Genetic insights into resting heart rate and its role in cardiovascular disease.

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

The Groningen electrocardiographic criteria for left ventricular hypertrophy: a sex-specific analysis.

The sensitivity of electrocardiogram (ECG) criteria to detect left ventricular hypertrophy (LVH) is low, especially in women. We determined sex-specific sensitivities of ECG-LVH criteria, and developed new criteria, using cardiovascular magnetic resonance imaging (CMR). Sensitivities of ECG-LVH criteria were determined in participants of the UK Biobank (N = 3632). LVH was defined when left ventricular mass was > 95% confidence interval (CI) according to age and sex. In a training cohort (75%, N = 2724), sex-specific ECG-LVH criteria were developed by investigating all possible sums of QRS-amplitudes in all 12 leads, and selecting the sum with the highest pseudo-R2 and area under the curve to detect LVH. Performance was assessed in a validation cohort (25%, N = 908), and association with blood pressure change was investigated in an independent cohort. Sensitivities of ECG-LVH criteria were low, especially in women. Newly developed Groningen-LVH criterion for women (QV2 + RI + RV5 + RV6 + SV2 + SV4 + SV5 + SV6) outperformed all ECG-LVH criteria with a sensitivity of 42% (95% CI 35-49%). In men, newly developed criterion ((RI + RV5 + SII + SV2 + SV6) × QRS duration) was equally sensitive as 12-lead sum with a sensitivity of 44% (95% CI 37-51%) and outperformed the other criteria. In an independent cohort, the Groningen-LVH criteria were strongest associated with change in systolic blood pressure. Our proposed CMR sex-specific Groningen-LVH criteria improve the sensitivity to detect LVH, especially in women. Further validation and its association with clinical outcomes is warranted.

Sex-Based Differences in Unrecognized Myocardial Infarction.

Background Myocardial infarction is an important cause of morbidity and mortality in both men and women. Atypical or the absence of symptoms, more prevalent among women, may contribute to unrecognized myocardial infarctions and missed opportunities for preventive therapies. The aim of this research is to investigate sex-based differences of undiagnosed myocardial infarction in the general population. Methods and Results In the Lifelines Cohort Study, all individuals ≥18 years with a normal baseline ECG were followed from baseline visit till first follow-up visit (≈5 years, n=97 203). Individuals with infarct-related changes between baseline and follow-up ECGs were identified. The age- and sex-specific incidence rates were calculated and sex-specific cardiac symptoms and predictors of unrecognized myocardial infarction were determined. Follow-up ECG was available after a median of 3.8 (25th and 75th percentile: 3.0-4.6) years. During follow-up, 198 women experienced myocardial infarction (incidence rate 1.92 per 1000 persons-years) compared with 365 men (incidence rate 3.30; P<0.001 versus women). In 59 (30%) women, myocardial infarction was unrecognized compared with 60 (16%) men (P<0.001 versus women). Individuals with unrecognized myocardial infarction less often reported specific cardiac symptoms compared with individuals with recognized myocardial infarction. Predictors of unrecognized myocardial infarction were mainly hypertension, smoking, and higher blood glucose level. Conclusions A substantial proportion of myocardial infarctions are unrecognized, especially in women. Opportunities for secondary preventive therapies remain underutilized if myocardial infarction is unrecognized.

Proactive screening for symptoms: A simple method to improve early detection of unrecognized cardiovascular disease in primary care. Results from the Lifelines Cohort Study.

Cardiovascular disease (CVD) often goes unrecognized, despite symptoms frequently being present. Proactive screening for symptoms might improve early recognition and prevent disease progression or acute cardiovascular events. We studied the diagnostic value of symptoms for the detection of unrecognized atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD) and developed a corresponding screening questionnaire. We included 100,311 participants (mean age 52 ± 9 years, 58% women) from the population-based Lifelines Cohort Study. For each outcome (unrecognized AF/HF/CAD), we built a multivariable model containing demographics and symptoms. These models were combined into one 'three-disease' diagnostic model and questionnaire for all three outcomes. Results were validated in Lifelines participants with chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM). Unrecognized CVD was identified in 1325 participants (1.3%): AF in 131 (0.1%), HF in 599 (0.6%), and CAD in 687 (0.7%). Added to age, sex, and body mass index, palpitations were independent predictors for unrecognized AF; palpitations, chest pain, dyspnea, exercise intolerance, health-related stress, and self-expected health worsening for unrecognized HF; smoking, chest pain, exercise intolerance, and claudication for unrecognized CAD. Area under the curve for the combined diagnostic model was 0.752 (95% CI 0.737-0.766) in the total population and 0.757 (95% CI 0.734-0.781) in participants with COPD and DM. At the chosen threshold, the questionnaire had low specificity, but high sensitivity. In conclusion, a short questionnaire about demographics and symptoms can improve early detection of CVD and help pre-select people who should or should not undergo further screening for CVD.

