bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of the renin angiotensin system inhibitors on inflammatory markers: a systematic review and meta-analysis of 32 randomized controlled trials
Authors: Awad K , Zaki M M , Mohammed M , Banach M
Published: October 2021

Background

Inflammation plays a critical role in the etiology of cardiovascular disease (CVD). The renin-angiotensin system inhibitors including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to be effective in reducing elevated blood pressure. However, the information on their potential effect on inflammatory markers including C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) is still lacking.

Purpose

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to synthesize evidence about effect of ACEIs and ARBs on selected inflammatory markers.

Methods

PubMed, Scopus, and Embase were searched from inception until February 15, 2021. We included RCTs that assessed the effect of ACEIs or ARBs, compared with placebo, on any of the following markers: CRP, IL-6, or TNF-α. Mean changes in the relevant markers levels were pooled as a standardized mean difference (SMD) with a 95% confidence interval (CI) under the random-effects model. Heterogeneity was assessed using I2 and χ2 tests.

Results

Thirty-two RCTs (n=3,403 patients) were included in the analysis. Overall pooled analysis suggested that ACEIs significantly reduced plasma levels of CRP (SMD: −1.08 [95% CI: −1.57 to −0.59]; I2: 95%), IL-6 (SMD: −0.75 [95% CI: −1.41 to −0.09]; I2: 81%), and TNF-α (SMD: −1.77 [95% CI: −2.82 to −0.73]; I2: 95%). This lowering effect remained statistically significant by perindopril in terms of all relevant markers, by quinapril and ramipril in terms of IL-6 and by enalapril in terms of TNF-α. As for the ARBs as a class, they showed a statistically significant reduction only in terms of CRP (SMD: −0.14 [95% CI: −0.28 to −0.01]; I2: 0%) and did not significantly affect any of the other markers. Moreover, the ARBs individual drugs did not show any significant effect on any of the relevant markers except for valsartan that significantly reduced plasma levels of IL-6 (SMD: −0.42 [95% CI: −0.80 to −0.04]; I2: 0%).

Conclusions

Based on the results of this meta-analysis, ACEIs showed a beneficial lowering effect on CRP, IL-6, and TNF-α, while ARBs were effective as a class only in terms of CRP reduction. Further larger RCTs are warranted to confirm these results particularly in case of individual drugs and to assess the significance of these reductions in terms of CVD prevention.

Funding Acknowledgement

Type of funding sources: None.
Low testosterone accelerates vascular damage in hypertensive smokers with more than a 20-pack-year smoking history
Authors: Ioakeimidis N , Terentes-Printzios D , Sigala E , Xydis P , Gardikioti V , Gourgouli I , Georgakopoulos C , Tsioufis K , Vlachopoulos C
Published: October 2021

Purpose

Testosterone deficiency and cigarette smoking are both associated with increased cardiovascular (CV) mortality risk. Aim of the study is to investigate the impact of low testosterone level on vascular function and structure changes related to cumulative tobacco smoke exposure in patients with arterial hypertension.

Methods

Indices of vascular function and structure including carotid-femoral pulse wave velocity (PWV) and carotid intima media thickness (cIMT) were measured in 263 hypertensive males divided into 4 age-matched groups according to pack-years of smoking as never smokers (0.0 pack-years), light smokers (0.1–20.0 pack-years), moderate smokers (20.1–40.0 pack-years), and heavy smokers (>40 pack-years). Plasma total testosterone (TT) levels were measured in all patients.

Results

PWV and cIMT progressively increased from never smokers and light smokers to moderate and heavy smokers (overall P<0.001 and P<0.01 respectively). The hypertensive males of each smoking group were further classified according to measured low or normal TT levels (low TT<3.5 ng/ml). Figure shows mean PWV and cIMT of the smoking/TT groups. Systolic and diastolic BP was higher in patients with TD compared to subjects with normal TT in moderate and severe heavy smokers (all P<0.05) and similar in light and never smokers. LDL-C levels were comparable between men with TD and normal TT across the four smoking groups. The difference in aortic PWV between TD and normal TT shows a progressive increase from light to moderate and heavy smokers. Similarly, the difference in cIMT between TD and normal TT is also positively correlated with cumulative tobacco exposure. All associations remained statistically significant even after adjustment for BP differences.

Conclusions

The deficiency in TT levels accelerates vascular wall damage of large arteries among hypertensive smokers with more than 20 pack-years tobacco exposure. Considering the predictive value of vascular biomarkers, the findings of this study imply the possibility that the measurement of baseline testosterone level could be an unfavourable marker of smoking-related cardiovascular risk among moderate and heavy smokers with arterial hypertension.

Funding Acknowledgement

Type of funding sources: None. TT, tobacco smoke exposure, PWV and IMT
Associations between serum triglycerides and abdominal aortic calcification in a cross-sectional study from the United States of America
Authors: Penson P , Javed S , Banach M , Lip G Y H
Published: October 2021

Background

Abdominal aortic calcification (AAC) has recently been recognised as a risk factor for cardiovascular disease, as it shares pathophysiological mechanisms with coronary artery disease.

Purpose

We investigated relationships between AAC and traditional cardiovascular risk factors in a cross-sectional epidemiological cohort from the USA

Methods

We used data from the National Health and Nutrition Evaluation Survey (NHANES) from the years 2103–2014. Dual-energy X-ray absorptiometry (DXA scans) were performed for a subset of 3140 NHANES participants over the age of 40. The images were scored according to ACC-24, a 24-point scale.

