Highlights • Truncating titin variants are found in chemotherapy-induced cardiomyopathy • Phenotypic expression after chemotherapy illustrates a second-hit like phenomenon • Genetic testing prior to ...chemotherapy may improve risk stratification
In the past decade many Genome-wide Association Studies (GWAS) were performed that discovered new associations between single-nucleotide polymorphisms (SNPs) and various phenotypes. Imputation ...methods are widely used in GWAS. They facilitate the phenotype association with variants that are not directly genotyped. Imputation methods can also be used to combine and analyse data genotyped on different genotyping arrays. In this study we investigated the imputation quality and efficiency of two different approaches of combining GWAS data from different genotyping platforms. We investigated whether combining data from different platforms before the actual imputation performs better than combining the data from different platforms after imputation.
In total 979 unique individuals from the AMC-PAS cohort were genotyped on 3 different platforms. A total of 706 individuals were genotyped on the MetaboChip, a total of 757 individuals were genotyped on the 50K gene-centric Human CVD BeadChip, and a total of 955 individuals were genotyped on the HumanExome chip. A total of 397 individuals were genotyped on all 3 individual platforms. After pre-imputation quality control (QC), Minimac in combination with MaCH was used for the imputation of all samples with the 1,000 genomes reference panel. All imputed markers with an r2 value of <0.3 were excluded in our post-imputation QC.
A total of 397 individuals were genotyped on all three platforms. All three datasets were carefully matched on strand, SNP ID and genomic coordinates. This resulted in a dataset of 979 unique individuals and a total of 258,925 unique markers. A total of 4,117,036 SNPs were available when imputation was performed before merging the three datasets. A total of 3,933,494 SNPs were available when imputation was done on the combined set. Our results suggest that imputation of individual datasets before merging performs slightly better than after combining the different datasets.
Imputation of datasets genotyped by different platforms before merging generates more SNPs than imputation after putting the datasets together.
Amyloidosis is a collection of systemic diseases characterised by misfolding of previously soluble precursor proteins that become infiltrative depositions, thereby disrupting normal organ structure ...and function. In the heart, accumulating amyloid fibrils lead to progressive ventricular wall thickening and stiffness, resulting in diastolic dysfunction gradually progressing to a restrictive cardiomyopathy. The main types of cardiac amyloidosis are amyloid light chain (AL) amyloidosis caused by an underlying plasma cell dyscrasia, amyloid transthyretin (TTR) amyloidosis of wild-type (normal) TTR at older age (ATTRwt) and hereditary or mutant amyloid TTR (ATTRm) in which a genetic mutation leads to an unstable TTR protein. Overall survival is poor once heart failure develops, underlining the need for early referral and diagnosis. Treatment for AL amyloidosis has improved markedly over the last decades, and TTR amyloidosis gene silencers and orally available transthyretin stabilisers are ready to enter the clinical arena after recent positive outcome trials. Novel therapies aiming at fibril degradation with monoclonal antibodies are under investigation. In this review, we focus on ‘red flag’ signs and symptoms, diagnosis and management of cardiac amyloidosis which differs considerably from the general management of heart failure. Only by increasing awareness, prognosis for patients with this devastating disease can be improved.
Vaccines against coronavirus 2019 disease (COVID-19) have shown to be greatly effective in preventing viral spread, serious illness and death from this infectious disease and are therefore critical ...for the management of the COVID-19 pandemic. However, the listing of myocarditis and pericarditis as possible rare side effects of the messenger RNA (mRNA) vaccines against COVID-19 by regulatory agencies has sparked discussion on the vaccines’ safety. The most important published cohort studies to date demonstrat that myocarditis is a very rare side effect after COVID-19 mRNA vaccination, with an incidence of approximately 1–4 cases per 100,000 vaccinated persons. Young males (16–29 years) appear to be at highest risk, predominantly after receiving the second dose. The disease course is self-limiting in a vast majority of cases: 95% of patients show a rapid resolution of symptoms and normalisation of cardiac biomarkers, electro- and echocardiographic findings within days. Importantly, the available data suggest that the incidence rate of myocarditis in the context of COVID-19 is much greater than the risk of this side effect following vaccination. We conclude that the benefit of vaccination against COVID-19 outweighs the potential risk of myocarditis and pericarditis in both adolescents and adults. Prospective follow-up of patients who have developed these complications after vaccination is required to assess long-term outcomes.
Antiplatelet therapy is the standard treatment for the prevention of cardiovascular events (CVEs). High on-treatment platelet reactivity (HPR) is a risk factor for secondary CVEs in patients ...prescribed aspirin and/or clopidogrel. The present review and meta-analysis was aimed at assessing the ability of individual platelet-function tests to reliably identify patients at risk of developing secondary CVEs.
