bluuebunny/crossref_metadata_2025 huggingface dataset:
Does dulaglutide impact a composite outcome reflecting atherosclerosis? A post-hoc analysis of the REWIND trial
Authors: Ferrannini G , Mellbin L , Kirabo F , Ramasundarahettige C , Herstein H G , Ryden L
Published: October 2022

Background

It has been postulated that the cardioprotective effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 2 diabetes (T2DM) may retard the progression of atherosclerosis.

Purpose

The aim of this post-hoc analysis of the REWIND trial was to test the hypothesis that treatment with dulaglutide impacts a clinical outcome that reflects atherosclerosis in patients with type 2 diabetes (T2DM).

Methods

In the double-blind, placebo-controlled REWIND trial recruiting 9901 patients (46.3% women, mean age 66 years) with T2DM and cardiovascular disease (CVD) or varying levels of CV risk, a weekly subcutaneous injection of dulaglutide 1.5 mg reduced the hazard of MACE by 12% versus placebo. This post hoc analysis assessed the impact of dulaglutide on atherosclerosis-related outcomes comprising a composite of the first of CV death, nonfatal myocardial infarction, nonfatal ischaemic stroke and any revascularization including coronary, peripheral or carotid. Cox proportional hazards models were used to estimate the effect of randomized treatment. The effect in selected subgroups (Table 1) was estimated by including each subgroup and an interaction term in the model for the primary outcome. The composite of any component of the primary endpoint and non-cardiovascular death was considered as a secondary outcome.

Results

The primary endpoint occurred in 799 (16.1%) patients in the dulaglutide group and 870 (17.6%) patients in the placebo group (incidence rates: 3.25/100 person-years vs 3.58/100 person-years; HR 0.91, 95% CI 0.83–1.00; p=0.05) during a median follow-up of 5.4 years. This finding was consistent regardless of sex, body mass index, previous CVD or not and diabetes duration. The incidence of the secondary outcome was also lower in the dulaglutide group (HR; 95% CI: 0.91; 0.83–0.99; p=0.03).

Conclusion

Dulaglutide was associated with a 9% reduced index of atherosclerosis in patients with T2DM and CVD or high CV risk. This finding supports the hypothesis that dulaglutide may retard progression of atherosclerosis.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): EliLilly and Company
Causes of excess mortality in diabetes patients without coronary artery disease
Authors: Olesen K , Gyldenkerne C , Thrane P G , Maeng M
Published: October 2022

Background

Diabetes (DM) patients without coronary artery disease (CAD) by coronary angiography have a similar risk of myocardial infarction and cardiac death as non-DM patients without CAD. Yet, even with absence of CAD, patients with DM have higher mortality compared to non-DM patients.

Aims

To examine the underlying causes of death in patients undergoing coronary angiography depending on DM and CAD.

Methods

We included every patient with no previous history of CAD who underwent coronary angiography in Western Denmark between 2003–2016. Patients were stratified by DM and CAD and followed for a maximum of 10 years. We estimated the 10-year cumulative risk of all-cause death and cause-specific death. Causes of death were categorized as “cardiovascular”, “pulmonary”, “cancer”, “renal”, “bleeding-related”, and “other” based on ICD-10 codes listed as underlying causes of death obtained from death certificates. Deaths where DM was listed as the underlying cause of death (i.e. ICD-10 code DE1) were included in the category “other”.

Results

We included 132,432 patients, of whom 33% had neither DM nor CAD, 5% had DM only, 51% had CAD only, and 11% had both DM and CAD. Mean age was 64 years. Median follow-up was 6.3 year (inter-quartile range 3.8–10.0). During follow-up, 35,036 (26.5%) patients died. Patients with both DM and CAD had the highest 10-year mortality (47.4%, 95% CI 46.3–48.4), followed by CAD only (33.3%, 95% CI 32.8–33.7), DM only (30.7%, 95% CI 29.3–32.2), and patients with neither DM nor CAD (21.6%, 95% CI 21.1–22.1). The proportion of cardiovascular deaths were similar in patients with DM only (29.2%, 95% CI 27.0–31.5, Figure) and patients with neither DM nor CAD (29.7%, 95% CI 28.8–30.7). Patients with DM were more likely to die from causes categorized as “other” compared to patients with neither DM nor CAD [38.4% (95% CI 36.0–40.9) versus 30.2% (95% CI 29.3–31.2)]. Among patients with DM only, 43.7% of deaths classified as “other” were attributable to DM-related complications such as ketoacidosis and diabetic nephropathy.

Conclusion

Despite absence of CAD, DM remained associated with increased mortality. Excess mortality was primarily driven by patients dying of DM-related microvascular complications and ketoacidosis. Thus, despite absence of CAD, patients with DM require continued preventative measures to reduce DM-related mortality.

Funding Acknowledgement

Type of funding sources: Public hospital(s). Main funding source(s): Aarhus University Hospital
Microvascular complications, coronary artery disease and the risk of cardiovascular disease in diabetes patients undergoing coronary angiography: a cohort study from the Western Denmark Heart Registry
Authors: Olesen K , Gyldenkerne C , Thrane P G , Maeng M
Published: October 2022

Background

Diabetes is associated with an increased risk of both microvascular macrovascular complications. The association between microvascular disease and cardiovascular risk, however, is less explored.

Aims

We aimed to estimate the cardiovascular risk associated with microvascular disease in diabetes patients with and without coronary artery disease.