We performed binary logistic regression to investigate relationships between demographic variables (age, sex, poverty income ratio, & educational status) CV risk factors (triglycerides (fasting, and non-fasting) LDL-C, HDL-C systolic blood pressure, body mass index, smoking status & diabetes) medicine use (statins, antihypertensives and antiplatelets) and AAC status (patients with a score ≥2 on the 24-point scale were considered AAC positive). Non normally-distributed variables were categorised for the purposes of analysis.

Results

Participants with AAC were older (mean 65.5 years ± SD 11.7) than unaffected individuals (56.1±11.1) AAC was also associated with higher BMI (28.7±5.8 v. 27.6±4.8 kg/m2), and higher systolic blood pressure (131.3±19.5 v 125.8±18.4 mmHg).

We found a strong relationship between plasma triglyceride concentrations and AAC. In univariate analysis, fasting triglycerides above the first quartile were associated with approximately double the risk of AAC, compared to those in the first quartile (see table). This relationship persisted when the analysis was adjusted for demographics, risk factors and medicine use. A similar pattern was seen with non-fasting triglycerides (see table).

Conclusions

We found a strong relationship between triglycerides and AAC. Further work is required to determine whether this observation can be validated in other cohorts, and whether interventions to reduce triglyceides can alter the progression of AAC.

Funding Acknowledgement

Type of funding sources: None. Odds ratios (95% CI) for AAC
Impaired endothelial glycocalyx predicts adverse outcome in subjects without overt cardiovascular disease: a 6-year follow-up study
Authors: Ikonomidis I , Thymis J , Simitsis P , Katsanos S , Triantafyllou C , Kousathana F , Pavlidis G , Kountouri A , Polyzogopoulou E , Katogiannis K , Vlastos D , Kostelli G , Triantafyllidi H , Lekakis J , Lambadiari V
Published: October 2021

Aim

Endothelial glycocalyx is involved in the clinical course of atherogenesis. The purpose of this study was to investigate whether disturbance of glycocalyx integrity is related with increased cardiovascular risk.

Methods

Perfused Boundary Region (PBR), a marker of glycocalyx integrity, was measured non-invasively in sublingual microvessels with a diameter ranging from 5–25 μm using a dedicated camera (Sideview, Darkfield Imaging). Increased PBR indicates reduced glycocalyx thickness. We measured baseline PBR in 400 apparently healthy subjects, without established cardiovascular disease. We prospectively monitored the occurrence of major cardiovascular events (MACE-death, myocardial infarction, stroke and heart failure hospitalization) during a 6-year follow-up period using electronic records and clinic visits.

Results

Forty-three MACE were documented during follow-up. Subjects with PBR at 5–9 μm microvessel diameter greater than 1.15 μm (mean value of the study cohort) had 2-fold higher risk for MACE than those with lower PBR in a model including sex, age, hyperlipidemia, diabetes, hypertension, current smoking, family history of coronary artery disease and treatment with ACEi/ARBs or lipid lowering agents (hazard ratio (HR): 2.49; 95% CI: 1.23–5.02, p=0.011, net reclassification improvement (NRI): 25%; C-statistic: 0.738). PBR5-9 ≥1.15 was an independent and additive predictor of outcome when added in a model including SCORE, risk factors not included in SCORE (diabetes, family history of CAD) and medication (HR: 2.48 NRI: 23.8%, C-statistic increase from 0.629 to 0.678, for all cardiac events and HR: 4.19, NRI: 33.1%, C-statistic increase from 0.654 to 0.734 for death myocardial infarction and stroke, p<0.01).

Conclusion

Endothelial glycocalyx integrity is an independent and additive predictor to atherosclerotic risk factors for adverse outcome at 6 years follow-up in individuals without diagnosed cardiovascular disease.

Funding Acknowledgement

Type of funding sources: None.
Socioeconomic disparity in cardiovascular disease: a proteomic approach
Authors: Shafi B H , Boettcher M , Ejupi A , Osler M , Lange T , Prescott E
Published: October 2021

Background and purpose

A large unexplained social disparity in the occurrence of cardiovascular disease (CVD) has been documented. The precise mechanism behind these disparities is largely unknown. Biomarkers have improved our understanding of the pathophysiology of CVD. In this study we investigated differences in 184 biomarkers linked to CVD, with the aim of understanding the underlying mechanisms behind socioeconomic disparity in CVD and explore potential preventive measures.

Methods

We included 1144 participants from the Copenhagen City Heart Study, age 55- 64 years, without known CVD. Socioeconomic position (SEP) was defined by educational length in years. Blood samples were obtained and analyzed in two CVD proteomics panels (CVD panel II and III) with a total of 184 protein biomarkers. Associations between biomarkers and SEP were investigated by Pearson correlation coefficient and linear regression with multivariate adjustment for CVD risk factors.

Results

Median educational length was 10 (IQR 7–11) years. Of the measured biomarkers 53 were significantly correlated (p value <0.05) to educational length, 17 positively and 36 negatively (fig. 1). After adjusting for age and gender, 41 biomarkers and after multivariate adjustment 14 biomarkers remained significantly associated with educational length. Some of the strongest negative associations was seen for Leptin (LEP), Von Willebrand factor (vWF), Interleukin-6 (IL6), Fibroblast growth factor 21 (FGF21), Renin (REN) and Growth/differentiation factor 15 (GDF_15) while the strongest positive associations were seen for Growth Hormone (GH), Receptor for advanced glycosylation end products (RAGE) and Myoglobin (MB) (fig. 2).

