Sex Differences in Myocardial and Vascular Aging.

It is well known that cardiovascular disease manifests differently in women and men. The underlying causes of these differences during the aging lifespan are less well understood. Sex differences in cardiac and vascular phenotypes are seen in childhood and tend to track along distinct trajectories related to dimorphism in genetic factors as well as response to risk exposures and hormonal changes during the life course. These differences underlie sex-specific variation in cardiovascular events later in life, including myocardial infarction, heart failure, ischemic stroke, and peripheral vascular disease. With respect to cardiac phenotypes, females have intrinsically smaller body size-adjusted cardiac volumes and they tend to experience greater age-related wall thickening and myocardial stiffening with aging. With respect to vascular phenotypes, sexual dimorphism in both physiology and pathophysiology are also seen, including overt differences in blood pressure trajectories. The majority of sex differences in myocardial and vascular alterations that manifest with aging seem to follow relatively consistent trajectories from the very early to the very later stages of life. This review aims to synthesize recent cardiovascular aging-related research to highlight clinically relevant studies in diverse female and male populations that can inform approaches to improving the diagnosis, management, and prognosis of cardiovascular disease risks in the aging population at large.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling.

Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (ß = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.

Modelling spatial patterns in host-associated microbial communities.

Microbial communities exhibit spatial structure at different scales, due to constant interactions with their environment and dispersal limitation. While this spatial structure is often considered in studies focusing on free-living environmental communities, it has received less attention in the context of host-associated microbial communities or microbiota. The wider adoption of methods accounting for spatial variation in these communities will help to address open questions in basic microbial ecology as well as realize the full potential of microbiome-aided medicine. Here, we first overview known factors affecting the composition of microbiota across diverse host types and at different scales, with a focus on the human gut as one of the most actively studied microbiota. We outline a number of topical open questions in the field related to spatial variation and patterns. We then review the existing methodology for the spatial modelling of microbiota. We suggest that methodology from related fields, such as systems biology and macro-organismal ecology, could be adapted to obtain more accurate models of spatial structure. We further posit that methodological developments in the spatial modelling and analysis of microbiota could in turn broadly benefit theoretical and applied ecology and contribute to the development of novel industrial and clinical applications.

Diabetes status-related differences in risk factors and mediators of heart failure in the general population: results from the MORGAM/BiomarCaRE consortium.

BACKGROUND: The risk of heart failure among diabetic individuals is high, even under tight glycemic control. The correlates and mediators of heart failure risk in individuals with diabetes need more elucidation in large population-based cohorts with long follow-up times and a wide panel of biologically relevant biomarkers. METHODS: In a population-based sample of 3834 diabetic and 90,177 non-diabetic individuals, proportional hazards models and mediation analysis were used to assess the relation of conventional heart failure risk factors and biomarkers with incident heart failure. RESULTS: Over a median follow-up of 13.8 years, a total of 652 (17.0%) and 5524 (6.1%) cases of incident heart failure were observed in participants with and without diabetes, respectively. 51.4% were women and the mean age at baseline was 48.7 (standard deviation [SD] 12.5) years. The multivariable-adjusted hazard ratio (HR) for heart failure among diabetic individuals was 2.70 (95% confidence interval, 2.49-2.93) compared to non-diabetic participants. In the multivariable-adjusted Cox models, conventional cardiovascular disease risk factors, such as smoking (diabetes: HR 2.07 [1.59-2.69]; non-diabetes: HR 1.85 [1.68-2.02]), BMI (diabetes: HR 1.30 [1.18-1.42]; non-diabetes: HR 1.40 [1.35-1.47]), baseline myocardial infarction (diabetes: HR 2.06 [1.55-2.75]; non-diabetes: HR 2.86 [2.50-3.28]), and baseline atrial fibrillation (diabetes: HR 1.51 [0.82-2.80]; non-diabetes: HR 2.97 [2.21-4.00]) had the strongest associations with incident heart failure. In addition, biomarkers for cardiac strain (represented by nT-proBNP, diabetes: HR 1.26 [1.19-1.34]; non-diabetes: HR 1.43 [1.39-1.47]), myocardial injury (hs-TnI, diabetes: HR 1.10 [1.04-1.16]; non-diabetes: HR 1.13 [1.10-1.16]), and inflammation (hs-CRP, diabetes: HR 1.13 [1.03-1.24]; non-diabetes: HR 1.29 [1.25-1.34]) were also associated with incident heart failure. In general, all these associations were equally strong in non-diabetic and diabetic individuals. However, the strongest mediators of heart failure in diabetes were the direct effect of diabetes status itself (relative effect share 43.1% [33.9-52.3] and indirect effects (effect share 56.9% [47.7-66.1]) mediated by obesity (BMI, 13.2% [10.3-16.2]), cardiac strain/volume overload (nT-proBNP, 8.4% [-0.7-17.4]), and hyperglycemia (glucose, 12.0% [4.2-19.9]). CONCLUSIONS: The findings suggest that the main mediators of heart failure in diabetes are obesity, hyperglycemia, and cardiac strain/volume overload. Conventional cardiovascular risk factors are strongly related to incident heart failure, but these associations are not stronger in diabetic than in non-diabetic individuals. Active measurement of relevant biomarkers could potentially be used to improve prevention and prediction of heart failure in high-risk diabetic patients.