Methods

We included every patient who underwent coronary angiography in Western Denmark between 2003–2016. Patients were stratified by microvascular disease (defined as diagnosis retinopathy, nephropathy, or peripheral neuropathy) and coronary artery disease by angiography. Outcomes included major adverse cardiovascular events (myocardial infarction, ischemic stroke, and cardiac death) as a combined outcome and as separate outcomes. Patients were followed for a maximum of 10 years. We estimated 10-year cumulative incidence of each outcome. Incidence rate ratios (IRR) were estimated by a modified Poisson regression model using diabetes patients with neither microvascular disease nor coronary artery disease as reference.

Results

We included 19,295 patients with diabetes, of whom 1,268 (6.6%) had microvascular disease, 10,161 (52.7%) had coronary artery disease, 3,113 (16.3%) had both microvascular disease and coronary artery disease, and 4,753 (24.6%) had neither microvascular nor coronary artery disease. Median follow-up was 5.9 years (interquartile range 3.3–9.0) Patients with microvascular disease had an increased risk of major adverse cardiovascular events compared to diabetes patients with neither microvascular disease nor coronary artery disease (13.6% versus 10.0%, adjusted IRR 1.45, 95% CI 1.19–1.77, Figure 1). This increased risk was driven by a 3.9% higher risk of ischemic stroke (adjusted IRR 1.53, 95% CI 1.14–2.05, Figure 2), while microvascular disease was not associated with an increased risk of myocardial infarction (adjusted IRR 1.08, 95% CI 0.72–1.62) or cardiac death (adjusted IRR 0.99, 95% CI 0.63–1.56). Patients with both microvascular disease and coronary artery disease had the highest risk of major adverse cardiovascular events (29.3%, adjusted IRR 3.06, 95% CI 2.67–3.50).

Conclusion

Microvascular disease in diabetes patients without angiographic coronary artery disease is associated with an increased cardiovascular risk. However, this was driven by a higher risk of ischemic stroke than by higher rates of myocardial infarction or cardiac death. In fact, diabetes patients with microvascular disease but no coronary artery disease had the same risk of ischemic stroke as those with combined microvascular disease and coronary artery disease.

Funding Acknowledgement

Type of funding sources: Public hospital(s). Main funding source(s): Aarhus University Hospital
Therapeutic value of tafamidis in patients with wild-type transthyretin amyloidosis (ATTRwt) with cardiomyopathy based on cardiovascular magnetic resonance (CMR) imaging
Authors: Chamling B , Bietenbeck M , Korthals D , Drakos S , Vehof V , Stalling P , Weil M , Meier C , Yilmaz A
Published: October 2022

Background

Tafamidis was approved in Europe for the treatment of cardiomyopathy (CM) in patients with transthyretin amyloidosis (ATTR) in April 2020. So far, real-world data addressing the therapeutic value of tafamidis for the treatment of ATTR-CM are scarce. The purpose of this study was to carefully analyse the therapeutic benefit of tafamidis in patients with wild-type ATTR (ATTRwt) and CM (ATTRwt-CM) after one year of therapy based on serial multi-parametric cardiovascular magnetic resonance (CMR) imaging.

Purpose

The purpose of this study was to carefully analyse the therapeutic benefit of tafamidis in patients with wild-type transthyretin amyloidosis (ATTRwt) and cardiomyopathy (ATTRwt-CM) after one year of therapy based on serial multi-parametric cardiovascular magnetic resonance (CMR) imaging.

Methods

The present study comprised N=40 patients with ATTRwt-CM who underwent two serial multi-parametric CMR studies within a follow-up period of 12±3 months. Baseline (BL) clinical parameters, serum biomarkers and CMR findings were compared to follow-up (FU) values in patients with treated “with” tafamidis 61mg daily (n=20, group A) and those “without” tafamidis therapy (n=16, group B). CMR studies were performed on a 1.5-T system and comprised (amongst others) cine-imaging for assessment of cardiac anatomy and function including 3D longitudinal strain assessment. In addition, a modified Look-Locker inversion recovery (MOLLI) T1-mapping sequence was performed for measurement of pre- and post-contrast myocardial T1-values with additional calculation of extracellular volume fraction (ECV)-values.

Results

While left ventricular ejection fraction (LV-EF), left ventricular mass index (LVMi), left ventricular wall thickness (LVWT), native T1- and ECV-values remained unchanged in the tafamidis group A, a slight reduction in LV-EF (p=0.003) as well as a subtle increase in LVMi (p=0.034), in LVWT (p=0.001), in native T1- (p=0.038) and ECV-values (p=0.017) were observed in the untreated group B. Serum NT-proBNP levels showed an overall increase in both groups, however, with the untreated group B showing a relatively higher increase compared to the treated group A. Assessment of NYHA class did not result in significant intra-group differences when BL were compared with FU, but a trend to improvement in the treated group A compared to a worsening trend in the untreated group B (Δp=0.005).

Conclusion

Tafamidis does not improve cardiac phenotype in patients with ATTRwt-CM after one year of therapy. However, tafamidis seems to slow down cardiac disease progression in patients with ATTRwt-CM compared to those without tafamidis therapy based on multi-parametric CMR data already after one year of therapy.

