Lifestyle and heart rate variability in the general population

Background: Cardiovascular diseases (CVD) are among the main causes of death worldwide. An unhealthy lifestyle, sleep-related breathing disorders and inflammation are all significantly and independently associated with an increased risk of cardiovascular events. The autonomic nervous system (ANS) is an important player within the cardiovascular system. Over the last years, heart rate variability (HRV) has become a validated measure of the autonomic function and was found to be associated with several cardiovascular risk factors, disease outcomes and mortality. To date, several aspects related to HRV among young adults remain unclear. Based on those gaps of knowledge, the general aim of this PhD thesis was to assess the relationships of HRV with lifestyle, sleep-related breathing disorders and inflammatory biomarkers among young and healthy adults from the general population. The specific aims were 1) to evaluate the prevalence of a healthy lifestyle and assess its relationship with HRV, 2) to assess the prevalence of sleep-related breathing disorders and investigate its association with HRV and 3) to assess the interrelationships between HRV and blood markers of inflammation. Methods: This PhD thesis is based on data from the Genetic and Phenotypic Determinants of Blood Pressure and other Cardiovascular Risk Factors (GAPP) study, a prospective population based cohort study. Overall, 2170 inhabitants of the Principality of Liechtenstein, aged between 25-41 years, without established CVD and a BMI ≤35kg/m2 were included in this study. Study participants obtained a 24-hour (h) Holter electrocardiogram (ECG), and careful post-processing was applied. Time- and frequency domain HRV variables and ambulatory heart rate (HR) were exported. The standard deviation of all normal RR intervals (SDNN) was pre-specified as the main HRV variable for all analyses. Personal, medical, lifestyle and nutritional information were assessed using standardized questionnaires. A fasting venous blood sample was taken to determine biomarkers. For assessment of sleep-related breathing disorders, a nocturnal pulse oximetry with additional nasal airflow recording was performed. Resting HR was recorded using a 10-second resting ECG. Multivariable linear regression models were constructed using HRV related parameters as the outcome variables. Results: Overall, 2170 participants (47% male) with a median age of 37 years were included. We found that only 11% of our population adopted a healthy lifestyle defined as a lifestyle-score of 6 or 7, whereas 5% had a very unhealthy lifestyle defined as a score of 0 or 1. In general, women had a higher lifestyle-score compared to men. Having a healthy lifestyle was significantly associated with SDNN, with a β-coefficient (95% confidence interval (CI)) of 0.14 (0.11; 0.17), p=0.0001 per one point increase in the lifestyle-score. This result was attenuated but remained significant after additional adjustment for either resting or ambulatory HR. In the second analysis we found that 9.6% of the population had an apnea-hypopnea index (AHI) ≥5, which is one important component for the diagnosis of an obstructive sleep apnea syndrome. After comprehensive multivariable adjustment, SDNN was inversely associated with categories of AHI and oxygen desaturation index (ODI). These relationships were strongly weakened after the additional adjustment for resting and 24-h HR and most of these relationships lost significance. Resting and ambulatory HR by itself were positively associated with increasing levels of AHI and ODI categories. However, only the relationships with ambulatory HR remained significant after the adjustment for HRV. In the final analysis, we found a close and independent link between HRV and inflammatory biomarkers. Inverse associations of SDNN with all available inflammatory biomarkers were found, with β-coefficients (95%CI) of -0.11 (-0.16;-0.07), p<0.0001 for high-sensitivity C-reactive protein, -0.13 (-0.17;-0.09), p<0.0001 for total leukocyte count, -0.12 (-0.16;-0.08), p<0.0001 for neutrophils, -0.04 (-0.09;0.00), p=0.05 for lymphocytes and -0.08 (-0.09;-0.02), p=0.005 for monocytes. These associations were strongly attenuated after additional adjustment for ambulatory HR and partly lost significance. Ambulatory HR by itself was positively associated with all inflammatory biomarkers, except lymphocytes. Conclusion: In this young and healthy population, HRV was significantly related to a comprehensive healthy lifestyle, sleep-related breathing disorders and inflammatory biomarkers, suggesting an interrelationship between the ANS and these entities. However, most of the information seems to be contained in HR, and the incremental information of HRV parameters was modest in most analyses. These data may allow some insights in the pathophysiology of CVD occurrence. Finally, the adoption of a healthy lifestyle was rather low in this population, underscoring the importance of healthy lifestyle promotion in the society. Outlook: More data are needed on the role of the autonomic function in the development of CVD outcomes and on the independent role of HRV in the prediction of cardiovascular risk factor progression or outcome occurrence

