Steffen Blum

Relationships of Measured and Genetically Determined Height With the Cardiac Conduction System in Healthy Adults

Background— Increasing height is an independent risk factor for atrial fibrillation, but the underlying mechanisms are unknown. We hypothesized that height-related differences in electric conduction could be potential mediators of this relationship. Methods and Results— We enrolled 2149 adults aged 25 to 41 years from the general population. Height was directly measured, and a resting 12-lead ECG obtained under standardized conditions. Multivariable linear regression models were used to evaluate the association between measured height and ECG parameters. Mendelian randomization analyses were then performed using 655 independent height-associated genetic variants previously identified in the GIANT consortium. Median age was 37 years, and median height was 1.71 m. Median PR interval, QRS duration, and QTc interval were 156, 88, and 402 ms, respectively. After multivariable adjustment, &bgr;-coefficients (95% confidence intervals) per 10 cm increase in measured height were 4.17 (2.65–5.69; P<0.0001) for PR interval and 2.06 (1.54–2.58; P<0.0001) for QRS duration. Height was not associated with QTc interval or the Sokolow–Lyon index. An increase of 10 cm in genetically determined height was associated with increases of 4.33 ms (0.76–7.96; P=0.02) in PR interval and 2.57 ms (1.33–3.83; P<0.0001) in QRS duration but was not related to QTc interval or Sokolow–Lyon index. Conclusions— In this large population-based study, we found significant associations of measured and genetically determined height with PR interval and QRS duration. Our findings suggest that adult height is a marker of altered cardiac conduction and that these relationships may be causal.

Risk factors for premature ventricular contractions in young and healthy adults

Background Premature ventricular contractions (PVCs) are associated with an increased risk of morbidity and mortality. Therefore, it was aimed to assess risk factors for the frequency of PVCs in young and healthy adults. Methods Our population-based study included 2048 healthy adults from the general population aged 25–41u2005years. PVC frequency was determined by 24-hour Holter ECG. We performed multivariable regression analysis using stepwise backward selection to identify factors independently associated with PVC frequency. Results Median age was 37u2005years, 953 (46.5%) were male. At least one PVC during the 24-hour monitoring period was observed in 69% of participants. Median number of detected PVCs was 2, the 95th percentile was 193. In multivariable regression analyses, we found 17 significant risk factors for PVC frequency. Low educational status (risk ratio (RR) 3.33; 95% CI 1.98 to 5.60), body height>median (1.58, 95% CI 1.11 to 2.24) and increasing levels of waist:hip ratio (2.15, 95% CI 1.77 to 2.61), N-terminal pro brain natriuretic peptide (1.52, 95% CI 1.30 to 1.76) and Sokolow-Lyon Index (1.38, 95% CI 1.15 to 1.66) (all p≤0.01) were associated with a higher PVC frequency. Physical activity (RR fourth vs first quartile 0.51, 95% CI 0.34 to 0.76) and increasing levels of haemoglobin (0.58, 95% CI 0.47 to 0.70) and glucagon-like peptide-1 (0.72, 95% CI 0.64 to 0.82) (all p<0.001) were related to a lower PVC frequency. Conclusions PVC occurrence is common even in healthy low-risk individuals, and its frequency is associated with several covariates mainly related to cardiovascular risk factors, markers of cardiac structure and function and socioeconomic status.

Prospective Assessment of Sex‐Related Differences in Symptom Status and Health Perception Among Patients With Atrial Fibrillation

Background We prospectively assessed sex‐specific differences in health perception, overall symptom status, and specific symptoms in a large cohort of patients with atrial fibrillation. Methods and Results We performed a prospective multicenter observational cohort study of 1553 patients with atrial fibrillation. Patients completed questionnaires about personal characteristics, comorbidities, and symptoms on a yearly basis. Mean age was 70±11 years among women and 67±12 years among men. Health perception on a visual analogue scale ranging from 0 to 100 (with higher scores indicating better health perception) was significantly lower in women than in men (70 [interquartile range: 50–80] versus 75 [interquartile range: 60–85]; P<0.0001). More women than men had any symptoms (85.0% versus 68.3%; P<0.0001), palpitations (65.2% versus 44.4%; P<0.0001), dizziness (25.6% versus 13.5%; P<0.0001), dyspnea (35.7% versus 21.8%; P<0.0001), and fatigue (25.3% versus 19.1%; P=0.006). At 1‐year follow‐up, symptoms decreased in both sexes but remained more frequent in women (49.1% versus 32.6%, P<0.0001). In multivariable adjusted longitudinal regression models, female sex remained an independent predictor for lower health perception (ß=−4.8; 95% CI, −6.5 to −3.1; P<0.0001), any symptoms (odds ratio [OR]: 2.6; 95% CI, 2.1–3.4; P<0.0001), palpitations (OR: 2.6; 95% CI, 2.1–3.2; P<0.0001), dizziness (OR: 2.9; 95% CI, 2.1–3.9; P<0.0001), dyspnea (OR: 2.1; 95% CI, 1.6–2.8; P<0.0001), fatigue (OR: 1.6; 95% CI, 1.2–2.2; P=0.0008), and chest pain (OR: 1.8; 95% CI, 1.3–2.6; P=0.001). Conclusions Women with atrial fibrillation have a substantially higher symptom burden and lower health perception than men. These relationships persisted after multivariable adjustment and during prospective follow‐up.