A systematic literature search was conducted to identify studies on platelet-reactivity measurements and CVEs. The main inclusion criteria were: (i) prospective study design; (ii) study medication, including aspirin and/or clopidogrel; and (iii) a platelet-function test being performed at baseline, before follow-up started. Of 3882 identified studies, 102 (2.6%; reporting on 44 098 patients) were included in the meta-analysis. With regard to high on-aspirin platelet reactivity (HAPR), 22 different tests were discussed in 55 studies (22 441 patients). Pooled analysis showed that HAPR was diagnosed in 22.2% of patients, and was associated with an increased CVE risk (relative risk RR 2.09; 95% confidence interval CI 1.77-2.47). Eleven HAPR tests independently showed a significantly increased CVE risk in patients with HAPR as compared with those with normal on-aspirin platelet reactivity. As regards high on-clopidogrel platelet reactivity (HCPR), 59 studies (34 776 patients) discussed 15 different tests, and reported that HCPR was present in 40.4% of patients and was associated with an increased CVE risk (RR 2.80; 95% CI 2.40-3.27). Ten tests showed a significantly increased CVE risk.
Patients with HPR are suboptimally protected against future cardiovascular complications. Furthermore, not all of the numerous platelet tests proved to be able to identify patients at increased cardiovascular risk.
Pharmacological lowering of inflammation has proven effective in reducing recurrent cardiovascular event rates. Aim of the current study is to evaluate lifestyle changes (smoking cessation, weight ...loss, physical activity level increase, alcohol moderation, and a summary lifestyle improvement score) in relation to change in plasma C-reactive protein (CRP) concentration in patients with established cardiovascular disease.
In total, 1794 patients from the UCC-SMART cohort with stable cardiovascular disease and CRP levels ≤10 mg/L, who returned for a follow-up study visit after median 9.9 years (IQR 5.4–10.8), were included. The relation between changes in smoking status, weight, physical activity, alcohol consumption, a summary lifestyle improvement score and change in plasma CRP concentration was evaluated with linear regression analyses.
Smoking cessation was related to a 0.40 mg/L decline in CRP concentration (β-coefficient −0.40; 95%CI -0.73,-0.07). Weight loss (per 1SD = 6.4 kg) and increase in physical activity (per 1 SD = 48 MET hours per week) were related to a decrease in CRP concentration (β-coefficients −0.25; 95%CI -0.33,-0.16 and −0.09; 95%CI -0.17,-0.01 per SD). Change in alcohol consumption was not related to CRP difference. Every point higher in the summary lifestyle improvement score was related to a decrease in CRP concentration of 0.17 mg/L (β-coefficient −0.17; 95%CI -0.26,-0.07).
Smoking cessation, increase in physical activity, and weight loss are related to a decrease in CRP concentration in patients with stable cardiovascular disease. Patients with the highest summary lifestyle improvement score have the most decrease in CRP concentration. These results may indicate that healthy lifestyle changes contribute to lowering systemic inflammation, potentially leading to a lower cardiovascular risk in patients with established cardiovascular disease.
Display omitted
•In patients with established cardiovascular disease (CVD), lifestyle improvements are related to a decrease in C-reactive protein (CRP).•These lifestyle improvements are smoking cessation, physical activity increase, and weight loss.•Multiple lifestyle changes are related to the most decrease in CRP concentration.•Lifestyle changes might reduce CVD risk partly through lowering systemic inflammation.
Background
Clinical management of heart failure with preserved ejection fraction (HFpEF) centres on treating comorbidities and is likely to vary between countries. Thus, to provide insight into the ...current management of HFpEF, studies from multiple countries are required. We evaluated the clinical profiles and current management of patients with HFpEF in the Netherlands.
Methods
We included 2153 patients with HFpEF (defined as a left ventricular ejection fraction ≥ 50%) from the CHECK-HF registry, which included patients from 2013 to 2016.
Results
Median age was 77 (IQR 15) years, 55% were women and the most frequent comorbidities were hypertension (51%), renal insufficiency (45%) and atrial fibrillation (AF, 38%). Patients between 65 and 80 years and those over 80 years had on average more comorbidities (up to 64% and 74%, respectively, with two or more comorbidities) than patients younger than 65 years (38% with two or more comorbidities,
p
-value < 0.001). Although no specific drugs are available for HFpEF, treating comorbidities is advised. Beta-blockers were most frequently prescribed (78%), followed by loop diuretics (74%), renin-angiotensin system (RAS) inhibitors (67%) and mineralocorticoid receptor antagonists (MRAs, 39%). Strongest predictors for loop-diuretic use were older age, higher New York Heart Association class and AF.
Conclusion
The medical HFpEF profile is determined by the underlying comorbidities, sex and age. Comorbidities are highly prevalent in HFpEF patients, especially in elderly HFpEF patients. Despite the lack of evidence, many HFpEF patients receive regular beta-blockers, RAS inhibitors and MRAs, often for the treatment of comorbidities.
Existing cardiovascular risk scores for patients with established cardiovascular disease (CVD) estimate residual risk of recurrent major cardiovascular events (MACE). The aim of the current study is ...to develop and externally validate a prediction model to estimate the 10-year combined risk of recurrent MACE and cardiovascular interventions (MACE+) in patients with established CVD.
