Does Heterogeneity Exist in Treatment Associations With Renin–Angiotensin–System Inhibitors or Beta-blockers According to Phenotype Clusters in Heart Failure with Preserved Ejection Fraction?

BACKGROUND: We explored the association between use of renin–angiotensin system inhibitors and beta-blockers, with mortality/morbidity in 5 previously identified clusters of patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analyzed 20,980 patients with HFpEF from the Swedish HF registry, phenotyped into young–low comorbidity burden (12%), atrial fibrillation–hypertensive (32%), older–atrial fibrillation (24%), obese–diabetic (15%), and a cardiorenal cluster (17%). In Cox proportional hazard models with inverse probability weighting, there was no heterogeneity in the association between renin–angiotensin system inhibitor use and cluster membership for any of the outcomes: cardiovascular (CV) mortality, all-cause mortality, HF hospitalisation, CV hospitalisation, or non-CV hospitalisation. In contrast, we found a statistical interaction between beta-blocker use and cluster membership for all-cause mortality (P = .03) and non-CV hospitalisation (P = .001). In the young–low comorbidity burden and atrial fibrillation–hypertensive cluster, beta-blocker use was associated with statistically significant lower all-cause mortality and non-CV hospitalisation and in the obese–diabetic cluster beta-blocker use was only associated with a statistically significant lower non-CV hospitalisation. The interaction between beta-blocker use and cluster membership for all-cause mortality could potentially be driven by patients with improved EF. However, patient numbers were diminished when excluding those with improved EF and the direction of the associations remained similar. CONCLUSIONS: In patients with HFpEF, the association with all-cause mortality and non-CV hospitalisation was heterogeneous across clusters for beta-blockers. It remains to be elucidated how heterogeneity in HFpEF could influence personalized medicine and future clinical trial design

Discovering Distinct Phenotypical Clusters in Heart Failure Across the Ejection Fraction Spectrum: a Systematic Review

Review Purpose: This systematic review aims to summarise clustering studies in heart failure (HF) and guide future clinical trial design and implementation in routine clinical practice. Findings: 34 studies were identified (n = 19 in HF with preserved ejection fraction (HFpEF)). There was significant heterogeneity invariables and techniques used. However, 149/165 described clusters could be assigned to one of nine phenotypes: 1) young, low comorbidity burden; 2) metabolic; 3) cardio-renal; 4) atrial fibrillation (AF); 5) elderly female AF; 6) hypertensive-comorbidity; 7) ischaemic-male; 8) valvular disease; and 9) devices. There was room for improvement on important methodological topics for all clustering studies such as external validation and transparency of the modelling process. Summary: The large overlap between the phenotypes of the clustering studies shows that clustering is a robust approach for discovering clinically distinct phenotypes. However, future studies should invest in a phenotype model that can be implemented in routine clinical practice and future clinical trial design. Graphical Abstract: HF = heart failure, EF = ejection fraction, HFpEF = heart failure with preserved ejection fraction, HFrEF = heart failure with reduced ejection fraction, CKD = chronic kidney disease, AF = atrial fibrillation, IHD = ischaemic heart disease, CAD = coronary artery disease, ICD = implantable cardioverter-defibrillator, CRT = cardiac resynchronization therapy, NT-proBNP = N-terminal pro b-type natriuretic peptide, BMI = Body Mass Index, COPD = Chronic obstructive pulmonary disease

Heart disease in the Netherlands: A quantitative update

In this review we discuss cardiovascular mortality, incidence and prevalence of heart disease, and cardiac interventions and surgery in the Netherlands. We combined most recently available data from various Dutch cardiovascular registries, Dutch Hospital Data (LMR), Statistics Netherlands (CBS), and population-based cohort studies, to provide a broad quantitative update. The absolute number of people dying from cardiovascular diseases is declining and cardiovascular conditions are no longer the leading cause of death in the Netherlands. However, a substantial burden of morbidity persists with 400,000 hospitalisations for cardiovascular disease involving over 80,000 cardiac interventions annually. In the Netherlands alone, an estimated 730,000 persons are currently diagnosed with coronary heart disease, 120,000 with heart failure, and 260,000 with atrial fibrillation. These numbers emphasise the continuous need for dedicated research on prevention, diagnosis, and treatment of heart disease in our country

Effect of acute exercise on uncoupling protein 3 is a fat metabolism-mediated effect

Department of Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands. [email protected] Human and rodent uncoupling protein (UCP)3 mRNA is upregulated after acute exercise. Moreover, exercise increases plasma levels of free fatty acid (FFA), which are also known to upregulate UCP3. We investigated whether the upregulation of UCP3 after exercise is an effect of exercise per se or an effect of FFA levels or substrate oxidation. Seven healthy untrained men [age: 22.7 +/- 0.6 yr; body mass index: 23.8 +/- 1.0 kg/m(2); maximal O2 uptake (VO2 max): 3,852 +/- 211 ml/min] exercised at 50% VO2 max for 2 h and then rested for 4 h. Muscle biopsies and blood samples were taken before and immediately after 2 h of exercise and 1 and 4 h in the postexercise period. To modulate plasma FFA levels and fat/glucose oxidation, the experiment was performed two times, one time with glucose ingestion and one time while fasting. UCP3 mRNA and UCP3 protein were determined by RT-competitive PCR and Western blot. In the fasted state, plasma FFA levels significantly increased (P < 0.0001) during exercise (293 +/- 25 vs. 1,050 +/- 127 micromol/l), whereas they were unchanged after glucose ingestion (335 +/- 54 vs. 392 +/- 74 micromol/l). Also, fat oxidation was higher after fasting (P < 0.05), whereas glucose oxidation was higher after glucose ingestion (P < 0.05). In the fasted state, UCP3L mRNA expression was increased significantly (P < 0.05) 4 h after exercise (4.6 +/- 1.2 vs. 9.6 +/- 3.3 amol/microg RNA). This increase in UCP3L mRNA expression was prevented by glucose ingestion. Acute exercise had no effect on UCP3 protein levels. In conclusion, we found that acute exercise had no direct effect on UCP3 mRNA expression. Abolishing the commonly observed increase in plasma FFA levels and/or fatty acid oxidation during and after exercise prevents the upregulation of UCP3 after acute exercise. Therefore, the previously observed increase in UCP3 expression appears to be an effect of prolonged elevation of plasma FFA levels and/or increased fatty acid oxidation