Funding Acknowledgement

Type of funding sources: None.
Influence of long-term sodium-glucose cotransporter 2 inhibition on cardiac remodeling in rats with type 1 diabetes mellitus
Authors: Rodrigues E A , Rosa C M , Campos D H S , Murata G M , Damatto F C , Souza L M , Rego A B G C , Oliveira L R S , Borim P A , Gatto M , Okoshi K , Okoshi M P
Published: October 2022

Background

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. However, as most clinical trials were performed in type 2 DM, the effects of SGLT2 inhibitors in patients with type 1 DM still need further clarification. In this study, we evaluated the effects of long-term treatment with the SGLT2 inhibitor dapagliflozin on cardiac remodeling, myocardial function, and energy metabolism in rats with type 1 DM.

Methods

Male Wistar rats were divided into three groups: control (C, n=15); DM (n=15); and DM treated with dapagliflozin (DM+DAPA, n=15) for 30 weeks. DM was induced by streptozotocin; DAPA was added to the rat chow (5 mg/kg/day). Cardiac performance was evaluated by echocardiogram and myocardial function in isolated left ventricular (LV) papillary muscle preparations. Myocardial energy metabolism enzyme activities were evaluated by spectrophotometry. Statistical analyzes: ANOVA and Tukey or Kruskal-Wallis and Dunn.

Results

DM+DAPA had lower glycemia than DM [C 112 (108–116); DM 531 (522–535)*; DM+DAPA 267 (179–339) mg/dL; p<0.05 vs C and DM+DAPA]. Echocardiogram showed that DM and DM+DAPA had left atrium and left ventricle dilatation with systolic and diastolic dysfunction; in DM+DAPA, the changes were attenuated in relation to DM. Developed tension and +dT/dt were higher in DM+DAPA than DM in basal condition. After inotropic stimulation with post-pause contraction, extracellular calcium concentration elevation, and isoproterenol addition to the nutrient solution, +dT/dt and –dT/dt were higher in DM+DAPA than DM. Hexokinase, phosphofructokinase, and pyruvate kinase activity was lower in DM than the C. Phosphofructokinase and pyruvate kinase activity was higher in DM+DAPA than DM.

Conclusion

Long-term dapagliflozin treatment attenuates cardiac remodeling and myocardial dysfunction and preserves hexokinase, phosphofructokinase and pyruvate kinase activity in rats with type 1 diabetes mellitus.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): CNPq - National Council for Scientific and Technological Developmentdoctor
Excess mortality in Aspirin and Dipyrone (Metamizole) co-medicated in patients with cardiovascular disease: a nationwide study
Authors: Polzin A , Dannenberg L , Helten C , Metzen D , Duecker C , Marschall U , L Hoest H , Hennig B , Petzold T , Jung C , Levkau B , Zeus T , Schroer K , Hohlfeld T , Kelm M
Published: October 2022

Background

Pain is a serious issue in our aging society. Metamizole is one of the most commonly used analgesics. In addition, metamizole has been shown to attenuate the pharmacodynamics response to aspirin as measured by platelet function tests. However, the extent to which this laboratory effect translates to clinical outcome in patients is unknown.

Methods

We conducted a nationwide analysis based on health insurance database including 9.2 million patients in Germany. All patients with a cardiovascular event in 2014 and subsequent secondary prevention with aspirin were followed up for 36 months. Inverse probability of treatment weighting (IPTW) analysis was performed to examine mortality rates between patients on aspirin-metamizole co-medication and aspirin medication alone. Myocardial infarction (MI) and stroke/transient ischemic attack (TIA) events were also documented.

Results

26,200 patients received continuous aspirin medication alone and 5,946 received co-medication with aspirin and metamizole. In the IPTW analysis, significantly increased mortality was observed in the co-medication group (15.6% vs. 24.4%, hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.56–1.76; p<0.0001). MI and stroke/TIA were also increased (MI: 1,370 [5.2%] vs. 355 [5.9%]; HR=1.18, 95% CI 1.05–1.32; p=0.0066, relative risk (RR) 1.14, absolute risk increase (ARI) 0.71%, number needed to harm (NNH) 140. Stroke/TIA: 1,901 [7.3%] vs. 506 [8.5%]; HR=1.22, 95% CI 1.11–1.35; p<0.0001, RR 1.17, ARI 1.21%, NNH 82).

Conclusion

In this nationwide observational study, aspirin-metamizole co-medication was associated with excess mortality. This was partly due to ischemic events (MI and stroke/TIA), which were also more frequent in the co-medication patients. Therefore, metamizole should be used with caution in aspirin-treated patients for secondary prevention

Funding Acknowledgement

Type of funding sources: None.
Impact of mental disease on the risk of atrial fibrillation in patients with diabetes mellitus: a nationwide population-based study
Authors: Bae N , Lee S , Choi E , Ahn H , Ahn H , Kwon S , Han K , Oh S , Lip G
Published: October 2022

Background

Diabetes mellitus (DM) is known to increase the risk of mental disorders, which increases the health care burden in these patients. Also, DM is one of the risk factors leading to atrial fibrillation (AF), and the presence of concomitant AF and DM adds to the increased risks of stroke and death. It is uncertain whether mental disease is an independent risk factor of incident AF in patients with DM.

Purpose

To investigate whether diabetic patients with mental disease have an increased risk of AF.

Methods

Using the Korea National Health Insurance Service database, we enrolled 2,512,690 patients diagnosed with DM without AF between 2009 and 2021. Newly diagnosed AF was identified during the follow-up period. We compared the risk of AF between patients with mental disease and those without.