Conclusion

SEP was associated with elevated levels of multiple biomarkers linked with CVD. The range of biomarkers indicate that pathways involving inflammation (IL6, LEP, RAGE), platelet-activation (vWF, IL6, RAGE), blood pressure (REN, LEP), MAPK cascade (GDF_15, FGF21, LEP, IL6, REN, GH) and weigh (LEP) regulation contribute to the socioeconomic gradient in CVD. Further exploration is needed to identify possible candidates for intervention.

Funding Acknowledgement

Type of funding sources: Public hospital(s). Main funding source(s): Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark.
Patients presenting with acute coronary syndromes have unreported coronary artery calcium on historical CT imaging
Authors: Bradley C , Aggarwal A , Goatman K , Jones G , Berry C , Good R
Published: October 2021

Introduction

Ischaemic heart disease (IHD) remains the leading cause of mortality globally1. The presence and extent of coronary artery calcification (CAC) is a strong predictor of cardiovascular events, and CAC scoring has been shown to be more predictive of cardiovascular events than other traditional risk assessment scores2.

Incidental coronary calcification can be detected and quantified on non-gated CT chest scans covering the heart in the field of view3. This finding is typically not reported4 and hence an opportunity to optimise cardiovascular risk assessment and treatment is missed.

Purpose

We sought to investigate whether patients presenting to our centre with an acute coronary syndrome (ACS) event had historical CT imaging demonstrating coronary artery calcification.

Methods

We retrospectively reviewed case records for all patients referred to our centre for an invasive coronary angiogram following their first known admission with an ACS event. ACS were defined according to contemporary guidelines from the European Society of Cardiology. We reviewed a 3 month period prior to the COVID-19 pandemic (01/01/2019–31/03/2019). The national imaging database was interrogated to identify previous CT imaging that includes the heart in the field of view. The presence of coronary calcification was confirmed and quantified using an ordinal scoring method previously described3. The clinical radiology reports for the scans were reviewed to determine the frequency of CAC being reported.

Demographic information was collected from our electronic patient record including the presence of risk factors for IHD. Prescribed medication prior to admission was also recorded using the on-admission medicines reconciliation documented in the electronic patient record.

Results

385 patients with first presentation of ACS were identified. 75 (19%) had a prior non-gated CT chest imaging. The most common indication for CT was for investigation of possible malignancy. The mean interval from CT imaging to ACS admission was 36 months.

CAC was present on 67 (89%) scans. The mean ordinal score was 4.04, corresponding to moderate CAC. The distribution of CAC by coronary artery revealed the majority of disease to involve the left anterior descending artery (Table 1). Only 12/67 (18%) of clinical radiology reports mentioned coronary calcification (Figure 1).

Patients with CAC frequently had additional risk factors for IHD. Despite this only 42% were prescribed antiplatelet therapy, and only 45% prescribed a statin.

Conclusions

A significant proportion of ACS admissions have evidence of CAC on historical CT scans. This finding is often not reported and the majority of patients with demonstrated coronary artery disease are not prescribed appropriate preventative therapies. Systematic reporting of this finding may have a significant impact on the prevention of acute cardiovascular events.

Funding Acknowledgement

Type of funding sources: None. Table 1
Polypill and its association with cardiovascular morbidity and mortality: meta-analysis from randomized controlled trials
Authors: Maraey A , Elsharnoby H , Elzanaty A , Khalil M , Younes A , Salem M
Published: October 2021

Background

Polypill or fixed dose combination pill (containing antihypertensive and cholesterol lowering agents) has shown, in multiple studies, to increase adherence and improve blood pressure and cholesterol measurements in at risk underprivileged populations. However, its long term effect on mortality, cardiovascular and cerebrovascular outcomes in high risk groups is not well-established.

Objective

To assess mortality, cardiovascular and cerebrovascular outcomes in higher risk patients using polypill containing fixed dose of Aspirin, antihypertensive drugs and Statin compared to standard care or placebo.

Methods

We queried MEDLINE, COCHRANE, and EMBASE databases for randomized controlled trials (RCTs) comparing polypill containing Aspirin, Statin and at least 2 antihypertensive medications, to standard care or placebo in patients with increased risk of cardiovascular diseases. We looked for trials including data about mortality, coronary and cerebrovascular events. We excluded trials that did not include outcomes of interest. 5 RCTs matching our criteria were included in our meta-analysis; UMPIRE 2013, IMPACT 2014, Kanyini GAP 2015, PolyIran 2019, and TIPS-3 2021.

Results

12828 patients (6419 in polypill vs 6409 in standard care/placebo groups) with known all-cause mortality, coronary events and cerebrovascular events outcomes were analyzed from 5 RCTs. For cardiovascular mortality outcome, 12205 patients (6108 in polypill vs 6097 in standard care/placebo groups) were analyzed from 4 RCTs since 1 RCT lacked data about cardiovascular mortality outcome. There was no difference between both groups in all four outcomes.

Risk ratio of all-cause morality and cardiovascular mortality in polypill group was 0.89 [95% CI 0.76–1.03, P=0.11, I2=0%] and 0.77 [95% CI 0.48–1.26, P=0.31, I2=59%] respectively (Figure 1).

Risk ratio of coronary events in polypill group was 0.88 [95% CI 0.64–1.20, P=0.41, I2=40%]. Relative risk of cerebrovascular events was 0.73 [95% CI 0.36–1.48, P=0.38, I2=63%] (Figure 2).

Conclusion

Polypill, despite being a practical solution to non-adherence in at risk underprivileged groups, does not improve mortality or major cardiovascular or cerebrovascular outcomes compared to standard care or placebo. Further efforts need to be made towards aggressive preventative measures and encouraging adherence to medications in groups at risk.