Smoking and High-Sensitivity Troponin I Levels in Young and Healthy Adults from the General Population

Lower troponin concentrations measured in smokers in a healthy population raise the question of whether a lower troponin threshold should be considered for tobacco users. We aim to evaluate differences in troponin levels according to the smoking status in healthy young adults. Participants aged 25–41 years were enrolled in a population-based observational study. The smoking status was self-assessed, and participants were classified as never-, past-, and current smokers. Pack-years of smoking were calculated. High-sensitivity cardiac troponin I (hs-cTnI) concentrations were measured from thawed blood samples, and associations were assessed using multivariable linear regression analyses. We included 2155 subjects in this analysis. The mean (SD) age was 35.4 ± 5.22 years; 53% were women. The median hs-cTnI levels across smoking status categories were 0.70 (interquartile range 0.43–1.23) ng/L in never smokers (n = 1174), 0.69 (interquartile range 0.43–1.28) ng/L in past smokers (n = 503), and 0.67 (interquartile range 0.41–1.04) ng/L in current smokers (n = 478), p = 0.04. The troponin levels remained significantly lower in current smokers after adjustment for potential confounders (β-coefficient [95%CI] of −0.08 [−0.25; −0.08], p < 0.001). Our results confirm that current smokers have lower hs-cTnI levels than past or never smokers, with a significant dose–response relationship among current smokers. The absolute differences in hs-cTnI levels were small

Relationship Between High-Sensitivity Cardiac Troponin I and Blood Pressure Among Young and Healthy Adults

BACKGROUND The aim of this study was to evaluate the relationship of cardiac troponin (cTn) levels with conventional and ambulatory blood pressure (BP) in young and healthy adults. METHODS We performed a population based cross-sectional analysis among 2,072 young and healthy adults aged 25-41 years free of cardiovascular disease and diabetes mellitus. cTnI was measured using a highly sensitive (hs) assay. The relationships of high sensitivity cardiac tropononin I (hs-cTnI) with office and 24-hour BP were assessed using multivariable regression analyses. RESULTS Median age was 37 years and 975 (47%) participants were male. hs-cTnI levels were detectable in 2,061 (99.5%) individuals. Median (interquartile range) hs-cTnI levels were 0.98 (0.71; 1.64) ng/L among men and 0.48 (0.33; 0.71) ng/L among women. Systolic BP, but not diastolic BP, gradually increased across hs-cTnI quartiles (118, 120, 121, and 122 mm Hg for conventional BP; P = 0.0002; 122, 123, 124, and 124 mm Hg for 24-hour BP, P = 0.0001). In multivariable linear regression analyses, the β estimates for systolic BP per 1-unit increase in log transformed hs-cTnI were 2.52 for conventional BP (P = 0.0001); 2.75 for 24-hour BP (P < 0.0001); 2.71 and 2.41 (P < 0.0001 and P = 0.0002) for day and nighttime BP, respectively. There was a significant relationship between hs-cTnI and the Sokolow-Lyon Index (odds ratio (95% confidence interval): 2.09 (1.37; 3.18), P < 0.001). CONCLUSION Using a hs assay, hs-cTnI was detectable in virtually all participants of a young and healthy population. hs-cTnI was independently associated with systolic BP and left ventricular hypertroph

Blood Omega-3 Fatty Acids Are Inversely Associated With Albumin-Creatinine Ratio in Young and Healthy Adults (The Omega-Kid Study).

