Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer:The CVSS Study

BACKGROUND: The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. METHODS AND RESULTS: A total of 1002 CCSs (age range, 23– 48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age-and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4– 2.8) for HF stage A and 4.6 (95% CI, 4.1– 5.1) for the composite of HF stage B to D in an age-and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (β, −4.30 [95% CI, −5.70 to −2.80]), soft tissue sarcoma (β, −1.60 [95% CI, −2.90 to −0.30]), and renal tumors (β, −1.60 [95% CI, −2.80 to −0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. CONCLUSIONS: The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.</p

Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer:The CVSS Study

BACKGROUND: The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. METHODS AND RESULTS: A total of 1002 CCSs (age range, 23– 48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age-and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4– 2.8) for HF stage A and 4.6 (95% CI, 4.1– 5.1) for the composite of HF stage B to D in an age-and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (β, −4.30 [95% CI, −5.70 to −2.80]), soft tissue sarcoma (β, −1.60 [95% CI, −2.90 to −0.30]), and renal tumors (β, −1.60 [95% CI, −2.80 to −0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. CONCLUSIONS: The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.</p

Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer:The CVSS Study

BACKGROUND: The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. METHODS AND RESULTS: A total of 1002 CCSs (age range, 23– 48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age-and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4– 2.8) for HF stage A and 4.6 (95% CI, 4.1– 5.1) for the composite of HF stage B to D in an age-and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (β, −4.30 [95% CI, −5.70 to −2.80]), soft tissue sarcoma (β, −1.60 [95% CI, −2.90 to −0.30]), and renal tumors (β, −1.60 [95% CI, −2.80 to −0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. CONCLUSIONS: The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.</p

Cardiovascular risk categories in patients with nonalcoholic fatty liver disease and the role of low-density lipoprotein cholesterol

Cardiovascular disease (CVD) is the leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD). The current analysis expands the knowledge on atherogenic lipid profiles in NAFLD by modeling changes in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) in a prospectively enrolling real-life study cohort to inform physicians on the cardiovascular (CV) event risk based on these changes. A total of 304 patients with histologically confirmed NAFLD were included (mean age, 52 years; equal sex distribution). Of these, 129 (42.4%) patients exhibited a NAFLD activity score ≥4 and 186 (61.2%) had at least intermediate fibrosis ≥F2. The median TC levels were 209 mg/dL (interquartile range [IQR], 183, 239), LDL-C 131 mg/dL (IQR, 103, 152), and high density lipoprotein cholesterol (HDL-C) 45 mg/dL (IQR, 38, 52). Only 16.9% of patients received lipid-lowering therapy. According to the LDL/HDL ratio, 69 (23.7%) patients exhibited a high CV risk. The 10-year CV event risk according to the Framingham risk score (FRS) was low in 91 (41.2%), intermediate in 59 (26.7%), and high in 71 (32.1%) patients and higher in the ≥F2 NAFLD population. A moderate increase in LDL-C levels by 20 mg/dL led to a transition of 20% of patients into the high-risk group when assessing the LDL/HDL ratio. According to the FRS, 6 (2.7%) patients moved from low to intermediate and 11 (4.9%) from intermediate to high CV risk. Conclusion: Patients with NAFLD exhibit a substantial CV event risk and are frequently undertreated with lipid-lowering medication. Moderate increases in LDL-C would result in worsening of the CV event risk in approximately 7.8% of all patients without a history of CVD. E

Quality of life in patients with transcatheter aortic valve implantation: an analysis from the INTERVENT project

BackgroundTranscatheter aortic valve implantation (TAVI) is a standard treatment for patients with aortic valve stenosis due to its very low mortality and complication rates. However, survival and physical integrity are not the only important factors. Quality of life (QoL) improvement is a crucial part in the evaluation of therapy success.MethodsPatients with TAVI were questioned about their QoL before, one month and one year after the intervention as part of the INTERVENT registry trial at Mainz University Medical Center. Three different questionnaires were included in the data collection (Katz ADL, EQ-5D-5l, PHQ-D).ResultsWe included 285 TAVI patients in the analysis (mean age 79.8 years, 59.4% male, mean EuroSCORE II 3.8%). 30-day mortality was 3.6%, complications of any kind occurred in 18.9% of the patients. Main finding was a significant increase in the general state of health measured on the visual analog scale by an average of 4.53 (± 23.58) points (BL to 1-month follow-up, p = 0.009) and by 5.19 (± 23.64) points (BL to 12-month follow-up, p = 0.016). There was also an improvement of depression symptoms, which was reflected in a decrease in the total value of the PHQ-D by 1.67 (± 4.75) points (BL to 12-month follow-up, p = 0.001). The evaluation of the EQ-5D-5l showed a significant improvement in mobility after one month (M = −0.41 (± 1.31), p &lt; 0.001. Regarding the independence of the patients, no significant difference could be found. Apart from that, patients with risk factors, comorbidities or complications also benefited from the intervention despite their poor starting position.ConclusionWe could show an early benefit of QoL in TAVI patients with significant improvement in the subjective state of health and a decrease in symptoms of depression. These findings were consistent over 1 year of follow up