The effect of feedback on cardiovascular risk factors on optimization of primary prevention: The PharmLines initiative.

BACKGROUND: It is unknown whether population based single assessment of cardiovascular disease (CVD) risk and feedback to individuals and general practitioners results in initiation of preventive cardiovascular pharmacotherapy in those at risk. METHODS: The population based cohort study Lifelines was linked to the IADB.nl pharmacy database to assess information on the initiation of preventive medication (N = 48,770). At the baseline visit, information on cardiovascular risk factors was collected and reported to the participants and their general practitioners. An interrupted-time-series-analysis was plotted, in which the start year of blood pressure and lipid lowering medication was displayed in years before or after the baseline visit. Subsequently, predictors of the initiation of pharmacotherapy were determined and possible reduction in cardiovascular events that could be achieved by optimal treatment of individuals at risk. RESULTS: Before the Lifelines baseline visit, 34% (out of 1,527, 95% Confidence interval (CI) 32%-36%) and 30% (out of 1,991, 95%CI 28%-32%) of the individuals at risk had a blood pressure or lipid lowering drug prescription, respectively. In those at risk, the use of blood pressure lowering medication, increased substantially during the year of the baseline visit. Treating individuals at increased risk (≥5% 10-year risk) with lipid or blood pressure lowering medication (N = 8515 and N = 6899) would have prevented 162 and 183 CVD events, respectively, in the upcoming five years. CONCLUSION: Primary prevention of CVD in the general population appears suboptimal. Feedback of cardiovascular risk factors resulted in a substantial increase of blood pressure lowering medication and extrapolated health benefits.

Effect of Systolic Blood Pressure on Left Ventricular Structure and Function: A Mendelian Randomization Study.

We aimed to estimate the effects of a lifelong exposure to high systolic blood pressure (SBP) on left ventricular (LV) structure and function using Mendelian randomization. A total of 5596 participants of the UK Biobank were included for whom cardiovascular magnetic resonance imaging and genetic data were available. Major exclusion criteria included nonwhite ethnicity, major cardiovascular disease, and body mass index >30 or <18.5 kg/m2. A genetic risk score to estimate genetically predicted SBP (gSBP) was constructed based on 107 previously established genetic variants. Manual cardiovascular magnetic resonance imaging postprocessing analyses were performed in 300 individuals at the extremes of gSBP (150 highest and lowest). Multivariable linear regression analyses of imaging biomarkers were performed using gSBP as continuous independent variable. All analyses except myocardial strain were validated using previously derived imaging parameters in 2530 subjects. The mean (SD) age of the study population was 62 (7) years, and 52% of subjects were female. Corrected for age, sex, and body surface area, each 10 mm Hg increase in gSBP was significantly (P<0.0056) associated with 4.01 g (SE, 1.28; P=0.002) increase in LV mass and with 2.80% (SE, 0.97; P=0.004) increase in LV global radial strain. In the validation cohort, after correction for age, sex, and body surface area, each 10 mm Hg increase in gSBP was associated with 5.27 g (SE, 1.50; P<0.001) increase in LV mass. Our study provides a novel line of evidence for a causal relationship between SBP and increased LV mass and with increased LV global radial strain.

Contributions of Interactions Between Lifestyle and Genetics on Coronary Artery Disease Risk.