Gut Microbiome over a Lifetime and the Association with Hypertension.

PURPOSE OF REVIEW: Microorganisms living within an ecosystem create microbial communities and play key roles in ecosystem functioning. During their lifespan, humans share their bodies with a variety of microorganisms. More than 10-100 trillion symbiotic microorganisms live on and within human beings, and the majority of these microorganisms populate the distal ileum and colon (referred to as the gut microbiota). Interactions between the gut microbiota and the host involve signaling via chemical neurotransmitters and metabolites, neuronal pathways, and the immune system. Hypertension is a complex and heterogeneous pathophenotype. A reductionist approach that assumes that all patients who have the same signs of a disease share a common disease mechanism and thus should be treated similarly is insufficient for optimal blood pressure management. Herein, we have highlighted the contribution of the gut microbiome to blood pressure regulation in humans. RECENT FINDINGS: Gut dysbiosis-an imbalance in the composition and function of the gut microbiota-has been shown to be associated with hypertension. Gut dysbiosis occurs via environmental pressures, including caesarean section, antibiotic use, dietary changes, and lifestyle changes over a lifetime. This review highlights how gut dysbiosis may affect a host's blood pressure over a lifetime. The review also clarifies future challenges in studies of associations between the gut microbiome and hypertension.

Electrocardiographic findings in migraineurs: results of the Finnish Health 2000 survey.

BACKGROUND: The precise relation between migraine and cardiovascular diseases remains unknown, but cardiac autonomic regulation as reflected by electrocardiography is poorly studied in migraineurs. AIMS OF THE STUDY: To search whether electrocardiographic findings may elucidate the mechanisms linking migraine with cardiovascular diseases. METHODS: We compared electrocardiographic findings in headache-free subjects (n=5,317) and people with migraine (n=490) in a Finnish population cohort. RESULTS: The frequency of cardiac rhythm and conduction disorders did not differ between the groups but left ventricular hypertrophy was more often seen in migraineurs than in non-migraineurs (odds ratio (OR)=1.32, 95% confidence interval (CI) 1.0; 1.74, p<0.05). In migraineurs reporting frequent attacks, cardiovascular diseases were associated with longer QTc intervals (p<0.05). After excluding confounders, migraineurs had longer PR intervals (160.3 vs 159.8 ms, mean difference (MD)=3.14, 95% CI 0.65; 5.62, p<0.05) than non-migraineurs. PR intervals (MD=6.6, CI 1.51; 11.68, p<0.05) and the probability of left ventricular hypertrophy (OR=1.98, CI 1.2; 3.26, p<0.05) were different in males with and without migraine, especially in patients with frequent attacks, but not in females. CONCLUSIONS: Our findings support the notion that there are interactions between migraine and cardiovascular disorders and suggest that electrocardiographic screening in migraineurs should be considered during clinical work-up.