Long-term survival after initial hospital admission for peripheral arterial disease in the lower extremities

ABSTRACT: Background As the population ages, peripheral arterial disease (PAD) in the lower extremities will become a larger public health problem. Awareness in patients as well clinicians of the high risk of morbidity and mortality is important but seems currently low. Insights in absolute mortality risks following admission for PAD in the lower extremities can be useful to improve awareness as they are easy to interpret. Methods A nationwide cohort of 4,158 patients with an initial admission for PAD in the lower extremities was identified through linkage of the national hospital and population register in 1997 and 2000. Results Over 60% of 4,158 patients were men. 28 days, 1 year and 5 year mortality risk were 2.4%, 10.3% and 31.0% for men and 3.5%, 10.4% and 27.4% for women. Coronary heart disease and stroke were frequent cause of death. Five years mortality risk was higher for men compared to women (HR 1.36, 95% CI 1.21-1.53). Conclusions Our findings demonstrate that, 5 year mortality risk is high, especially in men and comparable to that of patients admitted for acute myocardial infarction or ischemic stroke. Though, in general population the awareness of the severity of PAD in the lower extremities is significantly lower than that for any other cardiovascular disease and it seems that cardiovascular risk factor management for prevention in PAD patients is very modes

Development of an objectively measured walkability index for the Netherlands

Background Walkability indices have been developed and linked to behavioural and health outcomes elsewhere in the world, but not comprehensively for Europe. We aimed to 1) develop a theory-based and evidence-informed Dutch walkability index, 2) examine its cross-sectional associations with total and purpose-specific walking behaviours of adults across socioeconomic (SES) and urbanisation strata, 3) explore which walkability components drive these associations. Methods Components of the index included: population density, retail and service density, land use mix, street connectivity, green space, sidewalk density and public transport density. Each of the seven components was calculated for three Euclidean buffers: 150 m, 500 m and 1000 m around every 6-digit postal code location and for every administrative neighbourhood in GIS. Componential z-scores were averaged, and final indices normalized between 0 and 100. Data on self-reported demographic characteristics and walking behaviours of 16,055 adult respondents (aged 18–65) were extracted from the Dutch National Travel Survey 2017. Using Tobit regression modelling adjusted for individual- and household-level confounders, we assessed the associations between walkability and minutes walking in total, for non-discretionary and discretionary purposes. By assessing the attenuation in associations between partial indices and walking outcomes, we identified which of the seven components drive these associations. We also tested for effect modification by urbanization degree, SES, age and sex. Results In fully adjusted models, a 10% increase in walkability was associated with a maximum increase of 8.5 min of total walking per day (95%CI: 7.1–9.9). This association was consistent across buffer sizes and purposes of walking. Public transport density was driving the index’s association with walking outcomes. Stratified results showed that associations with minutes of non-discretionary walking were stronger in rural compared to very urban areas, in neighbourhoods with low SES compared to high SES, and in middle-aged (36–49 years) compared to young (18–35 years old) and older adults (50–65 years old). Conclusions The walkability index was cross-sectionally associated with Dutch adult’s walking behaviours, indicating its validity for further use in research

Surgery in Adults With Congenital Heart Disease

Background-A significant proportion of patients with congenital heart disease require surgery in adulthood. We aimed to give an overview of the prevalence, distribution, and outcome of cardiovascular surgery for congenital heart disease. We specifically questioned whether the effects of surgical treatment on subsequent long-term survival depend on sex. Methods and Results-From the Dutch Congenital Corvitia (CONCOR) registry for adults with congenital heart disease, we identified 10 300 patients; their median age was 33.1 years. Logistic and Cox regression models were used to assess the association of surgery in adulthood with sex and with long-term survival. In total, 2015 patients (20%) underwent surgery for congenital heart disease in adulthood during a median follow-up period of 15.1 years; in 812 patients (40%), it was a reoperation. Overall, both first operations and reoperations in adulthood were performed significantly more often in men compared with women (adjusted odds ratio = 1.4 [95% confidence interval, 1.2-1.6] and 1.2 [95% confidence interval, 1.0-1.4], respectively). Patients with their third and fourth or more surgery in adulthood had a 2- and 3-times-higher risk of death compared with patients never operated on (adjusted hazard ratio = 1.9 [95% confidence interval, 1.0-3.6] and 2.7 [95% confidence interval, 1.1-6.3], respectively). Men with a reoperation in adulthood had a 2-times-higher risk of death than women (adjusted hazard ratio = 1.9; 95% confidence interval, 1.0-3.5). Conclusions-Of predominantly young adults with congenital heart disease, one fifth required cardiovascular surgery during a 15-year period; in 40%, the surgery was a reoperation. Men with congenital heart disease have a higher chance of undergoing surgery in adulthood and have a consistently worse long-term survival after reoperations in adulthood compared with women. (Circulation. 2011;124:2195-2201.