Atherosclerosis and Its Impact on the Outcomes of Patients with Deep Venous Thrombosis

Introduction: Atherosclerosis and pulmonary embolism (PE) affect cardiovascular mortality substantially. We aimed to investigate the impact of atherosclerosis on the outcomes of patients with deep venous thrombosis (DVT) and to identify the differences in DVT patients with and without PE. Methods: Patients with DVT with and without symptomatic atherosclerosis (defined as coronary artery disease, myocardial infarction and/or peripheral artery disease) as well as with and without PE under oral anticoagulation were enrolled during January 2011–April 2013 and compared. The impact of symptomatic atherosclerosis on several outcomes was analyzed. Results: Overall, 509 DVT patients (70.0 [56.0–77.0] years, 51.9% females) were included in this study. Among them, 179 (36.3%) had symptomatic atherosclerosis and 204 (40.1%) a concomitant PE. DVT patients with symptomatic atherosclerosis were older (74.0 [IQR 65.0–80.0] vs. 63.0 [48.0–75.0] years, p p = 0.0087) and had a higher prevalence of classical CVRF and a higher Charlson comorbidity index (7.00 [5.00–8.00] vs. 4.00 [2.00–6.00], p p = 0.018) and hospitalizations (HR 1.64 [95%CI 1.21–2.21], p = 0.0012) and primary long-term outcome (HR 1.99 [95%CI 1.31–3.04], p = 0.0013) during the 2 years follow-up-period in DVT patients. DVT patients without PE had diabetes mellitus (28.2% vs. 16.3%, p p p < 0.01). Conclusions: Atherosclerosis was associated with isolated DVT (without PE) and increased mortality in DVT patients under oral anticoagulation. The profile of CVRF and comorbidities differed between DVT patients with and without a concomitant PE. In the case of DVT or PE, patients should be screened for concomitant atherosclerotic disease. Clinical Trial Registration: at clinicaltrials with Unique identifier NCT01809015

DNA methylation and cardiovascular disease in humans: a systematic review and database of known CpG methylation sites

Abstract Background Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking. Results A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function “DNA-binding transcription activator activity” (q = 1.65 × 10–11) and biological processes “skeletal system development” (q = 1.89 × 10–23). Gene enrichment demonstrated that general CVD-related terms are shared, while “heart” and “vasculature” specific genes have more disease-specific terms as PR interval for “heart” or platelet distribution width for “vasculature.” STRING analysis revealed significant protein–protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10–6) and atherosclerosis (p = 4.9 × 10–4). Conclusion This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship

Endothelial function assessed by digital volume plethysmography predicts the development and progression of type 2 diabetes mellitus

Background Endothelial dysfunction is a consequence of type 2 diabetes mellitus, but it is unclear whether endothelial dysfunction of conductance versus resistance vessels may also precede type 2 diabetes mellitus development. Methods and Results In a population‐based cohort of 15 010 individuals from the GHS (Gutenberg Health Study) (aged 35–74 years at enrollment in 2007–2012), we identified 1610 cases of incident pre–diabetes mellitus and 386 cases of incident type 2 diabetes mellitus by hemoglobin A1c (HbA1c) and/or medical history between 2012 and 2017. Endothelial function of conductance and resistance vessels was measured by flow‐mediated dilation and digital volume plethysmography–derived reactive hyperemia index, respectively. Multivariable regression modeling was used to estimate β coefficients of HbA1c levels at follow‐up and relative risks of incident (pre–)diabetes mellitus. Reactive hyperemia index was independently associated with HbA1c after multivariable adjustment for baseline HbA1c, sex, age, socioeconomic status, arterial hypertension, waist/height ratio, pack‐years of smoking, non–high‐density lipoprotein/high‐density lipoprotein ratio, physical activity, family history of myocardial infarction/stroke, prevalent cardiovascular disease, medication use, and C‐reactive protein (β=−0.020; P=0.0029). The adjusted relative risk per SD decline in reactive hyperemia index was 1.08 (95% CI, 1.02–1.15; P=0.012) for incident pre–diabetes mellitus and 1.16 (95% CI, 1.01–1.34; P=0.041) for incident type 2 diabetes mellitus. Flow‐mediated dilation independently increased the relative risk for developing pre–diabetes mellitus by 8% (95% CI, 1.02–1.14; P=0.012), but it was not independently associated with incident type 2 diabetes mellitus (relative risk, 1.01; 95% CI, 0.86–1.19; P=0.92) and with HbA1c (β=−0.003; P=0.59). Conclusions Endothelial dysfunction of resistance rather than conductance vessels may precede the development of (pre–)diabetes mellitus. Assessment of endothelial function by digital volume plethysmography may help to identify subjects at risk for development of type 2 diabetes mellitus

