Cardiovascular risk stratification in the general population and patients with coronary artery disease: Clinical studies on novel biochemical and echocardiographic markers

Coronary artery disease is one of the leading causes of mortality in the western world, and early identification is essential to reduce the burden of cardiovascular disease. Patients with coronary artery disease range from persons with subclinical disease to patients with acute coronary syndrome. The thesis aimed to improve the diagnostic and prognostic assessment of cardiovascular events in the general population and patients with stable and acute coronary syndrome. Mechanical dispersion is a novel echocardiographic marker that measures the contraction heterogeneity of the left ventricle. In a general population, increased mechanical dispersion was associated with established cardiovascular risk factors. NT-proBNP was superior to both novel and established biochemical and echocardiographic markers in the prediction of adverse outcomes. Mechanical dispersion gave incremental information to already established echocardiographic markers. Although high-sensitivity troponin T and I had similar abilities in the detection of coronary lesions, we found biological differences between the analytical assays that could impact the clinical interpretation

B-Type Natriuretic Peptide Is Associated with Indices of Left Ventricular Dysfunction in Healtahy Subjects from the General Population: The Akershus Cardiac Examination 1950 Study

Abstract Background Concentrations of B-type natriuretic peptide (BNP) reflect myocardial distension and stress, and are associated with poor prognosis in patients with cardiovascular disease. Accordingly, we hypothesized that concentrations of BNP would be associated with indices of adverse left ventricular (LV) remodeling and early stages of LV systolic and diastolic dysfunction in healthy participants from the general population. Methods We measured BNP in 1757 women and 1677 men free from known coronary heart disease participating in the prospective observational Akershus Cardiac Examination 1950 Study. All study participants underwent extensive cardiovascular phenotyping at baseline, including detailed echocardiography with assessment of indexed LV mass (LVMI), diastolic [tissue Doppler e’, E/e’ ratio, indexed left atrial volume (LAVI), maximal tricuspid regurgitation velocity (TRVmax), and E/A ratio], and systolic [global longitudinal strain (GLS) and LV ejection fraction (LVEF)] function. Results Study participants with the highest BNP concentrations had higher GLS, LVMI, e’, E/e’ ratio, LAVI, TRVmax, and E/A ratio. In adjusted analyses, both GLS and LVEF exhibited significant nonlinear associations with BNP, with reduced LV systolic function observed in both the low and high concentration range of BNP. Conclusions In healthy participants recruited from the general population, concentrations of BNP exhibit nonlinear associations with LV systolic function, and both low and high concentrations are associated with reduced LV systolic function. This supports the notion that natriuretic peptides are beneficial and elicit cardioprotective effects, and may have important implications for the interpretation of BNP measurements in the general population

Cardiac troponin I and T are associated with left ventricular function and structure: Data from the Akershus Cardiac Examination 1950 Study

Abstract Background Concentrations of cardiac troponin I (cTnI) and T (cTnT) are associated with clinical cardiac outcomes, but do not correlate closely in subjects recruited from the general population. Accordingly, we hypothesized that cTnI and cTnT concentrations would be influenced by different cardiovascular (CV) and non-CV risk factors and reflect different CV phenotypes. Methods We measured cTnI and cTnT with last generation assays in 1236 women and 1157 men with no known CV disease participating in the prospective observational Akershus Cardiac Examination 1950 Study. All study participants underwent extensive CV phenotyping at baseline, including detailed echocardiography. Results Concentrations of cTnI were measurable in 60.3% and cTnT in 72.5% of study participants (P < 0.001), and correlated moderately (r = 0.53; P < 0.001). cTnI was more strongly associated with male sex (P = 0.018), higher education (P < 0.001), history of hypertension (P < 0.001), and age (P < 0.001), whereas cTnT was more strongly associated with eGFR (P = 0.015). Both cTnI and cTnT were inversely associated with global longitudinal strain and positively associated with LV mass index (LVMI) in analyses adjusted for CV risk factors. The association between cTnI and LVMI was stronger than the association between cTnT and LVMI (P = 0.035). Concentrations of cTnI improved diagnostic accuracy for LV hypertrophy when added to established CV risk factors, but concentrations of cTnT did not improve these models further. Conclusions In a large community-based cohort examined with extensive echocardiography, concentrations of cTnI and cTnT are associated with subclinical LV hypertrophy and dysfunction. Concentrations of cTnI appear superior to cTnT in predicting subclinical LV hypertrophy