Background: Omega-3 fatty acids are associated with a lower risk of cardiovascular disease (CVD) and with beneficial effects on CV risk factors. The albumin-creatinine ratio (ACR) is a risk factor for CVD, all-cause mortality and accelerated glomerular filtration rate (GFR) decline in the general population. We aimed to investigate the association between n-3 PUFAS and ACR in heathy individuals with preserved GFR. Design and Methods: The present cross-sectional analysis is part of the GAPP study, a population-based cohort of healthy adults aged 25-41 years. Individuals with known CVD, diabetes, or a BMI >35 kg/m2 were excluded. eGFR was calculated according to the combined Creatinine/Cystatin C CKD-EPI formula. ACR was obtained from a fasting morning urine sample. The Omega-3 Index (relative amount of EPA and DHA of total fatty acids in %) was obtained from whole blood aliquots. Results: Overall, 2001 participants (median age 37 years IQR 31; 40, 53% female) were included in this analysis. Median Omega-3 Index was 4.59 (IQR 4.06; 5.25) and median eGFR 111 ml/min/1.73 m2 (IQR 103; 118). Median ACR was 0.14 mg/mmol (IQR 0; 0.43). We found a significant inverse association of the Omega-3 Index with ACR (ratio 0.84, 95%CI 0.73-0.96; p = 0.011) which remained after comprehensive adjustment (ratio 0.86, 95%CI 0.74-1.00; p = 0.048). No association of the Omega-3 Index with eGFR was found. The adjusted difference in eGFR per 1-unit increase in Omega3-Index was -0.21 (95%CI -0.76; 0.35; p = 0.47). Conclusions: A higher Omega-3 Index was significantly associated with lower ACR in this young and healthy population with preserved eGFR. Omega-3 fatty acids may exhibit cardio- and nephroprotective effects in healthy individuals through modulation of ACR

Concentrations of Serum Brain Injury Biomarkers Following SARS-CoV-2 Infection in Individuals with and without Long-COVID-Results from the Prospective Population-Based COVI-GAPP Study.

It is unknown whether neurological symptoms are associated with brain injury after SARS-CoV-2 infections and whether brain injury and related symptoms also emerge in Long-COVID patients. Biomarkers such as serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) can be used to elucidate neuro-axonal and astroglial injuries. We investigated whether these biomarkers are associated with COVID-19 infection status, associated symptoms and Long-COVID. From 146 individuals of the general population with a post-acute, mild-to-moderate SARS-CoV-2 infection, sNfL and sGFAP were measured before, during and after (five and ten months) the infection. Individual symptoms and Long-COVID status were assessed using questionnaires. Neurological associated symptoms were described for individuals after a mild and moderate COVID-19 infection; however, sNfL (p = 0.74) and sGFAP (p = 0.24) did not change and were not associated with headache (p = 0.51), fatigue (p = 0.93), anosmia (p = 0.77) or ageusia (p = 0.47). In Long-COVID patients, sGFAP (p = 0.038), but not sNfL (p = 0.58), significantly increased but was not associated with neurological associated symptoms. Long-COVID status, but not post-acute SARS-CoV-2 infections, may be associated with astroglial injury/activation, even if neurological associated symptoms were not correlated

Insulin-Like Growth Factor-Binding Protein-7 and risk of congestive heart failure hospitalization in patients with atrial fibrillation.