Clinical profile and outcome of isolated pulmonary embolism: a systematic review and meta-analysisResearch in context

Summary: Background: Isolated pulmonary embolism (PE) appears to be associated with a specific clinical profile and sequelae compared to deep vein thrombosis (DVT)-associated PE. The objective of this study was to identify clinical characteristics that discriminate both phenotypes, and to characterize their differences in clinical outcome. Methods: We performed a systematic review and meta-analysis of studies comparing PE phenotypes. A systematic search of the electronic databases PubMed and CENTRAL was conducted, from inception until January 27, 2023. Exclusion criteria were irrelevant content, inability to retrieve the article, language other than English or German, the article comprising a review or case study/series, and inappropriate study design. Data on risk factors, clinical characteristics and clinical endpoints were pooled using random-effects meta-analyses. Findings: Fifty studies with 435,768 PE patients were included. In low risk of bias studies, 30% [95% CI 19–42%, I2 = 97%] of PE were isolated. The Factor V Leiden [OR: 0.47, 95% CI 0.37–0.58, I2 = 0%] and prothrombin G20210A mutations [OR: 0.55, 95% CI 0.41–0.75, I2 = 0%] were significantly less prevalent among patients with isolated PE. Female sex [OR: 1.30, 95% CI 1.17–1.45, I2 = 79%], recent invasive surgery [OR: 1.31, 95% CI 1.23–1.41, I2 = 65%], a history of myocardial infarction [OR: 2.07, 95% CI 1.85–2.32, I2 = 0%], left-sided heart failure [OR: 1.70, 95% CI 1.37–2.10, I2 = 76%], peripheral artery disease [OR: 1.36, 95% CI 1.31–1.42, I2 = 0%] and diabetes mellitus [OR: 1.23, 95% CI 1.21–1.25, I2 = 0%] were significantly more frequently represented among isolated PE patients. In a synthesis of clinical outcome data, the risk of recurrent VTE in isolated PE was half that of DVT-associated PE [RR: 0.55, 95% CI 0.44–0.69, I2 = 0%], while the risk of arterial thrombosis was nearly 3-fold higher [RR: 2.93, 95% CI 1.43–6.02, I2 = 0%]. Interpretation: Our findings suggest that isolated PE appears to be a specific entity that may signal a long-term risk of arterial thrombosis. Randomised controlled trials are necessary to establish whether alternative treatment regimens are beneficial for this patient subgroup. Funding: None

Disturbed Glucose Metabolism and Left Ventricular Geometry in the General Population

Background: This study sought to investigate the prevalence and clinical outcome of left ventricular (LV) geometry in prediabetes and type 2 diabetes mellitus (T2DM) and the impact of glucose metabolism on the incidence of left ventricular hypertrophy (LVH). Methods: 15,010 subjects (35–74 years) of the population-based Gutenberg Health Study were categorized into euglycemia, prediabetes, and T2DM according to clinical and metabolic (HbA1c) information. Clinical outcome was assessed via structured follow-up. Results: The study comprised 12,121 individuals with euglycemia (81.6%), 1415 with prediabetes (9.5%), and 1316 with T2DM (8.9%). Prevalence of LVH increased from euglycemia (10.2%) over prediabetes (17.8%) to T2DM (23.8%). Prediabetes and T2DM were associated with increased LV mass index (prediabetes: β1.3 (95% CI 0.78–1.81), p &lt; 0.0001; T2DM: β2.37 (95% CI 1.81; 2.92), p &lt; 0.0001) independent of age, sex, and cardiovascular risk factors (CVRF). The frequency of LVH was related to the presence of T2DM (prevalence ratio (PR)T2DM 1.2 (95% CI 1.06–1.35), p = 0.0038). T2DM was related to mortality independent of age, sex, and CVRF regardless of LVH (hazard ratio (HR)T2DM-LVH 2.67 (95% CI 1.94–3.66), p &lt; 0.0001; HRT2DM-noLVH 1.59 (95% CI 1.29–1.96), p &lt; 0.0001), prediabetes was only associated with outcome in individuals with LVH independent of age and sex (HRprediabetes-LVH 1.51 (95% CI 1.01–2.25), p = 0.045). Neither T2DM nor prediabetes were predictors of incident LVH after adjustment for clinical covariates. Conclusions: Prediabetes and T2DM promote alterations of cardiac geometry. T2DM and particularly the coprevalence of T2DM with LVH substantially reduce life expectancy. These findings highlight the need for new therapeutic and screening approaches to prevent and detect cardiometabolic diseases at an early stage