reduces HF risk and all-cause mortality in a real-world population.Figure 1Figure 2
The potential protective effect of dapagliflozin on the development of cardiotoxicity in cancer patients after one year of observation
Authors: Maragkoudakis S , Marketou M , Sideras M , Stratinaki M , Mavroudeas E S , Emiri F , Lilikaki G K , Tsakonas Dervakos N , Kafkala K
Published: October 2024

Introduction

Despite the widespread use of anthracyclines (ANT) and anti-HER2 agents as trastuzumab (TZB) in chemotherapy schemes, it is known the potential cardiotoxic effects that can limit the intensity and duration of treatments. The clinical trial "DECLARE-TIMI 58" (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), demonstrated that dapagliflozin, a Sodium glucose cotransporter 2 inhibitor, reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus.

Purpose

We aimed to study if dapagliflozin could exerts cardioprotective effects in anthracycline, carfilzomib and trastuzumab-induced cardiotoxicity through the analysis of ejection fraction (LVEF), global longitudinal strain (GLS) of both left and right ventricle, E/A ratio, E/e’ ratio, left atrium diameter, BNP/NT-pro-BNP and troponin I.

Methods

32 diabetic patients were randomized (16 dapagliflozin;16 placebo). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function as well as chemotherapeutic agents ). Our patients who were diagnosed with cancer at our medical center, receiving potentially cardiotoxic treatment: 52% were treated with only trastuzumab, 34% were treated with only anthracycline and 14% carfilzomib. The primary endpoint was the development of cardiotoxicity after treatment with chemotherapy. Cardiotoxicity was defined as a decrease of LVEF by 5% or more to less than 55% in the presence of symptoms of heart failure or an asymptomatic decrease in LVEF by 10% or more to less than 55%.

Results

In the first year of observation patients treated with dapagliflozin didn’t show any deterioration of LV GLS (¬19.8±2.8 vs ¬19.3±4.1%, p=0.403) There was no change in LVEF (57.8±4.9% vs 59±6.8%) and GLS of right ventricle (20.3±2.8% vs 20.0±3.6%). Conversely, patients treated with placebo, presented a significant impairment of LV GLS (¬20.8±2.1% vs ¬18.5±2.2%, p=0,001) while a borderline deterioration of EF was noticed after treatment with placebo(60±5.4 vs 56.7±6.7%, p=0,045).

Conclusions

At the best of our knowledge, our study is the first to investigate the prophylactic use of dapagiflozin in the development of non-ischemic cardiomyopathy in diabetic patients receiving anthracycline or trastuzumab,carflilzomib therapies. Treatment with dapagliflozin prevented deterioration of myocardial function and preserved ejection fraction
P2Y12 inhibitor monotherapy after short DAPT in acute coronary syndrome: a systematic review and meta-analysis
Authors: Galli M , Laudani C , Occhipinti G , Spagnolo M , Gragnano F , D'amario D , Navarese E P , Mehran R , Valgimigli M , Capodanno D , Angiolillo D J
Published: October 2024

Background

P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) has been proposed as an alternative to standard 12-month DAPT for balancing ischemic and bleeding risks in patients with acute coronary syndrome (ACS). However, it remains uncertain how different P2Y12 inhibitors used as monotherapy affect outcomes.

Purpose

To explore the clinical impact of different P2Y12 inhibitors as monotherapy versus standard 12-month DAPT.

Methods

Randomized controlled trials (RCTs) comparing P2Y12 inhibitor monotherapy after a short course of DAPT (≤3 months) versus standard 12-month DAPT in ACS were included. The primary endpoint was major adverse cardiovascular events (MACE). Secondary endpoints included single components of MACE, net adverse clinical events (NACE), any bleeding, and major bleeding. All analyses were run according to the pre-specified subgroup based on the P2Y12 inhibitor used as monotherapy.

Results

Six RCTs including a total of 23,884 ACS patients were included. Mean DAPT duration in the monotherapy arm was 59 days. Compared with standard 12-month DAPT, P2Y12 inhibitor monotherapy after a short course of DAPT was associated with a significant reduction in any bleeding (odds ratio, OR, 0.55; 95% CI 0.44–0.70) and major bleeding (OR 0.48 95% CI 0.36–0.62) without significant interaction for subgroup differences according to the P2Y12 inhibitor used. There were no differences in MACE (OR 0.92; 95% CI 0.74–1.15) or individual ischemic or mortality endpoints between P2Y12 inhibitor monotherapy and standard DAPT. However, there was a significant subgroup difference (pint=0.013) in MACE according to the agent used, with a reduced risk with ticagrelor (OR 0.82; 95% CI 0.69–0.97) but not with clopidogrel (OR 1.32; 95% CI: 0.94–1.84). Significant subgroup differences between ticagrelor and clopidogrel monotherapy were also found in all-cause death (pint=0.038), NACE (pint=0.030), and myocardial infarction (pint=0.015). Trial sequential analysis showed conclusive evidence of improved NACE with ticagrelor monotherapy, but not with clopidogrel monotherapy, compared with standard DAPT.