Funding Acknowledgement

Type of funding sources: None. Figure 1Figure 2
Lipoprotein(a) levels are not independently associated with endogenous steroid hormone levels, in contrast to other non-genetic and genetic factors: the population-based SKIPOGH study
Authors: Tessitore E , Dobretz K , Dhayat N A , Estoppey S , Kern I , Ponte B , Pruijm M , Vogt B , Vuilleumier N , Bochud M , Mach F , Ehret G
Published: October 2021

Introduction

Lipoprotein(a) [Lp(a)] is an LDL-like molecule that is likely causally related to cardiovascular events. Lp(a) levels are highly variable, by more two orders of magnitude, and most of this variability appears to be of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of the variation of endogenous hormone levels on Lp(a) is unknown.

Purpose

To investigate the association between Lp(a) levels and non-genetic factors, as endogenous steroid hormone levels, in contrast to genetic factors.

Methods

We investigated the association of 28 endogenous steroids with Lp(a) levels and compared the association to other non-genetic and genetic variables in a prospective, population-based sample (N=1,021).

Results

The average age of the participants was 51 years and 53% were female. Median Lp(a) levels were 62 (±204) mg/l and the 90th and 99th percentile of Lp(a) was 616mg/l and 1035 mg/l respectively. The prevalence of a Lp(a) elevation ≥700mg/l was 3.2% and Lp(a) varied greatly from undetectable to 1,690mg/l. Age explained 2.0% of Lp(a) variability (p<0.001), 1% was explained by LDL levels (p=0.001), and 40% by two single nucleotide polymorphisms near the Lp(a) gene that have been previously described. Lp(a) levels were on average almost two times more elevated in secondary prevention and in individuals with very elevated LDL levels (≥4.9 mmol/l). Of the 28 endogenous steroid hormones assessed, 5-androstene-3b,16α,17β-triol, androsterone, 16α-hydroxy DHEA, and estriol were nominatively associated with serum Lp(a) levels and explained 0.4–1% of Lp(a) variability in univariate analyses, but they did not reach significance in multi-variate models.

Conclusion

Our results confirm previous findings demonstrating that the majority of the Lp(a) variation in the general population is of genetic origin. Age and LDL-levels explain a further small part of Lp(a) variability. Endogenous hormone levels do not contribute significantly to the wide range of variability.

Funding Acknowledgement

Type of funding sources: None. Coefficient plot Lp(a) and variables
Imaging-based body fat depots and new-onset atrial fibrillation in general population
Authors: Lu Z , Tilly M J , Aribas E , Bos D , De Knegt R , Ikram M A , De Groot N M S , Voortman T , Kavousi M
Published: October 2021

Background

Obesity is a well-established risk factor for incident atrial fibrillation (AF). Whether different body fat depots differentially associate with AF development remains largely unknown.

Purpose

We aimed to investigate the associations between various body fat depots and the risk of new-onset AF among middle-aged and elderly individuals from general population.

Methods

In the prospective population-based cohort study, body composition was assessed using dual-energy X-ray absorptiometry (DXA) and total body mass, lean mass, fat mass, android and gynoid fat were analyzed (N=3468). Liver fat and epicardial fat were assessed using computed tomography (CT) (N=2145). A body fat score was defined by adding tertiles of each fat depot. All participants were followed for the occurrence of AF until 1st Jan. 2014. Principle component analysis was conducted to identify body fat distribution patterns. Time-to-event analyses were performed using Cox proportional hazards regression analysis. Hazard ratios (HR) and 95% confidence-intervals (95% CI), adjusted for cardiovascular risk factors, were calculated.

Results

Mean (standard deviation) of age for participants in DXA study and CT study was 74.42 (6.85) and 68.66 (6.41) years, respectively. AF incidence rate was 13.1 per 1000 person-years during a median follow-up time of 9.62 years. In the adjusted model, fat mass (HR; 95% CI: 1.33; 1.05–1.68), lean mass (1.40; 1.15–1.72), gynoid fat mass (1.36; 1.12–1.65), and total body mass (1.51; 1.21–1.89) were significantly associated with new-onset AF. Of note, android-to-gynoid fat ratio was inversely associated with incident AF (HR; 95% CI: 0.81; 0.70–0.94). Larger body fat score was associated with increased risk of incident AF (P for trend <0.01). Two fat distribution patterns were identified. Adherence to the fat- and gynoid fat- pattern (P for trend = 0.035), but not muscle- and visceral fat- pattern (P for trend = 0.35), was significantly associated with larger risk of new-onset AF.

Conclusions

Various body fat depots were associated with new-onset AF. Larger values of total body mass carried the highest risk for incident AF. The inverse association between android to gynoid fat ratio with AF presents a novel finding. A significant dose-response relationship between body fat accumulation and risk of new-onset AF was observed, implying a collective impact of fat depots on AF development. Findings also suggest that various fat depots, characterized by different fat distribution patterns, may exert differential combined effect on the risk of incident AF.

Funding Acknowledgement

Type of funding sources: None. Fat depots and atrial fibrillation
Intervention-specific association of weight variability with major adverse cardiovascular events in overweight or obese adults with type 2 diabetes mellitus
Authors: Zhuang X D , Liu M H , Zhang S Z , Christopher O , Liao X X
Published: October 2021

Background

Weight variability is associated with cardiovascular outcomes in diabetic patients. However, the effect of higher weight variability caused by intensive lifestyle intervention (ILI) on cardiovascular outcomes in diabetic patients is not well established. We aimed to evaluate the intervention-specific association between weight variability with major adverse cardiovascular event (MACE) among overweight or obese adults with diabetes.