Left ventricular hypertrophy and other cardiac risk factors in migraineurs.

BACKGROUND: The influence of cardiovascular risk factors on the probability of cardiovascular diseases in migraineurs is still being discussed. AIMS OF THE STUDY: To further elucidate the mechanisms of these relationships, we assessed the associations between migraine and cardiovascular risk factors, including those that have been recently shown to improve the prediction of cardiovascular events. METHODS: We used the data of the Finnish Health 2000 Survey (BRIF8901), consisting of 5737 subjects aged 30 years or older. In total, 488 participants reported migraine. In addition to conventional cardiovascular risk factors, educational attainment, presence of electrocardiographic signs of left ventricular hypertrophy and hemoglobin A1c were also included in the logistic regression analyses. RESULTS: Migraine was found to be associated with female sex (Odds ratio (OR) = 3.75, p < .001), lower age (B = 0.99, p < .001), lower high-density lipoprotein cholesterol (OR = 1.23, p < .05), higher diastolic blood pressure (OR = 1.31, p < .05), and left ventricular hypertrophy (OR = 1.32, p < .05), the probability of the last one increasing with migraine attack frequency. CONCLUSIONS: Left ventricular hypertrophy, most probably as a consequence of migraine-related arterial hypertension and dyslipidemia, may play a role in the relationship between migraine and cardiovascular events. The nature of this finding calls for further studies.

Age of Hypertension Onset: Overview of Research and How to Apply in Practice.

PURPOSE OF REVIEW: To review the current evidence on research related to age of hypertension onset-its definition, correlates, heritability, and association with adverse outcomes. We also propose a framework for implementing assessment of hypertension onset age into clinical practice. RECENT FINDINGS: Prior studies have used both objective measurements and self-report to determine age of hypertension onset or early-onset hypertension. Yet, no criterion for standard definition currently exists for either. Data from epidemiological and clinical studies demonstrate that early-onset hypertension is a highly heritable trait that confers an increased risk for cardiovascular death and end-organ damage compared with late-onset hypertension. Literature to date suggests that (parental) age of hypertension onset can be feasibly assessed for estimating (1) risk of future hypertension in non-hypertensive persons; and (2) the propensity for cardiovascular disease in individuals with established hypertension.

Population trends in aortic valve surgery in Finland between 2001 and 2016.

Objectives. To investigate nationwide changes in procedure rates, patient selection, and prognosis after all surgical aortic valve replacements. Design. Patients undergoing primary surgical aortic valve replacement between 2001 and 2016 were identified from three nationwide registers with compulsory reporting to examine trends in aortic valve surgery over four four-year time periods. Results. A total of 12,139 surgical aortic valve replacement procedures (mean age 61.9 ± 11.8 years, 39.1% women) were performed. The total number of biological valves increased from 1001 (42.9%) to 2526 (75.5%) from 2001-2004 to 2013-2016 (p < .001). During the first and last time periods the comorbidity burden increased; share of patients with hypertension increased from 37.5% to 46.9% (p < .001), diabetes from 14% to 16.5% (p = .01) and previous stroke from 5.2% to 7.2% (p = .01). The proportion of women undergoing surgery decreased from 40% to 36.1% from 2001-2004 to 2013-2016, respectively (p = .01). Overall 28-day mortality was 3.5%. In patients with biologic valve the multivariable-adjusted risk of short-term mortality decreased steadily in every four-year period from 2001-2004 to 2005-2008 (HR, 0.66; 95% CI 0.47-9.92), 2009-2012 (HR, 0.54; 95% CI, 0.39-0.75) and 2013-2016 (HR, 0.41; 95% CI, 0.29-0.58), whereas short-term mortality remained similar in patients with mechanical valve. The risk of four-year postoperative mortality after all surgical aortic valve replacements stayed constant. Conclusions. The use of biologic aortic valve prosthesis has increased from 2001 to 2016. The proportion of women has declined markedly. The short-term mortality has decreased and the long-term mortality has stayed constant despite increasing comorbidity burden.

The validity of heart failure diagnoses in the Finnish Hospital Discharge Register.