Results

Among the total population, 828,929 (32.99%; mean age 61.58±11.28; 56.71% female) patients were diagnosed with mental diseases (Figure 1). Anxiety (564,786 patients, 68.13%) was the most common mental disease, while depression was the second most common (313,773 patients, 37.85%). Diabetic patients with mental diseases had a higher percentage of women, hypertension, dyslipidemia, chronic kidney failure, congestive heart failure, obstructive sleep apnea, and thyroid disease. During a median 7.0 years (IQR 5.93–8.07) follow-up, 34,523 were diagnosed new-onset AF (4.66 per 1,000 person-year). In multivariate analysis, diabetic patients with mental disorders showed a higher risk of new-onset AF (HR 1.19; 95% CI 1.17–1.21; p-value <0.0001) (Figure 2). Among mental diseases, depression, insomnia, and anxiety were associated with increased risks of new-onset AF (HR 1.15; 95% CI 1.12–1.17; HR 1.15; 95% CI 1.13–1.18; and HR 1.19; 95% CI, 1.67–1.21; all p-value <0.0001, respectively), whereas bipolar disorder and schizophrenia showed non-statistically significant trends (due to small numbers). Subgroup analyses showed that younger age had significant interactions with depression, insomnia, and anxiety.

Conclusion

Mental diseases, especially depression, insomnia, and anxiety, showed an increased risk of AF in patients with DM. Awareness and prompt diagnosis and management of AF would be necessary for these high-risk populations at risk of incident AF.

Funding Acknowledgement

Type of funding sources: None.
Anxiety and depression among ambulatory and hospitalized patients with cardiovascular long-COVID-19 presentation referred to cardiology consultation after COVID-19 infection
Authors: Rasmus P , Kasprzak J D , Chudzik M , Lipert A
Published: October 2022

Introduction

COVID-19 is connected with varying degrees of emotional stress. Patients (pts) who are hospitalized with severe COVID-19 (C19) are located in single rooms without a permanent attendant to prevent contamination. All personnel serving these pts come into contact with patients with personal full-body protective garment. Ambulatory C19 pts, usually with less severe presentation, are treated in more comfortable conditions.

Purpose

To evaluate the impact of the psychosocial changing conditions on individuals' psyche and to analyse the differences in terms of experienced anxiety and depression among the ambulatory and hospital patients referred to post-C19 cardiology consultation.

Methods

The study involved 388 pts with persistent cardiovascular symptoms, including 198 ambulatory patients (130 females and 68 males) and 190 hospital patients (128 females and 62 males) referred to the cardiology consultation (mean age 4.9±12.9 and 50.5±14.4 years, respectively). The data were collected using the specially designed questionnaire related to descriptive characteristics of the patients and to standardized questionnaires: the State-Trait Anxiety Inventory (STAI) and Beck's Depression Inventory (BDI).

Results

Abnormal psychological metrics was common in the study pts. Indicators of anxiety were lower in the ambulatory than in hospitalized pts (p<0.001). Depression level was also lower in the ambulatory pts (p<0.001). The same differences were statistically significant in both female and male pts subsets. However, anxiety and depression were more pronounced among female than male pts. Very strong positive correlation was observed between anxiety - state and depression among ambulatory patients, both females and males (p<0.05).

Conclusions

C19 convalescents with persistent symptoms of presumed cardiovascular origin present with abnormal psychological traits including increased anxiety and depression especially in individuals requiring hospital treatment. For this reason, it is necessary to plan the interventions particularly in hospitalized pts to reduce their anxiety and depression levels and to create psychological support programs.

Funding Acknowledgement

Type of funding sources: None.
Brief, intensive group-based cognitive therapy integrated in cardiac rehabilitation reduces psychological distress in cardiac patients with anxiety and depression a randomized controlled
Authors: Holdgaard A , Eklo Kjesbu I , Funch Lassen C , Eckhardt-Hansen C , Prescott E , Kruuse Rasmussen H
Published: October 2022

Background/Introduction

Patients with coronary artery disease (CAD) and valvular heart disease (VHD) often suffer from psychological distress, which in turn leads to impaired quality of life, delayed return to work, and increased morbidity and mortality. European guidelines emphasize recognition and intervention, but evidence-based treatment options are limited and perceived as costly. Manageable interventions addressing psychological distress in cardiac patients are needed.

Purpose

To develop an efficient and cost-effective model for cardiac patients to reduce psychological distress.

Methods

A multi-center randomized clinical trial in patients with newly diagnosed CAD and/or surgically treated VHD, part of the workforce and concomitant psychological distress (defined as Hospital Anxiety and Depression scale (HADS) Anxiety ≥8 or Depression ≥8). The patients were randomized to five sessions of group-based cognitive-behavioral therapy plus cardiac rehabilitation (Intervention, I) or cardiac rehabilitation alone (Control, C). Furthermore, 41 cardiac patients (male gender 85.4%, age 57±6.4 years) without psychological distress (background, B) participated as reference group to follow the natural course. The primary outcome was a total HADS score at three months. Secondary outcomes were return to work, adherence to CR (participation in >80% of planned training sessions), adherence to lifestyle interventions for CVD risk factor goals, HeartQoL (is a disease-specific questionnaire that measures cardiac quality of life), and cardiovascular readmissions after 12 months.