Methods

In 3,859 participants from the Action for Health in Diabetes (Look AHEAD) trial, multivariate-adjusted Cox regression models were used to evaluate the associations of weight variability measured by variability independent of the mean (VIM) with MACE and secondary outcomes in intensive lifestyle intervention (ILI) and diabetes support & education (DSE) arm, respectively.

Results

During a median follow-up of 9.6 years, 255 (12.9%) participants in the ILI arm and 247 (13.2%) participants in the DSE arm developed MACE. Participants with the highest quartile of weight variability (VIM Q4) experienced a 2.23-fold higher risk of MACE compared with the lowest quartile (VIM Q1) in the DSE arm (hazard ratio [HR] 2.23; 95% CI 1.51–3.30), but not the ILI arm (HR 1.05; 95% CI 0.73–1.50). Moreover, compared with the lowest weight variability (VIM Q1), participants with the highest weight variability (VIM Q4) were not associated with all secondary outcomes in the ILI arm (all P>0.05) but were associated with the higher risks of secondary cardiovascular composite outcome (HR 1.88; 95% CI 1.20–2.95), all-cause mortality (HR 3.19; 95% CI 1.75–5.82), and myocardial infarction (HR 1.95; 95% CI 1.12–3.37) in the DSE arm.

Conclusions

Among the overweight or obese individuals with type 2 diabetes mellitus, rising weight variability was independently associated with increased MACE risks in the DSE arm but not the ILI arm. Therefore, a guideline-recommended ILI strategy for weight loss should be adopted to improve cardiovascular outcomes without considering the effect of high weight variability.

Funding Acknowledgement

Type of funding sources: None.
Clinical epidemiology and costs of type 2 diabetic patients with or without prior coronary artery disease or stroke. A longitudinal 5-year claims-data analysis of over 7 million inhabitants
Authors: Maggioni A P , Dondi L , Andreotti F , Ronconi G , Calabria S , Piccinni C , Pedrini A , Esposito I , Martini N
Published: October 2021

Aims

Contemporary, real-world data on type 2 diabetes mellitus (T2DM) are limited. We analysed prevalence, comorbidities, outcomes and costs of T2DM patients with and without coronary artery disease (CAD) or stroke in >7 million inhabitants.

Methods

T2DM patients were identified in 2015 (accrual period) from the Ricerca e Salute (ReS) database linking administrative records to demographics. From 2013–2015 information, four cohorts were considered: #1 with CAD and/or stroke; #2 without CAD and/or stroke; #3 with chronic CAD but no myocardial infarction or stroke; #4 with chronic CAD undergoing percutaneous coronary interventions (PCI). Hospitalizations, drugs and other outpatient care were assessed from 2015 to 2017.

Results

Prevalence of T2DM was 6% (441,085/7,365,954). CAD and/or stroke in the previous 3 years affected 7.5% of T2DM patients (33,153); this cohort was generally older, of male sex, with more comorbidities, prescriptions, and hospital admissions (50% versus 13.4%) compared to cohort #2. Yearly costs were >3-fold for cohort #1 versus #2, main drivers being hospitalizations in the former and drugs in the latter. Unexpectedly, two-year cardiovascular events were significantly higher in cohort #4 compared to any other (Figure). Guideline-recommended therapies were suboptimal in all cohorts.

Conclusions

The present analysis points to three areas of potential improvement in T2DM management: 1) undertreatment of T2DM patients with recommended drugs; 2) three-fold recurrences and costs in T2DM patients with, compared to those without, prior cardiovascular events; 3) highest risk of events in those with chronic CAD and PCI, warranting specific studies aimed at defining more effective preventive strategies.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): This research was partially supported by an unrestricted grant from Astra Zeneca. Astra Zeneca was not involved in data collection, analysis and interpretation, in writing the report, nor in deciding to submit the article for publication.
Clinical benefit of direct oral anticoagulants vs. vitamin-K antagonist in octogenarians with atrial fibrillation
Authors: Bonanad C , Garcia-Blas S , Diez Villanueva P , Ariza A , Tarazona F J , Bertomeu-Gonzalez V , Facila L , Torres J , Nunez J , Cordero A
Published: October 2021

Background

Direct oral anticoagulants (DOACs) have demonstrated to the be more effective and safer than vitamin-K antagonist (VKA) for stroke prevention in patients with atrial fibrillation (AF). AF prevalence increases exponentially with age but octogenarians were underrepresented in clinical trials.

Methods

We performed a metanalysis with currently available studies that assessed the effect of DOACS vs. VKA in patients with age ≥80 and AF after performing a systematic search. The primary endpoints analyzed were stroke and all-cause death. Secondary endpoints were major bleeding, according to each study definitions, intracranial bleeding and gastrointestinal (GI) bleeding. The raw numbers of incident end-points reported in each study were used. A random effects model was selected because significant heterogeneity was observed; sensitivity analyses tested potential sources of heterogeneity, publication bias and the small-study effect.

Results

A total of 147,067 patients from 16 studies were included, 71,913 treated with DOACs and 75,154 with VKA. Inclusion criteria for the study was age ≥80 in 13 studies, ≥85 in two and ≥90 in one. Mean age of patients included all the studies was 86.2 (2.6) years. According to the study drug, 34,448 received rivaroxaban; 20,295 apixaban; 14,641 dabigatran, 492 edoxaban and; 2,037 any DOAC. No difference in mean age was observed according to the study drug.