BACKGROUND The occurrence of congestive heart failure (CHF) hospitalization among patients with atrial fibrillation (AF) is a poor prognostic marker. OBJECTIVE To assess whether Insulin-Like Growth Factor-Binding Protein-7 (IGFBP-7), a marker of myocardial damage, identifies AF patients at high risk for this complication. METHODS We analyzed two prospective multicenter observational cohort studies including 3,691 AF patients. Levels of IGFBP-7 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured from frozen plasma samples at baseline. The primary endpoint was hospitalization for CHF. Multivariable adjusted Cox-regression analyses were constructed. RESULTS Mean age was 69±12 years, 1,028 (28%) were females and 879 (24%) had a history of CHF. The incidence per 1,000 patient-years across increasing IGFBP-7 quartiles was 7, 10, 32 and 85. The corresponding multivariable adjusted hazard ratios (aHRs) [95%CI] were 1.0, 1.05 [0.63;1.77], 2.38 [1.50;3.79], and 4.37 [2.72;7.04] (p for trend <0.001). In a subgroup of 2,812 patients without pre-existing CHF at baseline, the aHRs were 1.0, 0.90 [0.47;1.72], 1.69 [0.94;3.04], and 3.48 [1.94;6.24] (p for trend <0.001). Patients with IGFBP-7 and NT-proBNP levels above the biomarker-specific median had a higher risk of incident CHF hospitalization (aHR 5.20 [3.35; 8.09]) compared to those with only one elevated marker (elevated IGFBP-7 aHR 2.17[1.30;3.60]; elevated NT-proBNP aHR 1.97[1.17;3.33]) or no elevated marker (reference). CONCLUSION Higher plasma levels of IGFBP-7 were strongly and independently associated with CHF hospitalization in AF-patients. The prognostic information provided by IGFBP-7 was additive to that of NT-proBNP

Sex differences of vascular brain lesions in patients with atrial fibrillation.

OBJECTIVE To examine sex differences in prevalence, volume and distribution of vascular brain lesions on MRI among patients with atrial fibrillation (AF). METHODS In this cross-sectional analysis, we included 1743 patients with AF (27% women) from the multicentre Swiss Atrial Fibrillation study (SWISS-AF) with available baseline brain MRI. We compared presence and total volume of large non-cortical or cortical infarcts (LNCCIs), small non-cortical infarcts, microbleeds (MB) and white matter hyperintensities (WMH, Fazekas score ≥2 for moderate or severe degree) between men and women with multivariable logistic regression. We generated voxel-based probability maps to assess the anatomical distribution of lesions. RESULTS We found no strong evidence for an association of female sex with the prevalence of all ischaemic infarcts (LNCCI and SNCI combined; adjusted OR 0.86, 95% CI 0.67 to 1.09, p=0.22), MB (adjusted OR 0.91, 95% CI 0.68 to 1.21, p=0.52) and moderate or severe WMH (adjusted OR 1.15, 95% CI 0.90 to 1.48, p=0.27). However, total WMH volume was 17% larger among women than men (multivariable adjusted multiplicative effect 1.17, 95% CI 1.01 to 1.35; p=0.04). Lesion probability maps showed a right hemispheric preponderance of ischaemic infarcts in both men and women, while WMH were distributed symmetrically. CONCLUSION Women had higher white matter disease burden than men, while volume and prevalence of other lesions did not differ. Our findings highlight the importance of controlling risk factors for cerebral small vessel disease in patients with AF, especially among women

Subclinical sleep apnoea and plasma levels of endothelin-1 among young and healthy adults.

OBJECTIVE Obstructive sleep apnoea (OSA) is a risk factor for vascular disease and other adverse outcomes. These associations may be at least partly due to early endothelin-1 (ET-1)-mediated endothelial dysfunction (ED). Therefore, we assessed the relationships between subclinical sleep apnoea and plasma levels of ET-1. METHODS We performed a population-based study among 1255 young and healthy adults aged 25-41 years. Cardiovascular disease, diabetes or a body mass index >35 kg/mwere exclusion criteria. Plasma levels of ET-1 were measured using a high-sensitivity, single-molecule counting technology. The relationships between subclinical sleep apnoea (OSA indices: respiratory event index (REI), oxygen desaturation index (ODI), mean night-time blood oxygen saturation (SpO)) and ET-1 levels were assessed by multivariable linear regression analysis. RESULTS Median age of the cohort was 35 years. Median ET-1 levels were 2.9 (IQR 2.4-3.6) and 2.5 pg/mL (IQR 2.1-3.0) among patients with (n=105; 8%) and without subclinical sleep apnoea (REI 5-14), respectively. After multivariable adjustment, subclinical sleep apnoea remained significantly associated with plasma levels of ET-1 (β=0.13 (95% CI 0.06 to 0.20) p=0.0002 for a REI 5-14; β=0.10 (95% CI 0.03 to 0.16) p=0.003 for an ODI≥5). Every 1% decrease in mean night-time SpOincreased ET-1 levels by 0.1 pg/mL, an association that remained significant after multivariable adjustment (β=0.02 (95% CI 0.003 to 0.033) p=0.02). CONCLUSIONS In this study of young and healthy adults, we found that participants with subclinical sleep apnoea had elevated plasma ET-1 levels, an association that was due to night-time hypoxaemia. Our results suggest that ED may already be an important consequence of subclinical sleep apnoea

Real-world cost-effectiveness of pulmonary vein isolation for atrial fibrillation: a target trial approach.