Background: Contemporary validation studies of register-based heart failure diagnoses based on current guidelines and complete clinical data are lacking in Finland and internationally. Our objective was to assess the positive and negative predictive values of heart failure diagnoses in a nationwide hospital discharge register. Methods: Using Finnish Hospital Discharge Register data from 2013-2015, we obtained the medical records for 120 patients with a register-based diagnosis for heart failure (cases) and for 120 patients with a predisposing condition for heart failure, but without a heart failure diagnosis (controls). The medical records of all patients were assessed by a physician who categorized each individual as having heart failure (with reduced or preserved ejection fraction) or no heart failure, based on the definition of current European Society of Cardiology heart failure guidelines. Unclear cases were assessed by a panel of three physicians. This classification was considered as the clinical gold standard, against which the registers were assessed. Results: Register-based heart failure diagnoses had a positive predictive value of 0.85 (95% CI 0.77-0.91) and a negative predictive value of 0.83 (95% CI 0.75-0.90). The positive predictive value decreased when we classified patients with transient heart failure (duration <6 months), dialysis/lung disease or heart failure with preserved ejection fraction as not having heart failure. Conclusions: Heart failure diagnoses of the Finnish Hospital Discharge Register have good positive predictive value and negative predictive value, even when patients with pre-existing heart conditions are used as healthy controls. Our results suggest that heart failure diagnoses based on register data can be reliably used for research purposes.

The relation of work-related factors with ambulatory blood pressure and nocturnal blood pressure dipping among aging workers.

OBJECTIVES: Individuals with reduced nocturnal blood pressure (BP) dipping are at increased risk of cardiovascular disease compared to persons with normal BP dipping. Although the relation of work-related factors and BP has been studied extensively, very little is known of the association between work-related factors and 24-h BP patterns in aging workers. We examined the cross-sectional relation of work-related risk factors, including occupational status, work-time mode, job demands and job control, with ambulatory BP in aging workers, focusing on nocturnal BP dipping. METHODS: 208 workers (mean age 62 ± 3 years; 75% women) from two Finnish population-based cohort studies underwent 24-h ambulatory BP monitoring. Work-related factors were inquired using a questionnaire. Nocturnal BP dipping was calculated as [1 - (asleep BP/awake BP)] × 100. RESULTS: Shift workers demonstrated a higher nocturnal diastolic BP dipping than regular day workers (19% vs. 17%, p = 0.03) and had a significantly higher systolic awake BP than regular day workers (136.5 mmHg vs. 132.5 mmHg, p = 0.03). Participants with high job demands demonstrated a smaller nocturnal systolic BP dipping than participants with low job demands (14% vs. 16%, p = 0.04). We did not observe significant differences in nocturnal systolic or diastolic BP dipping between groups categorized by occupational status or job control. CONCLUSIONS: Although shift workers have a higher daytime BP than regular daytime workers, they exhibit greater nighttime BP dipping. Participants with high job demand had smaller nighttime BP dipping than participants with low job demand. Job control or occupation did not affect the 24-h ambulatory BP profile of aging workers.

Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe).

BACKGROUND: Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood. METHODS: In N=79 793 individuals without AF diagnosis at baseline (median age, 49.6 years; age range, 24.1-97.6 years; 51.7% women) from 4 community-based European studies (FINRISK, DanMONICA, Moli-sani Northern Sweden) of the BiomarCaRE consortium (Biomarker for Cardiovascular Risk Assessment in Europe), we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years. RESULTS: Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men. Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18; 95% confidence interval [CI], 1.12-1.23 in women versus 1.31; 95% CI 1.25-1.38 in men; interaction P value of 0.001). Total cholesterol was inversely associated with incident AF with a greater risk reduction in women (hazard ratio per SD, 0.86; 95% CI, 0.81-0.90 versus 0.92; 95% CI, 0.88-0.97 in men; interaction P value of 0.023). No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index. CONCLUSIONS: Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies.

Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients.