Mechanical dispersion as a marker of left ventricular dysfunction and prognosis in stable coronary artery disease

Assessment of global longitudinal strain (GLS) is superior to ejection fraction (EF) in the evaluation of left ventricular (LV) function in patients with stable coronary artery disease (CAD). However, the role of mechanical dispersion (MD) in this context remains unresolved. We aimed to evaluate the potential role of MD as a marker of LV dysfunction and long-term prognosis in stable CAD. EF, GLS and MD were assessed in 160 patients with stable CAD, 1 year after successful coronary revascularization. Serum levels of high-sensitivity cardiac troponin I (hs-cTnI) and amino-terminal pro B-type natriuretic peptide (NT-proBNP) were quantified as surrogate markers of LV dysfunction. The primary endpoint was defined as all-cause mortality, the secondary endpoint was defined as the composite of all-cause mortality and hospitalization for acute myocardial infarction or heart failure during follow-up. Whereas no associations between EF and the biochemical markers of LV function were found, both GLS and MD correlated positively with increasing levels of hs-cTnI (R = 0.315, P < 0.001 and R = 0.442, P < 0.001, respectively) and NT-proBNP (R = 0.195, P = 0.016 and R = 0.390, P < 0.001, respectively). Median MD was 46 ms (interquartile range [IQR] 37–53) and was successfully quantified in 96% of the patients. During a median follow-up of 8.4 (IQR 8.2–8.8) years, 14 deaths and 29 secondary events occurred. MD was significantly increased in non-survivors, and provided incremental prognostic value when added to EF and GLS. NT-proBNP was superior to the echocardiographic markers in predicting adverse outcomes. MD may be a promising marker of LV dysfunction and adverse prognosis in stable CAD

Serial blood pressure measurements, left ventricular remodelling and cardiovascular outcomes

Background Hypertension is a risk factor for the development of cardiovascular disease. Whether serial blood pressure (BP) measurements are more closely associated with subclinical left ventricular (LV) remodelling and better predict risk of cardiovascular events over individual BP measurements are not known. Methods We assessed systolic BP, diastolic BP and pulse pressure at several time points during adulthood in 1333 women and 1211 men participating in the Akershus Cardiac Examination 1950 Study. We defined serial BP measurements as the sum of averaged BPs from adjacent consecutive visits indexed to total exposure time between measurements. We assessed the associations between serial and individual BP measurements and (1) LV structure, function and volumes and (2) incident myocardial infarction, ischemic stroke, heart failure and cardiovascular death. Results All indices of higher serial BP measurements were associated with increased indexed LV mass, and the associations were stronger than those of individual BP measurements. Serial diastolic BP pressure was strongly and inversely associated with LV systolic function, while higher serial systolic BP was primarily associated with higher LV volumes. Both serial systolic (incidence rate ratio [IRR] 1.10, 95% CI 1.03 to 1.17) and diastolic BPs (IRR 1.14, 95% CI 1.02 to 1.27) were associated with increased incidence of clinical events. Conclusion In healthy community dwellers without established cardiovascular disease, different serial BP indices associate strongly with LV remodelling and cardiovascular outcomes. Whether the use of serial BP indices for guiding treatment is superior to individual measurements should be explored in additional prospective studies

Prevalence of atrial fibrillation and cardiovascular risk factors in a 63-65 years old general population cohort: The Akershus Cardiac Examination (ACE) 1950 Study

Objectives To investigate the sex-specific prevalence of atrial fibrillation (AF), including subclinical AF found by screening in a general population aged 63–65 years. The prevalence of cardiovascular risk factors and their association with AF will also be investigated. Methods: All participants underwent extensive cardiovascular examinations, including 12-lead ECG. History of AF and other cardiovascular diseases were self-reported. Subsequent validation of all reported or detected AF diagnoses was performed. Results: Mean age was 63.9±0.7 years. Prevalence of ECG-verified AF was 4.5% (women 2.4%, men 6.4%; p<0.001), including screen-detected AF in 0.3% (women 0.1%, men 0.6%; p<0.01). Hypertension was found in 62.0% (women 57.8%, men 66.0%; p<0.001). Overweight or obesity was found in 67.6% (women 59.8%, men 74.9%; p<0.001). By multivariate logistic regression, risk factors associated with AF were height (OR 1.67 per 10 cm; 95% CI 1.26 to 2.22; p<0.001), weight (OR 1.15 per 10 kg; 95% CI 1.01 to 1.30; p=0.03), hypertension (OR 2.49; 95% CI 1.61 to 3.86; p<0.001), heart failure (OR 3.51; 95% CI 1.71 to 7.24; p=0.001), reduced estimated glomerular filtration rate (OR 2.56; 95% CI 1.42 to 4.60; p<0.01) and at least one first-degree relative with AF (OR 2.32; 95% CI 1.63 to 3.31; p<0.001), whereas male sex was not significantly associated (OR 1.00; 95% CI 0.59 to 1.68; p=0.99). Conclusion: In this cohort from the general population aged 63–65 years, we found a higher prevalence of known AF than previously reported below the age of 65 years. The additional yield of single time point screening for AF was low. Body size and comorbidity may explain most of the sex difference in AF prevalence at this age