Prevalence and predictors of atrial fibrillation type among individuals with recent onset of atrial fibrillation

OBJECTIVEnAtrial fibrillation (AF) is considered to be a progressive disease, starting with intermittent episodes that progress over time to more sustained events. However, little is known about the prevalence of and predictors for AF type among patients with recent-onset AF. We aimed to address these issues among a selected population of patients with AF.nnnMETHODSnThe Basel atrial fibrillation cohort (BEAT-AF) study is an ongoing prospective multicentre cohort study among patients with AF. At baseline, we obtained information on the date of AF diagnosis, AF type, comorbidities, medication and lifestyle factors. For this analysis, 486 (31.4%) out of 1550 participants with recent-onset AF (defined as AF duration <24 months) were included. Predictors for AF type (non-paroxysmal vs paroxysmal) were obtained using multivariable adjusted logistic regression models.nnnRESULTSnMean age was 67 (59-75) years and 136 (28%) were women. Recent-onset paroxysmal AF was observed in 301 (62%) participants, 185 (38%) had non-paroxysmal AF - persistent AF in 148 (30.4%) and permanent AF in 37 (7.6%). In multivariable models, odds ratios for having non-paroxysmal AF around AF diagnosis were 1.03 per year increasing in age (95% confidence interval [CI] 1.01-1.05, p = 0.01); 2.70 (1.5-4.68, p = 0.0004) for history of heart failure; 3.82 (1.05-13.87, p = 0.04) for a history of hyperthyroidism and 1.04 (1.02-1.05, p <0.0001) per beat increase in heart rate.nnnCONCLUSIONnWe found a substantial proportion of AF patients with the non-paroxysmal form shortly after diagnosis. Predictors for non-paroxysmal AF were increasing age, history of heart failure or hyperthyroidism, and a higher heart rate.

Risk factors for heart failure hospitalizations among patients with atrial fibrillation

Background Patients with atrial fibrillation (AF) have an increased risk for the development of heart failure (HF). In this study, we aimed to detect predictors of HF hospitalizations in an unselected AF population. Methods The Basel Atrial Fibrillation Cohort Study is an ongoing observational multicenter cohort study in Switzerland. For this analysis, 1193 patients with documented AF underwent clinical examination, venous blood sampling and resting 12-lead ECG at baseline. Questionnaires about lifestyle and medical history were obtained in person at baseline and during yearly follow-up phone calls. HF hospitalizations were validated by two independent physicians. Cox regression analyses were performed using a forward selection strategy. Results Overall, 29.8% of all patients were female and mean age was 69 ±12 years. Mean follow-up time was 3.7 ±1.5 years. Hospitalization for HF occurred in 110 patients, corresponding to an incidence of 2.5 events per 100 person years of follow-up. Independent predictors for HF were body mass index (HR 1.40 [95%CI 1.17; 1.66], p = 0.0002), chronic kidney disease (2.27 [1.49; 3.45], p = 0.0001), diabetes mellitus (2.13 [1.41; 3.24], p = 0.0004), QTc interval (1.25 [1.04; 1.49], p = 0.02), brain natriuretic peptide (2.19 [1.73; 2.77], p<0.0001), diastolic blood pressure (0.79 [0.65; 0.96], p = 0.02), history of pulmonary vein isolation or electrical cardioversion (0.54 [0.36; 0.80], p = 0.003) and serum chloride (0.82 [0.70; 0.96], p = 0.02). Conclusions In this unselected AF population, several traditional cardiovascular risk factors and arrhythmia interventions predicted HF hospitalizations, providing potential opportunities for the implementation of strategies to reduce HF among AF patients.