OBJECTIVES Randomized controlled trials of pulmonary vein isolation (PVI) for treating atrial fibrillation (AF) have proven the procedure's efficacy. Studies assessing its empirical cost-effectiveness outside randomized trial settings are lacking. We aimed to evaluate the effectiveness and cost-effectiveness of PVI versus medical therapy for AF. METHODS We followed a target trial approach using the Swiss AF cohort, a prospective observational cohort study that enrolled AF patients between 2014 and 2017. Resource utilization and cost information was collected through claims data. Quality-of-life was measured with EQ-5D-3L utilities. We estimated incremental cost-effectiveness ratios from the perspective of the Swiss statutory health insurance system. RESULTS Patients undergoing PVI compared to medical therapy had a 5-year overall survival advantage with a hazard ratio of 0.75 (95%CI 0.46-1.21, p=0.69), a 19.8% standard deviation improvement in quality-of-life (95%CI 15.5-22.9%, p<0.001), at an incremental cost of 29,604 (95%CI 16,354-42,855, p<0.001) Swiss Francs (CHF). The estimated incremental cost-effectiveness ratio was CHF 158,612 per quality-adjusted life-year (QALY) gained within a 5-year time horizon. Assuming similar health effects and costs over 5 additional years changed the incremental cost-effectiveness ratio to CHF 82,195 per QALY gained. Results were robust to the sensitivity analyses performed. CONCLUSIONS Our results show that PVI might be a cost-effective intervention within the Swiss healthcare context in a 10-year time horizon, but unlikely to be so at 5-years, if a willingness-to-pay threshold of CHF100,000 per QALY gained is assumed. Given data availability, we find target trial designs are a valuable tool for assessing the cost-effectiveness of healthcare interventions outside of RCT settings

Real-World Cost-Effectiveness of Pulmonary Vein Isolation for Atrial Fibrillation: A Target Trial Approach

OBJECTIVES Randomized controlled trials of pulmonary vein isolation (PVI) for treating atrial fibrillation (AF) have proven the procedure's efficacy. Studies assessing its empirical cost-effectiveness outside randomized trial settings are lacking. We aimed to evaluate the effectiveness and cost-effectiveness of PVI versus medical therapy for AF. METHODS We followed a target trial approach using the Swiss-AF cohort, a prospective observational cohort study that enrolled patients with AF between 2014 and 2017. Resource utilization and cost information were collected through claims data. Quality of life was measured with EQ-5D-3L utilities. We estimated incremental cost-effectiveness ratios (ICERs) from the perspective of the Swiss statutory health insurance system. RESULTS Patients undergoing PVI compared with medical therapy had a 5-year overall survival advantage with a hazard ratio of 0.75 (95% CI 0.46-1.21; P = .69) and a 19.8% SD improvement in quality of life (95% CI 15.5-22.9; P < .001), at an incremental cost of 29 604 Swiss francs (CHF) (95% CI 16 354-42 855; P < .001). The estimated ICER was CHF 158 612 per quality-adjusted life-year (QALY) gained within a 5-year time horizon. Assuming similar health effects and costs over 5 additional years changed the ICER to CHF 82 195 per QALY gained. Results were robust to the sensitivity analyses performed. CONCLUSIONS Our results show that PVI might be a cost-effective intervention within the Swiss healthcare context in a 10-year time horizon, but unlikely to be so at 5 years, if a willingness-to-pay threshold of CHF 100 000 per QALY gained is assumed. Given data availability, we find target trial designs are a valuable tool for assessing the cost-effectiveness of healthcare interventions outside of randomized controlled trial settings