Stroke incidence was available in the 16 studies. DOACs treatment was associated to 28% reduction of stroke (RR: 0.72 95% CI 0.63–0.82; p<0.001) (figure). All-cause mortality could be assessed in 12 studies and DOACs treatment was associated to 18% in mortality (RR: 0.82, 95% CI 0.70–0.96; p=0.012) (figure). DOACs treatment was not associated to reductions in major bleeding (RR: 0.85, 95% CI 0.69–1.04; p=0.108); in contrast, the highest effect of DOACs treatment was a 43% reduction of intracranial bleeding (RR: 0.47, 95% CI 0.36–0.60; p<0.001) (Figure 4). Finally, DOACs treatment was not associated higher of GI bleeding risk (RR: 1.08, 95% CI 0.76–1.53; p=0.678). Metaregression identified inclusion site in North-America (p<0.001), the ELDERCARE-AF results (p=0.023), control arm different than VKA (p=0.006) and the prevalence of hypertension (p=0.042) were outlined as main sources of heterogeneicity for stroke risk reduction. The type of DOAC was the main source of source of heterogeneicity for all-cause mortality (p<0.001) and major bleeding (p=0.03) risk reduction. No small-study effect was found for any endpoint except for intracranial bleeding (Harbor test p=0.029).

Conclusions

Treatment with DOACs in octogenarians reduces the incidence of stroke, all-cause mortality and intracranial bleeding as compared to VKA.

Funding Acknowledgement

Type of funding sources: None.
Impact of frailty on elderly patients with infective endocarditis
Authors: Perez Garcia C N , Olmos C , Garcia Arribas D , Lopez J , Ladron R , San Roman J A , Jeronimo A , Islas F , Ferrera C , Saenz-Bejar C , Vilacosta I
Published: October 2021

Introduction

Frailty studies focused on patients with infective endocarditis (IE) are scarce and its potential impact on patient outcomes is not well known.

The aim of this study is to describe the clinical profile and prognosis of elderly patients with IE, comparing patients who met the frailty criteria versus those who did not.

Methods

A total of 121 cases of confirmed IE were consecutively collected in three tertiary hospitals between 2017 and 2019. The patients were classified into two groups: Group I (n=49), patients with IE who met the Frail criteria for frailty, and Group II (n=72), those patients without frailty by this scale.

Results

The median age of our cohort was 77 years (69–82), and 62.8% were men. Frail patients were older than those in Group II, as shown in Table 1.

Regarding comorbidity, chronic anemia (40.8% vs 25%; p<0.060) was more common in Group I, as well as rheumatic manifestations at admission (12.2% vs 1.4%; p=0.014).

The most frequently isolated microorganisms were S. aureus (n=25), coagulase negative staphylococci (n=25), viridans group streptococci (n=14), and enterococci (n=14). Enterococci (16.3% vs 8.3%, p=0.177) and non-viridans streptococci (10.2% vs 2.8%); p=0.086) were more frequent in frail patients.

Vegetation (79.6% vs 80.6%; p=0.896) and periannular complications (24.5% vs 29.2%; p=0.571) were similar in both groups. No significant differences were found regarding the location of the infection.

The incidence of in-hospital complications was similar between both groups. Frail patients underwent surgery less frequently than those in Group II, and had higher predicted mortality on surgical risk scale scores. However, the percentage of patients who met the surgical criteria and were considered inoperable was similar (33.3% vs 26.2%; p=0.415). In-hospital mortality was similar in both groups. When analyzing in-hospital mortality according to the therapeutic strategy in Group I, a mortality of 34.5% was observed in frail patients with conservative medical treatment, compared to 47.1% in those patients who underwent surgery in the same group.

One third of our patients received outpatient antibiotic treatment, being significantly more frequent in Group I (39.6% vs 29.0%; p=0.232).

Conclusions

The elderly patients with IE and frailty criteria were older and more frequently had rheumatic symptoms at admission. Enterococci and non-viridans streptococci were isolated more frequently than in non-frailty patients. Surgery was less performed among frail patients, who had a higher predicted surgical risk. Although complications and in-hospital mortality were similar between both groups, in the group of frail patients, those with conservative management showed lower mortality compared to surgery.

Funding Acknowledgement

Type of funding sources: None.
Oxidized Low-Density Lipoproteins increases nivolumab-induced cardiotoxicity through TLR4/NF-KB and NLRP3 pathways
Authors: Quagliariello V , Bonelli A , Paccone A , Buccolo S , Iovine M , Botti G , Maurea N
Published: October 2021

Background

Atherosclerosis is now recognized as a chronic inflammatory disease. Oxidized low-density lipoprotein (Ox-LDL) is oxidatively modified form of LDL with a key role in induction and progressio of atherosclerosis. Recent findings reported that cardiovascular events (myocarditis and atherosclerosis) were higher after initiation of immune check-point inhibitors (ICIs), potentially mediated by accelerated progression of atherosclerosis.

Purpose

We evaluated whether ox-LDL-induced apoptosis through toll-like receptor-4 (TLR4)/Nuclear factor κB (NF-κB) signaling pathway and NLRP3 inflammasome during exposure of human cardiomyocytes to nivolumab turning the light on the mechanisms of cell inflammation induced by OxLDL in cardiotoxicity of ICIs.

Methods

Human fetal cardiomyocytes (HFC cell line) in co-culture with hPBMC, were exposed to clinically relevant concentration of nivolumab (100 nM) alone or combined to OxLDL at 1, 10 and 50 μg/mL for 24h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis and apoptosis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome, expression of TLR4 and NF-kB). In order to evaluate the pathways involved in OxLDL damages, TLR4 and NLRP3 inhibitor (TAK-242 and dapansutrile, respectively) were added during cell viability and apoptosis studies.