Fibroblast growth factor 23 and renal function among young and healthy individuals

Abstract Background: Fibroblast growth factor 23 (FGF-23), an osteocyte hormone involved in the regulation of phosphate metabolism, is associated with incident and progressive chronic kidney disease. We aimed to assess the association of FGF-23 with renal parameters, vascular function and phosphate metabolism in a large cohort of young and healthy individuals. Methods: Healthy individuals aged 25–41 years were included in a prospective population-based study. Fasting venous blood and morning urinary samples were used to measure plasma creatinine, cystatin C, endothelin-1, phosphate and plasma FGF-23 as well as urinary creatinine and phosphate. Multivariable regression models were constructed to assess the relationship of FGF-23 with parameters of renal function, endothelin-1 and fractional phosphate excretion. Results: The median age of 2077 participants was 37 years, 46% were males. The mean estimated glomerular filtration rate (eGFR – CKD-EPI creatinine-cystatin C equation) and fractional phosphate excretion were 110 mL/min/1.73 m2 and 8.7%, respectively. After multivariable adjustment, there was a significant inverse relationship of FGF-23 with eGFR (β per 1 log-unit increase −3.81; 95% CI [−5.42; −2.20]; p<0.0001). Furthermore, we found a linear association between FGF-23 and endothelin-1 (β per 1 log-unit increase 0.06; [0.01, 0.11]; p=0.01). In addition, we established a significant relationship of FGF-23 with fractional phosphate excretion (β per 1 log-unit increase 0.62; [0.08, 1.16]; p=0.03). Conclusions: Increasing plasma FGF-23 levels are strongly associated with decreasing eGFR and increasing urinary phosphate excretion, suggesting an important role of FGF-23 in the regulation of kidney function in young and healthy adults.

Relationships of kidney injury molecule-1 with renal function and cardiovascular risk factors in the general population.

BACKGROUNDnKidney injury molecule-1 (KIM-1) has been associated with kidney damage in patients with preexisting renal disease. However, little is known about the relationships of KIM-1 with renal function and cardiovascular risk factors in healthy individuals from the general population.nnnMETHODSnHealthy individuals aged 25-41years were enrolled in a population-based study. Main exclusion criteria were a BMI >35kg/m2, preexisting kidney disease or established cardiovascular disease. KIM-1 was measured from frozen plasma samples using a high-sensitivity assay. Multivariable linear regression models were constructed to assess the relationships of KIM-1 with renal function and various cardiovascular risk factors.nnnRESULTSnWe included 2060 individuals (47% men, median (interquartile range) age: 37 (31-40) years) in this analysis. Median KIM-1 levels were 82.5 (IQR 59.4-112.7) pg/ml. We found no significant relationship of KIM-1 with creatinine (adjusted β-coefficient (95% confidence interval) 0.0005 (-0.002; 0.003), p=0.61) and cystatin C (-0.02 (-0.21; 0.17), p=0.84). There were significant linear relationships of log-transformed KIM-1 with systolic blood pressure (adjusted β-coefficient (95% confidence interval) 0.07 (0.04; 0.09), p<0.0001), diastolic blood pressure (0.04 (0.02; 0.07), p=0.001), low-density lipoprotein cholesterol (0.09 (0.06; 0.11), p<0.0001), high-density lipoprotein cholesterol (0.07 (0.05; 0.1), p<0.0001), high-sensitivity C-reactive protein (0.05 (0.03; 0.07), p<0.0001), age (0.09 (0.07; 0.11), p<0.0001), BMI (0.04 (0.01; 0.06), p=0.005) and current smoking (0.12 (0.07; 0.17), p<0.0001).nnnCONCLUSIONnAmong healthy adults from the general population, plasma levels of KIM-1 were not associated with renal function but were independently related to multiple cardiovascular risk factors.

QTc interval, cardiovascular events and mortality in patients with atrial fibrillation

BACKGROUNDnA longer QTc interval has been associated with more adverse cardiovascular events and death in the general population. Little evidence is available on these relationships among patients with atrial fibrillation (AF).nnnMETHODSnWe performed a prospective observational multicenter cohort study of 1413 patients with AF. A resting 12‑lead electrocardiogram (ECG) was performed at baseline. QT interval was corrected for heart rate using the Bazett formula (QTc). Endpoints for this study included hospitalizations for congestive heart failure (CHF), a combination of cardiovascular death, myocardial infarction, stroke, systemic arterial embolism (MACE) and all-cause mortality.nnnRESULTSnMean age of our population was 68±12years and 420 (30%) participants were female. Median QTc was 432ms (interquartile range 409; 457). The mean follow-up time was 3.6±1.5years. After multivariable adjustment, there was a linear increase in risk with increasing QTc interval for incident CHF (hazard ratio (HR) per 1-SD increase in QTc 1.3 [95% CI 1.1; 1.6], p=0.008), MACE (HR 1.2 [1.0; 1.4], p=0.02) and all-cause mortality (HR 1.3 [1.0; 1.6], p=0.002). Results were consistent whether or not patients were in sinus rhythm on the baseline ECG (HR for CHF 1.7 versus 1.3, p interaction 0.08; HR for MACE 1.3 versus 1.2, p interaction 0.9; HR for all-cause mortality 1.4 versus 1.4, p interaction 0.9).nnnCONCLUSIONSnIn this large well-characterized cohort of AF patients, QTc interval was independently associated with adverse outcomes. These results were independent of the rhythm on the baseline ECG.