BACKGROUND: Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported. METHODS: To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P < 1 × 10- 5 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES. RESULTS: In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (ß = - 4.8%, P = 9.6 × 10- 9 for systolic and ß = - 4.3%, P = 2.2 × 10- 6 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 × 10- 5. The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (ß = - 0.8%, P = 0.4 for systolic and ß = - 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (ß = - 7.6 g/m2, P = 0.02). CONCLUSIONS: rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology.

Thyroid-stimulating hormone and risk of sudden cardiac death, total mortality and cardiovascular morbidity.

BACKGROUND: Previous data on the association of thyroid function with total mortality, cardiovascular disease (CVD) outcomes and sudden cardiac death (SCD) are conflicting or limited. We investigated associations of thyroid-stimulating hormone (TSH) with these outcomes in a nationwide population-based prospective cohort study. METHODS: We examined 5211 participants representative of the Finnish population aged ≥30 years in 2000-2001 and followed them for a median of 13.2 years. Using Cox proportional hazards regression models adjusted for baseline age, gender, smoking, diabetes, systolic blood pressure and total and high-density lipoprotein cholesterol, we assessed the associations of continuous baseline TSH and TSH categories (low [<0.4 mU/L], reference range [0.4-3.4 mU/L] and high [>3.4 mU/L]) with incident total mortality, SCD, coronary heart disease events, stroke, CVD, major adverse cardiac events and atrial fibrillation. RESULTS: High TSH at baseline was related to a greater risk of total mortality (HR 1.34, 95% CI 1.02-1.76) and SCD (HR 2.28, 95% CI 1.13-4.60) compared with TSH within the reference range. High TSH was not associated with the other outcomes (P ≥ .51), whereas low TSH was not associated with any of the outcomes (P ≥ .09). TSH at baseline over the full range did not have a linear relation with any of the outcomes (P ≥ .17). TSH showed a U-shaped association with total mortality after a restricted cubic spline transformation (P = .01). CONCLUSIONS: Thyroid function abnormalities could be linked with higher risks of total mortality and SCD. Large-scale randomized studies are needed for evidence-based recommendations regarding treatment of mild thyroid failure.

Population trends in mitral valve surgery in Finland between 1997 and 2014: the finnish CVD register.

OBJECTIVES: Contemporary, nationwide data on trends in mitral valve surgery are scarce. Our aim was to investigate changes in procedure rates, patient selection, and post-procedural prognosis of open-heart mitral valve surgery in Finland. DESIGN: We combined data from three nationwide administrative registers with compulsory reporting. We identified patients who had undergone first-ever open-heart mitral valve surgery between 1997 and 2014 and followed them for adverse events. We examined trends in mitral valve surgery over three six-year time periods (1997-2002, 2003-2008, and 2009-2014). RESULTS: 3684 mitral valve procedures (mean age: 67.0 ± 10.9 years, 42.6% women) were performed in 1997-2014 in Finland. During this period, mitral valve repair operations became more common than replacements and we observed an increasing trend in the use of bioprosthetic valves. Between 1997-2002 and 2009-2014, the mean age of patients undergoing mitral valve surgery and the proportion of urgent surgeries increased (p < .001 for both). The proportion of women undergoing surgery decreased while the share of patients with hypertension (p = .023) or diabetes (p = .026) increased. The multivariable-adjusted risk of 28-day (hazard ratio, 0.55; 95% confidence interval, 0.37-0.83) and 6-year (hazard ratio, 0.80; 95% confidence interval, 0.67-0.97) post-operative mortality was lower in the last six-year period than in 1994-1998. CONCLUSIONS: Short- and long-term mortality of mitral valve surgery patients in Finland has decreased from 1997 to 2014 despite the patients being older and having more comorbidities. Understanding the changing characteristics and prognosis of these patients is important for the interpretation of previous and future cohort studies and trials.

Risk for hypertension crosses generations in the community: a multi-generational cohort study.