PURPOSE OF THE REVIEW: To summarize current knowledge on interactions between genetic variants and lifestyle factors (G×L) associated with the development of coronary artery disease (CAD) and prioritize future research. RECENT FINDINGS: Genetic risk and combined lifestyle factors and behaviors have a log-additive effect on the risk of developing CAD. First, we describe genetic and lifestyle factors associated with CAD and then focus on G×L interactions. The majority of G×L interaction studies are small-scale candidate gene studies that lack replication and therefore provide spurious results. Only a few studies, of which most use genetic risk scores or genome-wide approaches to test interactions, are robust in number and analysis strategy. These studies provide evidence for the existence of G×L interactions in the development of CAD. Further G×L interactions studies are important as they contribute to our understanding of disease pathophysiology and possibly provide insights for improving interventions or personalized recommendations.

Author Correction: Causal Pathways from Blood Pressure to Larger QRS Amplitudes: a Mendelian Randomization Study.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Causal Pathways from Blood Pressure to Larger Qrs Amplitudes a Mendelian Randomization Study.

Abnormal QRS duration and amplitudes on the electrocardiogram are indicative of cardiac pathology and are associated with adverse outcomes. The causal nature of these associations remains uncertain and could be due to QRS abnormalities being a symptom of cardiac damage rather than a factor on the causal pathway. By performing Mendelian randomization (MR) analyses using summary statistics of genome wide association study consortia with sample sizes between 20,687 and 339,224 individuals, we aimed to determine which cardiovascular risk factors causally lead to changes in QRS duration and amplitude (Sokolow-Lyon, Cornell and 12-leadsum products). Additionally, we aimed to determine whether QRS traits have a causal relationship with mortality and longevity. We performed inverse-variance weighted MR as main analyses and MR-Egger regression and weighted median estimation as sensitivity analyses. We found evidence for a causal relationship between higher blood pressure and larger QRS amplitudes (systolic blood pressure on Cornell: 55SNPs, causal effect estimate per 1 mmHg = 9.77 millimeters·milliseconds (SE = 1.38,P = 1.20 × 10-12) and diastolic blood pressure on Cornell: 57SNPs, causal effect estimate per 1 mmHg = 14.89 millimeters·milliseconds (SE = 1.82,P = 3.08 × 10-16), but not QRS duration. Genetically predicted QRS traits were not associated with longevity, suggesting a more prominent role of acquired factors in explaining the well-known link between QRS abnormalities and outcome.

Population-based values and abnormalities of the electrocardiogram in the general Dutch population: The LifeLines Cohort Study.

BACKGROUND: Our aim is to present average values and prevalence of electrocardiographic (ECG) abnormalities among the general Dutch population in the LifeLines Cohort. HYPOTHESIS: The ECG values previously studied in the Caucasian population of smaller cohorts will be confirmed with ECG data from LifeLines. METHODS: ECG data of 152 180 individuals age 18 to 93 years were available. Individuals with cardiovascular risk factors were excluded to analyze the healthy population. Average values of the ECG for the healthy population were presented as means with 95% and 99% confidence intervals and as medians with first and 99th percentiles. RESULTS: Median heart rate was highest in the youngest and oldest individuals of the healthy population. Median duration of P wave, PQ interval, and QRS duration were longer in males compared with females. In contrast, median QT interval corrected for heart rate was higher in females. In general, the above-mentioned parameters increased with age. The prevalences of ECG abnormalities adjusted for the Dutch population were 0.9% for atrial fibrillation or flutter, 1.4% for premature atrial complexes, 0.5% for myocardial infarction, 2.1% for ventricular premature complexes, 1.0% for left ventricular hypertrophy, 8.1% for P-R interval >200 ms, and 0.8% for bundle branch block. CONCLUSIONS: Our study provides an overview of average values and ECG abnormalities and confirms data of previous smaller studies. In addition, we evaluate the age- and sex-dependent normal limits of the P wave and QRS duration and confirm in detail the frontal plane QRS-T angle on the ECG.

Prevalence of electrocardiographic unrecognized myocardial infarction and its association with mortality.