Results

Nivolumab exerts cytotoxic and pro-apoptotic effects in co-coltures of cardiomyocytes and hPBMC. OxLDL increases significantly the nivolumab-induced cardiotoxicity in a manner that is sensitive to TLR4 and NLRP3. Incubation of cardiomyocytes with ox-LDL (10 and 50 μg/mL) for 24 hours increased TLR4 and NF-κB expressions. Ox-LDL had pro-apoptotic effects in a concentration-dependent manner with the involvement of lipid peroxidation but not of intracellular calcium.

Conclusion

Ox-LDL exacerbates cardiotoxicity during exposure to nivolumab through pro-inflammatory mechanisms. These results place the first step to preclinical studies aimed to reduce ox-LDL during treatment with ICIs through pharmacological inhibition or by changing diet and lifestyle.

Funding Acknowledgement

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministero della Salute, Ricerca Corrente project
3D global longitudinal strain is the best predictor of late cardiotoxicity in non-Hodgkin's lymphoma
Authors: Mihalcea D , Balinisteanu A , Memis H , Cosmulescu G , Vladareanu A M , Vinereanu D
Published: October 2021

RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in non-Hodgkin's lymphoma (NHL) has a high risk of cardiotoxicity, with increased morbidity and mortality.

Aim

To define new parameters, such as 3D LV deformation, arterial stiffness and biomarkers able to detect late cardiotoxicity.

Methods

54 patients (26 men, 57±10 years) with NHL, scheduled to receive RCHOP, with LVEF>50%, were assessed at baseline, after the 4th cycle of RCHOP and 2 years after completion of therapy. Assessment included 3D echocardiography for LV EF and deformation - longitudinal, radial, circumferential, area strain (LS, RS, CS, AS), Arteriograph for pulse wave velocity (PWV) and biomarkers (troponin I, NT-pro-BNP). Cardiotoxicity was defined as a decrease of LVEF <50%, with >10% from the baseline value.

Results

11 patients (group I) developed cardiotoxicity, while 43 patients did not (group II) (LVEF decreased from 59±3 to 56±2 vs 58±3 to 47±2, p<0.0001). From baseline to 2 years there was a significant reduction of LS, CS and AS, and an increase of arterial stiffness and troponin I; however, changes were greater in group I vs group II (p=0.001) (see table). Even if NT-pro-BNP increased from baseline to 2 years, no significant changes were found between group I and II. Decrease of 3D LVEF correlated with changes of LS, AS, PWV, and troponin (r=0.64, r=0.42, r=−0.37 and r=−0.29, p<0.05). LS reduction after the 4th cycle was the best independent predictor for LVEF decrease after 2 years from therapy completion (R2=0.43, p=0.001); thus, decrease of LS with more than 26% after the 4th RCHOP cycle predicted late cardiotoxicity, after 2 years, with a sensitivity of 87% and specificity of 71% (AUC=0.867).

Conclusion

Assessment of 3D myocardial deformation, arterial stiffness and biomarkers is able to detect late cardiovascular toxicity, and to predict further decline of LVEF in patients with NHL. LS is the best independent predictor for late cardiotoxicity.

Funding Acknowledgement

Type of funding sources: None. 123 Cardiovascular toxicity parameters
Echocardiography and biomarker-based regression models for the detection of preeclampsia in pregnant women
Authors: Gencheva D , Nikolov F P , Uchikova E , Mihaylov R D , Pencheva P G
Published: October 2021

Introduction

Preeclampsia is characterized by more pronounced structural and functional changes in the maternal heart as assed echocardiographically and with biomarkers compared to normal pregnancy. Certain biomarkers and echocardiographic parameters could be combined to create regression models for a more accurate detection of the presence of preeclampsia.

Aim

To create and compare the differentiating abilities of several regression models for statistical certainty in establishing the diagnosis of preeclampsia in pregnant women using echocardiographic parameters and biomarkers.

Materials and methods

A prospective, single-center, clinical-epidemiological study was conducted with the participation of 87 women: 37 women with preeclampsia and 50 maternal and gestational age-matched healthy pregnant controls was conducted in a tertiary university hospital. Sixteen echocardiographic parameters that showed significant differences between the two groups and four serum biomarkers – Placental growth factor (PlGF), Galectin-3, high-sensitivity C-reactive protein and Interleukin-6, were analyzed for the women using ROC curve analysis and binary logistic regression.

Results

Individually PlGF had an AUC of 0.85 for differentiating preeclampsia from normotensive pregnancies, the ratio E/e' medial, the left ventricular global longitudinal strain (LV GLS) and Galectin-3 had AUCs of 0.82, 0.83 and 0.68 respectively. Three regression models were constructed, allowing better differentiation between women with preeclampsia and those with normotensive pregnancies. The model that provided the best accuracy (92%) included PlGF, left ventricular global longitudinal strain, the ratio E/e' medial and Galectin-3 with an AUC of 0.97, sensitivity 94% and specificity 90% for the optimal cut-off value. The model utilizing PlGF, E/e' medial and LV GLS had an accuracy of 90%, AUC 0.95, sensitivity 86% and specificity 92%. The third model consisting of only E/e' medial and LV GLS still had very good differentiating qualities with an AUC 0.88, an accuracy of 83%, sensitivity 86% and specificity 80%.