Results

148 patients were included, 67% men, mean age 54±7.5 years and median HADS score at baseline 15 (IQR 10–19) (Table 1). At 3 months HADS score improved significantly more in the intervention group (p<0.001) and this difference persisted at 6 months (p<0.001, Figure). Similar results were seen for HADS anxiety and HADS depression (Figure 1). HeartQol also improved more in the intervention group. 78% had returned to work at 6 months in the intervention group versus 67% in the control (p=0.11). There were no differences in other secondary outcomes

Conclusion

Brief cognitive-behavioral therapy provided by cardiac nurses to patients with CAD/VHD and a high HADS score significantly reduced psychological distress and quality of life. The program is simple and can be integrated with existing CR programs at low costs. Larger trials are needed to confirm the effect of the program on retaining cardiac patients in the workforce.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): The trial is fonded by TrygFonden
Selenium concentration and cardiovascular disease risk: Mendelian randomization study
Authors: Yuan S , Mason A M , Bruzelius M , Akesson A , Burgess S , Larsson S C
Published: October 2022

Background/Introduction

Selenium has been associated with cardiovascular disease (CVD) risk in observational studies; however, the causality of the association remains unestablished.

Purpose

To examine the associations of selenium concentrations with 15 CVDs using Mendelian randomization analysis.

Methods

Genetic variants significantly associated with concentrations of toenail and blood (TAB) and blood selenium in mild linkage disequilibrium (r2 <0.3) were used as instrumental variables. Summary-level data for 15 CVDs were obtained from the UK Biobank study (n=367,561), FinnGen study (n=218,792), and six international consortia. The inverse variance weighted method accounting for linkage disequilibrium was used to estimate the associations. Results for one outcome from different sources were combined using the fixed effect meta-analysis method. Bonferroni correction was used to account for multiple testing, and associations with P value ≤0.003 (0.05 / 15 outcomes) were described as significant. Associations with P value between ≤0.05 and >0.003 were regarded as suggestive associations.

Results

Genetically predicted concentrations of TAB selenium were not significantly associated with the risk of the 15 CVDs. However, there were suggestive associations of genetically predicted higher concentrations of TAB selenium with increased risk of atrial fibrillation and peripheral artery disease. The odds ratio per one-unit increase in log-transformed concentrations of TAB selenium was 1.07 (95% confidence interval, 1.01–1.12; P=0.019) for atrial fibrillation and 1.20 (95% confidence interval, 1.05–1.38; P=0.008) for peripheral artery disease. We observed no associations between genetically predicted blood selenium concentrations and risk of the 15 CVDs.

Conclusions

Genetically predicted higher concentrations of TAB or blood selenium were not associated with a lower risk of CVD, which suggests that high selenium status may not prevent CVD development. The suggestive positive associations of TAB selenium with atrial fibrillation and peripheral artery disease warrants verification.

Funding Acknowledgement

Type of funding sources: None.
Prognostic cut-off values of caffeine and cardiovascular events in a cohort of unselected men and women from general population
Authors: Tikhonoff V , Ciaghi G , Lievore N , Casiglia E
Published: October 2022

Background

Several studies focused on the effect of caffeine on the cardiovascular (CV) system and on CV outcome, with fairly contrasting results. Dietary caffeine is usually taken into consideration as a continuous variable, but researcher would prefer to use cut-off values more useful in clinical setting.

Purpose

The present study is aimed at defining in epidemiological setting and in population-based context the cut-off values of caffeine, if any, having a CV prognostic values, to confirm them in men and women of general population, and to establish whether caffeine of food origin contained in multiple sources used in everyday life.

Methods

The study cohort was represented by 1,668 unselected men and women aged 59.6±17.1 years living in an area in North-East Italy and sharing homogeneous lifestyle, randomly taken from general population. Multivariate dichotomic Cox regression models having fatal and morbid CV event as dependent variables, adjusted for age, sex, basal heart rate, body mass index, LDLC, individualized FEV1, β-blocking therapy, ethanol intake, diabetes mellitus, arterial hypertension, smoking, smoking, blood pressure were preliminarily used to search for an association between caffeine as a continuous variable and incident CV event. Prognostic cut-off values, identified by means of receiver operating curves (ROC) and able to discriminate between subjects doomed to develop the CV event, were then used as independent predictors to divide people into those cut-off in further multivariate Cox models adjusted for the confounders listed above.

Results

Daily intake of caffeine over a specific cut-off determined via the ROC curve analysis are associated to lower incidence of CV events in a 20-year follow-up period. This cut-off corresponds, for each events, to an interval between two groups of quintiles of caffeine intake. The cerebrovascular events and those due to heart failure and arrhythmias were reduced also in multivariate models adjusted for confounders. On the contrary, intake of caffeine over the cut-off was only apparently associated to lower incidence of coronary disease, but this unadjusted crude association was wales and not confirmed after adjustment.

Conclusions

In men but not in women, higher voluntary daily consumption of caffeine from any source reduces significantly and to a considerable extent, in a long follow-up, the incidence of cerebrovascular events, heart failure and arrhythmias. To have preventive effects on events the consumption of caffeine must be higher than a cut-off that corresponds to 280, 230 and 280 mg/day respectively, cut-off values always falling between the third and fourth quintile of caffeine consumption. No prognostic cut-off can be identified in women and in any sex in the case of coronary events. Specific studies will be mandatory to understand the reason of this sex-specific difference.