AIMS: Parental hypertension is known to predict high blood pressure (BP) in children. However, the extent to which risk for hypertension is conferred across multiple generations, notwithstanding the impact of environmental factors, is unclear. Our objective was therefore to evaluate the degree to which risk for hypertension extends across multiple generations of individuals in the community. METHODS AND RESULTS: We studied three generations of Framingham Heart Study participants with standardized blood pressure measurements performed at serial examinations spanning 5 decades (1948 through 2005): First Generation (n = 1809), Second Generation (n = 2631), and Third Generation (n = 3608, mean age 39 years, 53% women). To capture a more precise estimate of conferrable risk, we defined early-onset hypertension (age <55 years) as the primary exposure. In multinomial logistic regression models adjusting for standard risk factors as well as physical activity and daily intake of dietary sodium, risk for hypertension in the Third Generation was conferred simultaneously by presence of early-onset hypertension in parents [OR 2.10 (95% CI, 1.66-2.67), P < 0.001] as well as in grandparents [OR 1.33 (95% CI, 1.12-1.58), P < 0.01]. CONCLUSION: Early-onset hypertension in grandparents raises the risk for hypertension in grandchildren, even after adjusting for early-onset hypertension in parents and lifestyle factors. These results suggest that a substantial familial predisposition for hypertension exists, and this predisposition is not identical when assessed from one generation to the next. Additional studies are needed to elucidate the mechanisms underlying transgenerational risk for hypertension and its clinical implications.

Association of thyroid-stimulating hormone with lipid concentrations: an 11-year longitudinal study.

BACKGROUND: Scant data exist on the longitudinal association between thyroid function and lipid concentrations. We investigated associations of TSH and lipid concentrations cross-sectionally and longitudinally in a nationwide population sample. METHODS: A total of 5205 randomly sampled participants representative of Finns aged ≥30 years were examined in 2000-2001 and included in cross-sectional analyses. A total of 2486 were re-examined 11 years later and included in longitudinal analyses. With linear regression models adjusted for age, gender, smoking and body mass index, we assessed the associations of baseline TSH and TSH categories (low, reference range and high) with total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol; apolipoprotein A1 and B; and triglycerides at baseline and follow-up. RESULTS: At baseline, higher TSH associated with higher total cholesterol (ß = 0·025, standard error [SE] = 0·007, P < 0·001), LDL cholesterol (ß = 0·020, SE = 0·007, P = 0·002), apolipoprotein B (ß = 0·006, SE = 0·002, P < 0·001) and log triglycerides (ß = 0·008, SE = 0·003, P = 0·004), but not with other lipid outcomes. Higher baseline TSH associated with higher total cholesterol (ß = 0·056, SE = 0·026, P = 0·033), LDL cholesterol (ß = 0·057, SE = 0·023, P = 0·015) and apolipoprotein B (ß = 0·012, SE = 0·006, P = 0·028) at follow-up in women, but not with any lipid outcomes in men. Participants with high TSH at baseline had a 0·22 mmol/l (95% confidence interval 0·02-0·41 mmol/l) higher LDL cholesterol at follow-up (P = 0·028) than participants with TSH in the reference range (0·4-3·4 mU/l). However, exclusion of participants with high-risk baseline lipid values rendered these positive longitudinal associations nonsignificant (P ≥ 0·098). CONCLUSIONS: We could confirm a modest association between higher TSH and an adverse lipid profile cross-sectionally but not indisputably longitudinally.

Incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities - a nationwide population-based study.

BACKGROUND: Scant data exist on incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities in the general population. METHODS: We recorded ECG and measured conventional cardiovascular risk factors in 5667 Finns who were followed up for incident atrial fibrillation (AF). We obtained repeat ECGs from 3089 individuals 11years later. RESULTS: The incidence rates of prolonged P-wave duration, abnormal P terminal force (PTF), left P-wave axis deviation, and right P-wave axis deviation were 16.0%, 7.4%, 3.4%, and 2.2%, respectively. Older age and higher BMI were associated with incident prolonged P-wave duration and abnormal PTF (P≤0.01). Higher blood pressure was associated with incident prolonged P-wave duration and right P-wave axis deviation (P≤0.01). During follow-up, only prolonged P-wave duration predicted AF (multivariable-adjusted hazard ratio, 1.38; P=0.001). CONCLUSIONS: Modifiable risk factors associate with P-wave abnormalities that are common and may represent intermediate steps of atrial cardiomyopathy on a pathway leading to AF.