Conclusions

In patients with ACS, P2Y12 inhibitor monotherapy with either ticagrelor or clopidogrel after a short course of DAPT nearly halves bleeding compared with standard DAPT. Ticagrelor, but not clopidogrel monotherapy, reduced ischemic events and NACE compared with standard DAPT, supporting its use after aspirin discontinuation in ACS patients.
Vitamin C intake, psychological distress and health outcomes in patients with heart failure
Authors: Wu J , Kang J H , Lennie T A , Moser D K
Published: October 2024

Background

Patients with heart failure (HF) have lower dietary vitamin C intake than healthy adults, which may increase oxidative stress and worsen important patient-reported health outcomes (functional status and quality of life [QOL]). Patients with HF are more likely to have higher levels of psychological distress (anxiety and depressive symptoms). However, it is not known whether psychological distress is a link in the association of dietary vitamin C with health outcomes.

Objective

To examine the inter-relationships among dietary vitamin C intake, psychological distress (anxiety and depressive symptoms), and health outcomes (functional status and QOL) in patients with HF.

Method

We performed a secondary analysis of baseline data from 206 adults with HF (female: 33%, age: 61±12, NYHA class III/IV: 44%) with complete data on dietary vitamin C intake, anxiety, depressive symptoms, functional status, and QOL. Dietary vitamin C intake was assessed using a 4-day food diary and analyzed using the Nutrition Data System for Research software program. Low dietary vitamin C intake was defined as averaged daily intake below the estimated average requirement (EAR) from the Institute of Medicine of 75 mg/day for men and 60 mg/day for women. Anxiety was assessed using the Brief Symptom Inventory Anxiety subscale. Depressive symptoms were assessed using the Beck Depression Inventory II. Functional status was measured using the Duke Activity Status Index. Quality of life was measured using the Minnesota Living with Heart Failure Questionnaire. Linear regression was conducted using the PROCESS macro in SPSS.

Results

Eighty-four patients (41%) had low dietary vitamin C intake based on the EAR standard. In bivariate analyses, patients with low dietary vitamin C intake had higher levels of anxiety, depressive symptoms, poorer functional status, and worse QOL (all p <.005). In the mediation regression model, low dietary vitamin C intake was directly associated with higher levels of anxiety, but not with depressive symptoms. Depressive symptoms were directly associated with functional status and QOL. Dietary vitamin C intake was not directly associated with functional status or QOL. Low dietary vitamin C intake was indirectly associated with poor functional status through higher levels of anxiety and depressive symptoms (Figure 1). Similarly, low dietary vitamin C intake was indirectly associated with worse QOL (Figure 2).

Conclusion

Anxiety and depressive symptoms link the relationship between dietary vitamin C intake and functional status and between dietary vitamin C intake and QOL. Our findings highlight the importance of including interventions to enhance diet quality and psychological well-being as part of HF treatment to improve health outcomes.Vitamin C and functional statusVitamin C and quality of life
Trends and predictors of cardiac rehabilitation referrals and participation in patients undergoing elective percutaneous coronary intervention
Authors: Chen Y , Marshall A , Wu C J , Hattingh L , Howes L , Jayasinghe R , Poulter R , Rahman A , Starmer G , Singbal Y , Yadav R , Smith I
Published: October 2024

Background

Research evidence shows that greater cardiac rehabilitation (CR) referrals and participation can reduce cardiovascular mortality and morbidity, which leads to social and economic benefits (1). It remains unknown, however, what the CR referrals and participation are for patients following elective percutaneous coronary intervention (PCI).

Aim

Our aim was to identify the prevalence, trends, and predictors of CR referrals and participation in patients undergoing elective PCI between July 2017 and December 2021 among six public hospitals in one of the Australian states.

Methods

A retrospective observational study was conducted. Data were extracted from a state-wide Cardiac Outcomes Registry for patients who underwent elective PCI. Patients were identified if they were referred to CR following hospital discharge. CR participation has two assessments. The initial assessment focuses on a comprehensive cardiovascular risk factor review that occurs before attending a CR program, whereas the final assessment represents CR completion. We conducted descriptive and inferential statistical analyses.

Results

Out of 3081 patients who underwent elective PCI, 1845 (59.9%) had CR referrals. Of the 1845 patients who had CR referred, 1022 (55.4%) completed an initial assessment, and 400 (21.7%) completed both an initial and final assessment. The rate of CR referrals increased from 12.0% in 2017 to 23.5% in 2018 before decreasing slightly in 2019 and 2020 (21.0% and 22.8%, respectively). There was a decline in the proportion of patients who had an initial assessment from 44.0% in 2017 to 29.0% in 2021. The rate of the final assessment showed a slight increase from 32% in 2017 to 41% in 2021. Multivariate logistic regression showed that of those patients undergoing PCI, patients who stayed overnight were 9.9 times more likely to receive a CR referral than those with same-day discharge. However, for those who had CR referrals, overnight stay was not a predictor in completing the initial assessment. Similarly, of those who completed an initial assessment, overnight stay was also not a predictor in completing the final assessment; rather, those with a positive family history were more likely to complete the final assessment.

Conclusion

Our findings reveal a low CR referral rate in patients undergoing elective PCI, and overnight stay is a strong predictor for CR referrals. As a referral is a gateway to CR participation (2), more work is needed to explore the options to increase CR referrals, particularly for patients discharged on the same day as their procedure. Following referrals, overnight stay did not predict completion of initial and final assessments, indicating that other strategies are required to promote CR participation.