Conclusion

All three regression models showed better differentiating abilities than PlGF, LV GLS, E/e' medial, Galectin-3 or any other echocardiographic parameter or biomarker alone, which could be promising for their implementation in clinical practice. The utilization of echocardiographic parameters can greatly improve diagnostic accuracy for preeclampsia without raising the cost of the study.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): Medical university - Plovdiv
Pregnancy outcomes in women with severe congenital heart disease – a specialized centre experience
Authors: Ferreira V , Branco Mano T , Rito T , Ilhao Moreira R , Agapito A , Pinto F , Sousa L
Published: October 2021

Introduction

Progress in pediatric cardiology and cardiac surgery has dramatically raised the number of women with severe complex congenital heart disease (SC-CHD) that reach reproductive age. Pregnancy (P) in this group of women has an increased risk of adverse cardiac and neonatal events and its predictive factors are not fully defined. Our purpose was to assess the experience of our center regarding P and neonatal outcomes in women with SC-CHD.

Methods

Retrospective analysis of obstetric data in women with CHD followed at our institution. P and neonatal outcomes were evaluated regarding patients presenting SC-CHD and mild and moderate complexity CHD (MMC-CHD), according to ESC guidelines CHD complexity classification.

Results

The study enrolled 680 women with CHD (median age, 27.2 years) who experienced 1262 pregnancies, resulting in 998 live births. A previous corrective procedure was found in 334 women (49.1%). CHD complexity was considered mild, moderate and severe in 263 (38.7%), 359 (52.8%) and 58 (8.5%), respectively. SC-CHD included 38 women with cyanotic CHD and 18 with pulmonary vascular disease. The most common heart defect in SC-CHD pts was cyanotic tetralogy of Fallot (19.0%), followed by dextro-transposition of the great arteries with atrial switch /palliative procedure (13.8%) – Figure 1.

Pts with SC-CHD had successful deliveries in 56.1% comparing with 82.1% in MMC-CHD. Women with SC-CHD had significantly higher incidence of preterm birth (24.6% vs 7.4%, p<0.001), spontaneous abortion (26.3% vs 12.3%, p=0.004) and neonatal mortality (10.3% vs 2.3%) comparing with MMC-CHD. Low birth weight was also extremely more frequent in the SC-CHD group (44.7% vs 8.5%, p<0.001). No difference was found relating to the presence of CHD in infants from SC-CHD mothers compared to off-spring from MMC-CHD (8.4 vs 5.3%, p=0.407). Cesarian deliveries had similar rates independently of increased CHD complexity (34.2% vs 32.1%). Overall, pregnancy was quite well tolerated, although cardiac complications were more common in SC-CHD P (0.4% vs 4.3%, p 0.013). Only one maternal death was registered, during 1st trimester, in a woman with a large unrepaired ventricular septal defect and cyanosis.

Conclusion

Severe complex CHD remains a challenging condition for pregnancy with increased maternal and neonatal morbimortality. This emphasizes the importance of extensive prepregnancy counselling and centralization of care to address specific risks and requirements of the condition.

Funding Acknowledgement

Type of funding sources: None. Figure 1. Severe CHD
Cardiovascular outcomes in women with the highest classification of maternal cardiovascular risk in pregnancy
Authors: Nashat H , Rocha L , Constantine A , Pires A , Patel R , Swan L , Alexander D , Gatzoulis M A , Johnson M , Dimopoulos K , Rafiq I
Published: October 2021

Introduction

The modified world health organization (mWHO) classification of maternal risk is used to estimate morbidity and mortality in pregnant women with cardiovascular disease. Those in the highest risk category (mWHO Risk Class IV) are at greatest risk. Pregnancy is contraindicated in this patients.

Methods

This was a retrospective review of pregnant women classified as mWHO risk class IV, who were managed in a tertiary joint cardiac-obstetric pathway between 2008 and 2018.

Results

In total, there were 35 pregnancies in 30 women with the highest cardiovascular risk for adverse maternal outcomes. The mean maternal age at delivery was 29.3±5.2 years. Eleven (36%) patients were diagnosed with cardiovascular disease during pregnancy. Fourteen had a form of pulmonary arterial hypertension (46%), 6 (20%) had severe systemic ventricular dysfunction, 4 (13%) had severe mitral or aortic stenosis, 4 (13%) had aortic dilatation or inherited aortopathy, 1 (3%) had a history of peri-partum cardiomyopathy and 1 (3%) had severe native coarctation of the aorta. In the 30 pregnancies followed up in our centre, 29 (96%) were single foetus pregnancies and 1 (4%) was a twin pregnancy. There were 30 live births, 1 foetus was lost in the twin pregnancy. Of these 29 (96%) patients underwent elective caesarean section and 1 (4%) emergency caesarean section. Cardiovascular complications occurred in 18 (60%) women. Of these, 5 (28%) had atrial arrhythmias during pregnancy, 6 (33%) had worsening of pulmonary hypertension, 6 (33%) had decompensated heart failure. Three women had interventions during pregnancy: 1 had percutaneous intervention for coarctation of aorta due to foetal and maternal compromise, 1 had electrophysiological ablation for atrial arrhythmias to improve systemic ventricular function and 1 had an electrical cardioversion for atrial fibrillation. There were no deaths during pregnancy or in the peripartum period. One patient who presented at 34 weeks gestation with severe peripartum cardiomyopathy required early inotropic support followed by extracorporeal membrane oxygenation (ECMO) support post-delivery, died at 2 months post-partum.

Conclusions

With appropriate pre-pregnancy optimization, antepartum surveillance individualised peripartum care plans and multidisciplinary care throughout pregnancy, women at the highest risk for cardiovascular outcomes can have successful pregnancies, although the risk of cardiovascular complications remains high.

Funding Acknowledgement

Type of funding sources: None.