BACKGROUND: Identifying unrecognized myocardial infarction (MI) is important for secondary prevention. The aim of this study is to determine the prevalence and correlates of unrecognized MI and the association with mortality in the general population. METHODS: All participants ≥18years participating in the Lifelines population, a three-generation Cohort Study and Biobank, were included (n=152,180). Participants with unrecognized MI were matched with controls without MI (1:2) based on age and gender. Unrecognized MI was defined when no history of MI was reported in combination with electrocardiographic (ECG) signs corresponding to MI. A history of MI was defined as a reported history of MI in combination with ECG signs and/or the use of antithrombotic medication. RESULTS: MI was present in 1881(1.2%) of participants and was unrecognized in 431 (22.9%) participants. Under the age of 50years, percentages of unrecognized MI relative to the total amount of MI were 34% and 55% in men and women respectively. Compared to recognized MI, classical cardiovascular risk factors were less prevalent in participants with unrecognized MI. During a median follow- up time of 5, 4 and 4years, 4.4%, 6.4% and 2.2% of participants with unrecognized MI, recognized MI and without MI died, respectively. In a multivariable logistic regression unrecognized MI was an independent predictor of death. CONCLUSIONS: The prevalence of unrecognized MI is substantial and classical cardiovascular risk factors are less prevalent in participants with unrecognized MI. Nevertheless, unrecognized MI is associated with mortality. Risk stratification and early diagnosis is necessary to reduce the morbidity and mortality after MI.

Left ventricular ejection fraction and mortality in patients with ST-elevation myocardial infarction and bundle branch block.

BACKGROUND: The aim of our study is to assess the effect of bundle branch block (BBB) on mortality and left ventricular ejection fraction (LVEF) in ST-elevation myocardial infarction (STEMI) patients treated in the current era of percutaneous reperfusion therapy. PATIENTS AND METHODS: In this retrospective cohort study, a total of 1123 STEMI patients treated in the University Medical Center Groningen from January 2011 until May 2013 were included. The follow-up duration was 2-4 years. Transthoracic echocardiography was performed within 2 weeks after STEMI. RESULTS: In total, 23 (2.0%) patients presented with left BBB and 49 (4.4%) patients presented with right BBB. Two-year mortality after STEMI was 25.0% (n=18) in patients with BBB and 9.2% (n=97, P<0.001) in patients without BBB. Patients with BBB had more frequently a severely reduced LVEF (<30%) [20.0% (n=6) compared with 4.2% (n=21), P=0.002] and less frequently a normal LVEF [16.7% (n=5) compared with 35.7% (n=179), P=0.046]. After multivariable analysis, BBB did not remain an independent predictor of mortality, but was an independent predictor of reduced LVEF. CONCLUSION: The presence of a BBB was an independent predictor of a reduced LVEF. However, we found no effect of BBB on 2-year mortality in the current era of percutaneous reperfusion therapy.

The LifeLines Cohort Study: Prevalence and treatment of cardiovascular disease and risk factors.

BACKGROUND: The LifeLines Cohort Study is a large three-generation prospective study and Biobank. Recruitment and data collection started in 2006 and follow-up is planned for 30years. The central aim of LifeLines is to understand healthy ageing in the 21st century. Here, the study design, methods, baseline and major cardiovascular phenotypes of the LifeLines Cohort Study are presented. METHODS AND RESULTS: Baseline cardiovascular phenotypes were defined in 9700 juvenile (8-18years) and 152,180 adult (≥18years) participants. Cardiovascular disease (CVD) was defined using ICD-10 criteria. At least one cardiovascular risk factor was present in 73% of the adult participants. The prevalence, adjusted for the Dutch population, was determined for risk factors (hypertension (33%), hypercholesterolemia (19%), diabetes (4%), overweight (56%), and current smoking (19%)) and CVD (myocardial infarction (1.8%), heart failure (1.0%), and atrial fibrillation (1.3%)). Overall CVD prevalence increased with age from 9% in participants<65years to 28% in participants≥65years. Of the participants with hypertension, hypercholesterolemia and diabetes, respectively 75%, 96% and 41% did not receive preventive pharmacotherapy. CONCLUSIONS: The contemporary LifeLines Cohort Study provides researchers with unique and novel opportunities to study environmental, phenotypic, and genetic risk factors for CVD and is expected to improve our knowledge on healthy ageing. In this contemporary Western cohort we identified a remarkable high percentage of untreated CVD risk factors suggesting that not all opportunities to reduce the CVD burden are utilised.