Funding Acknowledgement

Type of funding sources: None.
Investigating myocardial energetic deficit across the spectrum of cardiac disease
Authors: Henry J A , Levelt E , Rayner J J , Hundertmark M J , Peterzan M A , Green P G , Watson W , Burrage M K , Arvidsson P , Lewis A J M , Chamley R , Neubauer S , Valkovic L , Rider O J
Published: October 2022

Introduction

The phosphocreatine-to-adenosine triphosphate ratio (PCr/ATP) is a sensitive marker of the energetic state of the heart and can be reliably measured non-invasively using 31Phosphorus magnetic resonance spectroscopy (31P-MRS). Derangements in cardiac energetics are a distinctive feature in the pathophysiology of several cardiac diseases, and thus potential therapeutic targets.

Purpose

We sought to compare cardiac PCr/ATP across a range of cardiac pathologies.

Methods

Using a 3D chemical shift 31P spectral acquisition we recorded PCr/ATP in 515 participants: athletes (n=17), healthy controls with normal weight (n=148), overweight (n=67) and with obesity (n=73), diabetes (n=23), heart failure with preserved ejection fraction (HFpEF) (n=33), heart failure with reduced ejection fraction (HFrEF) (n=63), amyloid (n=9), severe aortic stenosis (AS) (n=29), severe mitral regurgitation (MR) (n=18), and hypertrophic cardiomyopathy (HCM) (n=35).

Results

A spectrum of myocardial PCr/ATP exists ranging from normal in athletes (2.23±0.28) and those with normal weight (2.05±0.38) to severely impaired in severe MR (1.56±0.32) and cardiac amyloid (1.34±0.19, Figure 1). Despite normal systolic function (all LVEF >57%) those living with obesity and diabetes have lower PCr/ATP than normal (all p<0.001). In all groups with HF, regardless of aetiology, myocardial energetics were impaired (all p<0.001). Across the whole cohort PCr/ATP was negatively correlated with body mass index (r −0.28, p<0.001), age (r −0.34, p<0.001) and LV mass (r −0.1, p<0.001). PCr/ATP was not related to systolic or diastolic blood pressure in these cohorts.

Conclusions

We demonstrate a spectrum of energetic deficit in cardiac disease and this is affected by not only myocardial pathology but also by obesity and age. Derangements in myocardial energetics are present in myocardial pathologies independent of underlying aetiology.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): We acknowledge support from the British Heart Foundation Oxford Center of Research Excellence.
The AFLETES study: atrial fibrillation in veteran athLETEs and the risk of stroke
Authors: Pallikadavath S , Richards C , Bountziouka V , Sandilands A J , Graham-Brown M P M , Robinson T , Singh A , McCann G P
Published: October 2022

Background

Endurance athletes are at an increased risk of atrial fibrillation (AF) when compared to the general population. However, the risk of stroke in athletes who develop AF is not known.

Purpose

We aimed to assess the risk of stroke in endurance veteran athletes with AF when compared to those that remain in sinus rhythm.

Methods

A questionnaire was broadcasted through social media and sports clubs. Individuals that had competed in at least one competitive event and were ≥40 years old were included. Self-reported demographic, past medical history and training history data were collected and a CHA2DS2-VASc was calculated. Binary logistic regression was used to assess variables associated with AF and stroke.

Results

The survey received 1002 responses from 41 countries across Africa, Asia, Australasia, Europe, North and South America, and 942 were included in the final analysis. The average age was 52.4±8.5 years and 83.7% were male. The most common sports were cycling (n=677, 71.9%), running (n=558, 59.2%) and triathlon (n=245, 26%). There were 190 (20.2%) individuals who reported AF and 26 (2.8%) individuals who reported stroke, of which 14 (53.9%) had AF. Lifetime exercise dose (OR: 1.02, 95% CI: 1.00, 1.03, p=0.02) and swimming (OR: 1.56, 95% CI: 1.02, 2.39, p=0.04) were associated with AF in multivariable analysis. AF (OR: 4.18, 95% CI: 1.80, 9.72 p<0.01) was positively associated with stroke, even in individuals with a CHA2DS2-VASc of 0 or 1 (OR: 4.20, 95% CI: 1.83, 9.66, p<0.01) (Figure 1).

Conclusions

This survey provides early evidence that the risk of stroke in veteran endurance athletes who develop AF is not negligible, even in those deemed to be at low risk by CHA2DS2-VASc score. Longitudinal studies are needed to substantiate these findings to inform decisions around anticoagulation.

Funding Acknowledgement

Type of funding sources: None.
Relationships between plasma cytokine balance and cardiac magnetic resonance imaging in long-term post-COVID follow-up: a cross-sectional preliminary study
Authors: Simonini L , Sbrana S , Foffa I , Baroni M , Catapano G , Chiappino D , Grigoratos C , Marrone C , Losi P , Mannucci F , Salvadori S , Todiere G , Valenti E , Ait-Ali L , Aquaro G D
Published: October 2022

Background

COVID-19 infection can lead to a constellation of long-lasting post-infectious sequelae, including myocardial dysfunction, whose outcome is strongly affected by a fine-tuned balance between pro- and anti-inflammatory systemic immune responses. Plasma cytokines are key mediators of this immunological balance. In this preliminary study we evaluated the cross-sectional association between the circulating levels of the main pro- and anti-inflammatory cytokines and cardiac magnetic resonance (CMR) abnormalities.