Diagnostic Thresholds for Pre-Diabetes Mellitus and Diabetes Mellitus and Subclinical Cardiac Disease in the General Population: Data From the ACE 1950 Study

Background Diabetes mellitus (DM) is associated with left ventricular remodeling and incident heart failure, but the association between glycated hemoglobin A1c (HbA1c) and subclinical cardiac disease is not established. We aimed to determine the associations between HbA1c and (1) echocardiographic measures of left ventricular structure and function, and (2) cardiovascular biomarkers: cardiac troponin T, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), and CRP (C‐reactive protein). Methods and Results Participants (n=3688) born in 1950 from the population‐based ACE (Akershus Cardiac Examination) 1950 Study were classified as DM (HbA1c≥6.5% or self‐reported DM), pre‐DM (HbA1c 5.7%–6.5%), and no‐DM (HbA1c<5.7%). DM, pre‐DM, and no‐DM were classified in 380 (10%), 1630 (44%), and 1678 (46%) participants, respectively. Mean age was 63.9±0.7 years, mean body mass index was 27.2±4.4 kg/m2, and 49% were women. Higher HbA1c was associated with worse left ventricular systolic (ejection fraction and global longitudinal strain) and diastolic (E/e'‐ratio) function, myocardial injury (cardiac troponin T), inflammation (CRP), and impaired neurohormonal homeostasis (NT‐proBNP) (P<0.001 in unadjusted and P<0.01 in adjusted analysis for all). The associations between HbA1c and cardiovascular biomarkers were independent of the echocardiographic variables, and vice versa. Associations were nonlinear (P<0.05 for nonlinearity) and appeared stronger in the pre‐DM range of HbA1c than the no‐DM and DM range. Conclusions HbA1c was associated with indexes of subclinical cardiovascular disease, and this was more pronounced in pre‐DM. Our results suggest that cardiovascular preventive measures should be considered also in subjects with hyperglycemia and HbA1c below the established DM cutoff. Registration clinicaltrials.gov. Identifier: NCT01555411

Impact of Blood Pressure in the Early 40s on Left Atrial Volumes in the Mid-60s: Data From the ACE 1950 Study

Background Echocardiographic measures of left atrial volumes are powerful predictors of cardiovascular events and important for assessing diastolic dysfunction. Despite this, there is limited knowledge of factors influencing left atrial remodeling. In particular, the impact of blood pressure in those in their early 40s on left atrial volumes later in life has not been sufficiently elucidated. Methods and Results We linked data from individuals born in 1950 who participated in the Age 40 Program, and the ACE (Akershus Cardiac Examination) 1950 Study. We divided the study population into quartiles of systolic blood pressure in their early 40s and assessed the proportion of individuals with an enlarged left atrium in their mid‐60s. The associations between blood pressure and left atrial volumes were assessed in linear regression analyses. Of the 2591 individuals included in this study, 1302 (50.3%) were women, and the mean age in the Age 40 Program was 40.1±0.3 years. Systolic blood pressure was 128.1±13.6 mm Hg and diastolic blood pressure was 78.3±9.5 mm Hg. Mean age in the ACE 1950 Study was 64.0±0.6 years. The proportion of individuals with an enlarged left atrium increased across the quartiles of systolic blood pressure (P=0.001). Systolic blood pressure was independently associated with left atrial volumes; the end‐systolic volume was 0.09 mL (95% CI, 0.04–0.14 mL) larger per 1‐mm Hg higher systolic blood pressure. Conclusions Our findings suggest that increased blood pressure in those in their early 40s is relevant for left atrial remodeling later in life