Incidence and Predictors of Atrial Fibrillation Progression: A Systematic Review and Meta-Analysis

BACKGROUNDnMore sustained forms of atrial fibrillation (AF) are less amenable to treatment and associated with worse outcomes, but the incidence and predictors of AF progression are not well defined.nnnOBJECTIVEnThe purpose of this study was to perform a systematic review and meta-analysis assessing the incidence and predictors of AF progression.nnnMETHODSnPubMed, EMBASE, and the Cochrane Library were searched from inception to August 2017. AF progression was defined as progression from paroxysmal to persistent/permanent AF or as progression from persistent to permanent AF. Random effect models were used to calculate pooled cumulative incidence rates. Predictors related to between-study variability were assessed using meta-regression analyses.nnnRESULTSnWe identified 47 studies with 27,266 patients who were followed for 105,912 patient-years. The pooled incidence of AF progression was 8.1 per 100 patient-years of follow-up (95% confidence interval [CI] 7.1-9.1 per 100 patient-years of follow-up; I2 = 98%; Pxa0< .0001). The incidence was 7.1 per 100 patient-years of follow-up (95% CI 6.2-8.0 per 100 patient-years of follow-up; across 42 studies) for progression from paroxysmal to non-paroxysmal AF as compared with 18.6 per 100 patient-years of follow-up (95% CI 8.9-28.3 per 100 patient-years of follow-up; across 5 studies) for progression from persistent to permanent AF. Higher age (βxa0=xa05.4; 95% CI 1.4-9.4; P = .01; R2 = 14.3%) and the prevalence of hypertension (β = 5.2; 95% CI 1.0-9.4; P = .02; R2 = 18.0%) were associated with a higher AF progression rate. Follow-up duration (β = -4.5; 95% CI -5.8 to -3.3; P < .0001; R2 = 68.0%) and the prevalence of paroxysmal AF (β = -9.5; 95% CI -18.7 to -0.3; P = .04; R2 = 4.4%) were inversely associated with AF progression. Together these variables explained 73.8% of the observed between-study heterogeneity.nnnCONCLUSIONnThe incidence of AF progression appears to be relatively low, and the incidence seems to decrease with longer follow-up duration. Age, hypertension, baseline AF type, and follow-up duration explained a high percentage of the observed between-study heterogeneity.

Uptake of non-vitamin K antagonist oral anti coagulants in patients with atrial fibrillation – a prospective cohort study

AIMSnWe aimed to assess the uptake of non-vitamin K antagonist oral anticoagulants (NOACs) among patients with atrial fibrillation between 2010 and 2015 in Switzerland.nnnMETHODSnWe performed a prospective observational cohort study. At the baseline examination and during yearly follow-ups, we used questionnaires to obtain information about clinical characteristics and antithrombotic treatment. Stroke risk was assessed using the CHA2DS2-VASc score.nnnRESULTSn1545 patients were enrolled across seven centres in Switzerland. Mean age was 68 ± 12 years and 29.5% were female. The percentage of anticoagulated patients with an indication for oral anticoagulation (CHA2DS2-VASc score ≥2 in women and ≥1 in men) was 75% in 2010 and 80% in 2015 (p = 0.2). There was a gradual increase in the use of NOACs from 0% in 2010 to 29.8% in 2015 (p <0.0001). Out of 888 patients, who initially received a vitamin K antagonist (VKA), 86 (9.7%) were switched to an NOAC during follow-up. Use of aspirin as a monotherapy decreased from 23% in 2010 to 11% in 2015 (p <0.0001).nnnCONCLUSIONnAfter regulatory approval, the use of NOACs in Switzerland steadily increased to about 30% in 2015, whereas switches from VKAs to NOACs were infrequent. In parallel, the prescription of aspirin as monotherapy was more than halved, suggesting significant guideline-concordant improvements in oral anticoagulation use among patients with atrial fibrillation.