Methods

71 subjects (59% female, mean age 52±14) with previous diagnosis of COVID-19 infection were enrolled at our institution for MULTICOVID protocol, comprehensive of CMR and biomarkers assessment performed >3 months and <1 year following the first negative swab test. CMR protocols consisted of conventional sequences (cine, T2-weighted imaging, and late gadolinium enhancement [LGE]) and quantitative mapping sequences (T1, T2, and extracellular volume [ECV] mapping). Plasma levels of cytokines TNF-α, IL-1β, IL-1α, IFN-α2, IL-6, IL-8, IL-13, IL-10, IL-17A, IL-18, IP-10, MIG and MCP-1 were quantified by Multiplex Immunoassays on the Luminex technology platform. Soluble cardiologic and biochemical biomarkers were measured by routine laboratory analysis.

Results

After a median of 9 (IQR 6–11) months following negative swab, CMR was normal in 48 subjects, while in 23 (32%) it revealed tissue characterization abnormalities (myocardial late enhancement and/or edema). By multivariate regression analysis (adjusted for age, sex, vaccination, severity degrees of the initial COVID disease, presence of comorbidities, smoke, time interval between COVID diagnosis and CMR assessment) the cytokine ratio TNF-α/(IL-10+IL-13) was independently associated (OR=2.89, 95% CI 1.19–7.04, p=0.02) with CMR abnormalities. Interestingly, the cumulative pro-/anti-inflammatory cytokine ratio (IL-1β+TNF-α+IFN-α2+IL-6+IL-17A+IL-8)/(IL-10+IL-13) showed a positive (OR=1.70, 95% CI: 1.04–2.75) and significant (p=0.03) association with CMR imaging aspects. Also, the ratio IFN-α2/(IL-10+IL-13), although without achieving a complete statistical significance (p=0.09), was associated positively with CMR findings.

Conclusions

The preliminary results of this cross-sectional study suggest that the systemic inflammatory environment, long-lasting unbalanced towards a prevalent cytokine-driven pro-inflammatory condition following COVID infection, could affect the development of CMR-detectable myocardial edema and fibrosis in long-term post-COVID subjects.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): Tuscany Region
Effect of CPAP therapy on blood pressure in patients with OSA: a worldwide individual patient data meta-analysis
Authors: Pengo M , Schwarz E I , Barbe F , Drager L , Fava C , Ip M S M , Martinez Garcia M A , McEvoy D , Peker Y , Phillips C L , Soranna D , Steier J , Stradling J , Zambon A , Parati G
Published: October 2022

Background

Obstructive sleep apnoea (OSA) is a well-known cardiovascular risk factor and is frequently associated with hypertension. The treatment of OSA with continuous positive airway pressure (CPAP) can resolve apnoeas, hypoxia, and sympathetic hyperactivation. Meta-analyses of randomised controlled trials (RCTs) show that CPAP treatment modestly reduces blood pressure (BP) with a pronounced heterogeneity among different OSA patient subgroups.

Purpose

To study the effects of CPAP treatment on BP changes, and to identify predictors of BP response to CPAP through analysis of individual patient data from published RCTs.

Methods

Study groups who had published RCTs on the effect of CPAP therapy on BP in OSA were invited to share the individual patient data (i.e. BP values, history of hypertension and antihypertensive drugs use). The outcomes of interest were the group-difference (BP at follow-up – BP at baseline) in office and out-of-office BP. Data analysis was performed with a one-step approach using a linear regression model, with treatment as covariate, including a random effect. An additional analysis was performed by stratifying patients in three subgroups: normotension, controlled hypertension and uncontrolled hypertension, based on BP at baseline, history of hypertension or treatment with antihypertensive drugs. Lastly, we evaluated the determinants of CPAP associated BP changes.

Results

Individual patient data from 34 parallel-group RCTs (n=7,456, 72% males, body mass index, BMI 31.9±14.8 kg/m2, age 58.6±10.9 years, apnoea-hypopnoea index, AHI 35.5±20.6 /hour) were analysed. The overall CPAP effect was larger for 24-BP compared to office BP measurements (Table 1), the highest reductions being observed for nocturnal BP. The stratified analysis showed a consistent BP lowering effect in the group of patients with uncontrolled hypertension whereas there was no significant BP change in those with controlled hypertension or in normotensives (figure 1). Higher BP levels at baseline and history of hypertension were independent predictors of BP reduction by CPAP for office and 24-BP measurements. Younger age and more severe nocturnal oxygen desaturations predicted a larger treatment effect on office BP only.

Conclusions

BP response to CPAP in OSA patients varies in different patient groups as a function of baseline BP, the greatest reduction being observed in younger patients with uncontrolled BP. Thus, our individual patient data meta-analysis indicates that younger patients with uncontrolled hypertension and more severe nocturnal oxygen desaturations measured by minimum SpO2 are likely to benefit the most from CPAP treatment in terms of BP reduction.