Data of patients with established CVD from the UCC-SMART cohort (N = 8421) were used for model development, and patient data from REACH Western Europe (N = 14,528) and REACH North America (N = 19,495) for model validation. Predictors were selected based on the existing SMART risk score. A Fine and Gray competing risk-adjusted 10-year risk model was developed for the combined outcome MACE+. The model was validated in all patients and in strata of coronary heart disease (CHD), cerebrovascular disease (CeVD), peripheral artery disease (PAD).
External calibration for 2-year risk in REACH Western Europe and REACH North America was good, c-statistics were moderate: 0.60 and 0.58, respectively. In strata of CVD at baseline good external calibration was observed in patients with CHD and CeVD, however, poor calibration was seen in patients with PAD. C-statistics for patients with CHD were 0.60 and 0.57, for patients with CeVD 0.62 and 0.61, and for patients with PAD 0.53 and 0.54 in REACH Western Europe and REACH North America, respectively.
The 10-year combined risk of recurrent MACE and cardiovascular interventions can be estimated in patients with established CHD or CeVD. However, cardiovascular interventions in patients with PAD could not be predicted reliably.
•Risk of cardiovascular events and interventions combined (MACE+) is a relevant estimation of an individual's prognosis.•The current model predicts 10-year risk of MACE+ for a patient with CHD or CeVD.•Cardiovascular interventions in patients with PAD could not be predicted reliably.•Future studies could aim to increase model performance in patients with PAD.
To determine the (cost)-effectiveness of blood pressure lowering, lipid-lowering, and antithrombotic therapy guided by predicted lifetime benefit compared to risk factor levels in patients with ...symptomatic atherosclerotic disease.
For all patients with symptomatic atherosclerotic disease in the UCC-SMART cohort (1996-2018; n = 7697) two treatment strategies were compared. The lifetime benefit-guided strategy was based on individual estimation of gain in cardiovascular disease (CVD)-free life with the SMART-REACH model. In the risk factor-based strategy, all patients were treated the following: low-density lipoprotein cholesterol (LDL-c) < 1.8 mmol/L, systolic blood pressure <140 mmHg, and antithrombotic medication. Outcomes were evaluated for the total cohort using a microsimulation model. Effectiveness was evaluated as total gain in CVD-free life and events avoided, cost-effectiveness as incremental cost-effectivity ratio (ICER). In comparison to baseline treatment, treatment according to lifetime benefit would lead to an increase of 24 243 CVD-free life years 95% confidence interval (CI) 19 980-29 909 and would avoid 940 (95% CI 742-1140) events in the next 10 years. For risk-factor based treatment, this would be an increase of 18 564 CVD-free life years (95% CI 14 225-20 456) and decrease of 857 (95% CI 661-1057) events. The ICER of lifetime benefit-based treatment with a treatment threshold of ≥1 year additional CVD-free life per therapy was €15 092/QALY gained and of risk factor-based treatment €9933/QALY gained. In a direct comparison, lifetime benefit-based treatment compared to risk factor-based treatment results in 1871 additional QALYs for the price of €36 538/QALY gained.
Residual risk reduction guided by lifetime benefit estimation results in more CVD-free life years and more CVD events avoided compared to the conventional risk factor-based strategy. Lifetime benefit-based treatment is an effective and potentially cost-effective strategy for reducing residual CVD risk in patients with clinical manifest vascular disease.
Abstract
Aims
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by ventricular dysfunction and ventricular arrhythmias (VA). Adequate arrhythmic risk assessment is important to ...prevent sudden cardiac death. We aimed to study the incremental value of strain by feature-tracking cardiac magnetic resonance imaging (FT-CMR) in predicting sustained VA in ARVC patients.
Methods and results
CMR images of 132 ARVC patients (43% male, 40.6 ± 16.0 years) without prior VA were analysed for global and regional right and left ventricular (RV, LV) strain. Primary outcome was sustained VA during follow-up. We performed multivariable regression assessing strain, in combination with (i) RV ejection fraction (EF); (ii) LVEF; and (iii) the ARVC risk calculator. False discovery rate adjusted P-values were given to correct for multiple comparisons and c-statistics were calculated for each model. During 4.3 (2.0–7.9) years of follow-up, 19% of patients experienced sustained VA. Compared to patients without VA, those with VA had significantly reduced RV longitudinal (P ≤ 0.03) and LV circumferential (P ≤ 0.04) strain. In addition, patients with VA had significantly reduced biventricular EF (P ≤ 0.02). After correcting for RVEF, LVEF, and the ARVC risk calculator separately in multivariable analysis, both RV and LV strain lost their significance hazard ratio 1.03–1.18, P > 0.05. Likewise, while strain improved the c-statistic in combination with RVEF, LVEF, and the ARVC risk calculator separately, this did not reach statistical significance (P ≥ 0.18).
Conclusion
Both RV longitudinal and LV circumferential strain are reduced in ARVC patients with sustained VA during follow-up. However, strain does not have incremental value over RVEF, LVEF, and the ARVC VA risk calculator.
Graphical Abstract
Graphical Abstract
PDF