Funding Acknowledgement

Type of funding sources: None.
Low blood levels of the lncRNA MRPL20-AS1 are associated with severe obstructive sleep apnea
Authors: Zietzer A , Nachtsheim L , Duesing P , Von Krosigk M , Hosen M R , Breitrueck N , Goody P R , Klussmann J P , Nickenig G , Jansen F , Jansen S
Published: October 2022

Introduction

Obstructive sleep apnea syndrome (OSAS) is the most common sleep disorder and it is associated with arterial hypertension, heart failure, coronary artery disease as well as atrial fibrillation. The underlying pathomechanisms for this association are only incompletely understood. In recent years long non-coding RNAs (lncRNA) have been shown to be involved in various cardiovascular pathologies. The aim of this study is to identify lncRNAs which are associated with OSAS in order to provide potential therapeutic targets.

Methods and results

In order to tackle this issue, we included 23 Patients with a suspected OSAS in a pilot study and sampled blood on the evening before and on the morning after polysomnographic analysis. Citrate was used to inhibit clotting of the blood and cellular components were removed by centrifugation, before the plasma was stored at −80°C. One patient had no sign of OSAS as indicated by an Apnea/Hypopnea-Index (AHI) <5 per hour and was therefore excluded. The remaining 22 patients had a mean age of 44.45 years and a mean AHI of 28.38 per hour. Three of the patients were female and nineteen were male. In four of those patients with high AHI levels, we performed a RNA sequencing analysis from the citrate plasma and found MRPL20-AS1 to be the most significantly regulated lncRNA after the night of polysomnographic analysis (A). Low coding potential of MRPL20-AS1 was confirmed in silico via the Coding-Potential Assessment Tool (http://lilab.research.bcm.edu/) resulting in a coding probability of 0.06148. Then MRPL20-AS1 levels were measured via qPCR in the remaining patients. From 19 patients, we obtained evaluable results. We found that MRPL20-AS1 blood levels had the tendency to be lower after the night of polysomnographic assessment (B). Interestingly MRPL20-AS1 levels were inversely correlated with the AHI of the OSAS patients (C). This indicates that severe OSAS was associated with low levels of MRPL20-AS1 in our cohort (D). In order to further investigate these results in vitro, we subjected human coronary artery endothelial cells (HCAECs) to hypoxia (1% and 5% O2) for 24 h. We found that hypoxia leads to a significant downregulation of MRPL20-AS1 in HCAECs (E).

Conclusion

MRPL20-AS1 blood levels are lower in patients with severe OSAS after nocturnal hypoxia. In endothelial cells MRPL20-AS1 is downregulated after hypoxia. MRPL20-AS1 can therefore be useful to identify patients suffering from severe OSAS. Further investigations are needed to elucidate the biological function of MRPL20-AS1 in the context of OSAS and to investigate MRPL20-AS1 as a potential therapeutic target to counteract cardiovascular effects of OSAS

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): Unviversity of BonnUniversity of Cologne
Access to cardiac rehabilitation programs in patients with acute coronary syndrome: can referral be a step towards improvement? Insights from a multicentre national registry
Authors: Cabral M , Antunes A , Santos B , Loureiro M F , Morais J
Published: October 2022

The burden of cardiovascular disease remains on top of society's health problems, and acute coronary syndromes are undoubtedly a major cause. Cardiac rehabilitation programs (CRP) have been demonstrated to be a cost-effective strategy in reducing morbimortality and improving quality of life after an acute event. Despite this evidence and clinical recommendations, CRP are still globally underused. The lack of referral patients to CRP has been appointed as an important impediment to patients' participation.

This study aimed to clarify the main features of referred patients to CRP vs non-referred patients after an acute coronary syndrome (ACS).

The authors performed a retrospective analysis of adult patients with information about CRP destination, included in the Portuguese Registry on Acute Coronary Syndromes (ProACS) between October 2010 and December 2021. Comparison tests for parametric and non-parametric variables were performed. Logistic regression was applied for multivariate analysis. A p-value less than 0.05 was considered statistically significant.

A total of 28809 patients admitted for ACS were analysed, 22896 (79.5%) not referred for CRP (group 1) and 5913 (20.5%) were referred or even had a planned CRP. Table 1 shows the most important baseline characteristics and differences between groups. Table 2 demonstrate the group differences regarding admission diagnosis, complementary study results and in-hospital complications. Multivariate analysis established the following variables as independent factors for non-referral for CRP: age greater than 75 years (OR 0.80, 95% CI [0.72, 0.89]), history of valvular disease (OR 0.76, 95% CI [0.59, 0.97]), history of kidney disease (OR 0.65, 95% CI [0.54, 0.79]), admission diagnosis of unstable angina (UA) (OR 0.37, 95% CI [0.27, 0.50]), multivessel disease (OR 0.73, 95% CI [0.67, 0.80]), left ventricular ejection fraction less than 50% (OR 0.76, 95% CI [0.68, 0.84]), mechanical complication of myocardial infarction (OR 0.26, 95% CI [0.10, 0.67]) and acute heart failure during hospitalization (OR 0.67, 95% CI [0.58, 0.77]).

In conclusion, contrary to international results, women and patients with non-ST-segment elevation myocardial infarction were not negative predictors for referral to CRP. However, we observed that in our country, older patients, those with UA as an admission diagnosis, comorbidities and/or reduced systolic function are less referred to CRP by physicians. Paradoxically, these patients often have greater disease management complexity and poor outcomes. Besides that, the beneficial effects of cardiac rehabilitation in these groups have been demonstrated. Thus, it is extremely important to understand the limitations of referral in our country and implement strategies to overcome them.

Funding Acknowledgement

Type of funding sources: None.