Peripheral blood mitochondrial DNA content in relation to circulating metabolites and inflammatory markers: a population study

Mitochondrial DNA (mtDNA) content might undergo significant changes caused by metabolic derangements, oxidative stress and inflammation that lead to development and progression of cardiovascular diseases. We, therefore, investigated in a general population the association of peripheral blood mtDNA content with circulating metabolites and inflammatory markers. We examined 310 subjects (50.6% women; mean age, 53.3 years) randomly selected from a Flemish population. Relative mtDNA content was measured by quantitative real-time PCR in peripheral blood cells. Peak circulating metabolites were quantified using nuclear magnetic resonance spectroscopy. The level of inflammation was assessed via established inflammatory markers. Using Partial Least Squares analysis, we constructed 3 latent factors from the 44 measured metabolites that explained 62.5% and 8.5% of the variance in the contributing metabolites and the mtDNA content, respectively. With adjustments applied, mtDNA content was positively associated with the first latent factor (P = 0.002). We identified 6 metabolites with a major impact on the construction of this latent factor including HDL3 apolipoproteins, tyrosine, fatty acid with αCH2, creatinine, β-glucose and valine. We summarized them into a single composite metabolite score. We observed a negative association between the composite metabolic score and mtDNA content (P = 0.001). We also found that mtDNA content was inversely associated with inflammatory markers including hs-CRP, hs-IL6, white blood cell and neutrophil counts as well as neutrophil-to-lymphocyte ratio (P≤0.0024). We demonstrated that in a general population relative peripheral blood mtDNA content was associated with circulating metabolites indicative of perturbed lipid metabolism and with inflammatory biomarkers

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

Genetic and mtDNA contributions to early cardiovascular ageing and disease: a population study

Heart failure (HF) is a progressive disorder that begins with cardiovascular risk factors, proceeds to asymptomatic maladaptive left ventricular (LV) remodelling and dysfunction, and then evolves into clinically overt HF and disability. The genetic and molecular drivers that underlie progressive cardiac dysfunction and remodelling are only partially understood. The progression of LV dysfunction is associated with changes in cardiac energy production as well as consumption. Mitochondria, main myocardial adenosine triphosphate (ATP) producing organelles, contain several copies of circular mitochondrial DNA (mtDNA) molecules that are susceptible to oxidative damage. Accumulation of mtDNA damage in dysfunctional mitochondria might result in decreased overall cellular mitochondrial-to-nuclear DNA ratio (mtDNA content) early in the course of HF. On the other hand, cardiomyocyte contraction and relaxation depend on the balance of important electrolytes across the cellular membranes in cardiomyocytes. The electrolyte gradients are maintained by trans-membrane channels and active ATP dependent pumps. Marked decrease in mitochondrial ATP production leads to the inhibition of the Na-K-ATPase and to impaired LV function. Considering the known pathophysiological roles of both energy producing mitochondria and energy consuming electrolyte pumps in determination of LV function, biomarkers of mitochondrial function and genetic polymorphism of the Na/K ATPase require further study. To investigate the genetic and mitochondrial contributions to early changes in LV structure and/or function, this doctoral project builds on large-scale European population studies of cardiovascular phenotypes and outcomes. Using an epidemiological approach we will: (1) determine whether genetic factors contribute to LV diastolic function as assessed by echocardiographic Doppler velocities, (2) evaluate the possible association between LV function and polymorphisms in ATP12A gene encoding a subunit of an ATPase that can function as a Na+/K+ pump, (3) measure the peripheral blood mtDNA content in a general population sample and describe its distribution and determinants, (4) investigate whether echocardiographic indexes of LV structure and function are associated with mtDNA content measured in peripheral blood cells, (5) explore the relations between mtDNA content, circulating metabolites and markers of inflammation, (6) test the correlation between mtDNA content measured in cardiomyocytes and peripheral blood cells in patients with symptomatic HF.status: publishe

Prognostic Value of Left Ventricular Diastolic Dysfunction in a General Population

BACKGROUND: New techniques of Tissue Doppler Imaging (TDI) enable the measurement of myocardial velocities and provide information about left ventricular (LV) diastolic function. Recent studies explored the prognostic role of TDI‐derived indexes. However, these studies considered only total mortality and did not provide information on cardiovascular mortality and morbidity. Therefore, we investigated in continuous and categorical analyses whether Doppler diastolic indexes contained any prognostic information over and beyond traditional cardiovascular risk factors in a general population. METHODS AND RESULTS: We measured early and late diastolic peak velocities of mitral inflow (E and A) by conventional Doppler, and the mitral annular velocities (e' and a') by TDI in 793 participants (mean age 50.9 years). We calculated multivariable‐adjusted hazard ratios for conventional and TDI Doppler indexes, while accounting for family cluster and cardiovascular risk factors. Median follow‐up was 4.8 years (5th to 95th percentile, 3.0 to 5.4). With adjustments applied for covariables, e' velocity was a significant predictor of fatal and nonfatal cardiovascular (n=59; P=0.004) and cardiac events (n=40; P=0.001). TDI e' yielded a net reclassification improvement of 54.2% for cardiovascular and 64.0% for cardiac events. Hazard ratios of all cardiovascular (2.21; P=0.042) and cardiac (4.50; P=0.002) events were significantly elevated in participants with increased LV filling pressure compared with subjects with normal diastolic function. CONCLUSIONS: TDI e' velocity is a significant predictor of fatal and nonfatal cardiovascular events in a general population. Furthermore, we observed an increase in all cardiovascular events in the diastolic dysfunction group characterized by elevated LV filling pressure

Doppler Indexes of Left Ventricular Systolic and Diastolic Flow and Central Pulse Pressure in Relation to Renal Resistive Index

The cardio-renal interaction occurs via hemodynamic and humoral factors. Noninvasive assessment of renal hemodynamics is currently possible by assessment of renal resistive index (RRI) derived from intrarenal Doppler arterial waveforms as ((peak systolic velocity - end-diastolic velocity)/peak systolic velocity). Limited information is available regarding the relationship between RRI and cardiac hemodynamics. We investigated these associations in randomly recruited subjects from a general population.status: publishe

1A.04: CORRELATES OF PERIPHERAL BLOOD MITOCHONDRIAL DNA COPY NUMBER IN A GENERAL POPULATION

Mitochondrial DNA (mtDNA) molecules are highly susceptible to oxidative stress. Accumulation of mtDNA mutations leads to alterations of mitochondrial biogenesis and function that might result in decrease of mtDNA content within cells. This implies a possible role of mtDNA content as a potential biomarker in processes associated with oxidative stress and inflammation. However, data on correlates of the mtDNA content in a general population are sparse. Therefore, the objectives of the present study were to describe in a randomly recruited population sample the distribution and determinants of the peripheral blood mtDNA content.status: publishe

[OP.4B.04] LONGITUDINAL CHANGES IN LEFT VENTRICULAR STRUCTURE AND DIASTOLIC FUNCTION IN RELATION TO ARTERIAL PROPERTIES IN A GENERAL POPULATION

Serial imaging studies are needed to clarify the relation of change in left ventricular (LV) structure and function with arterial stiffness. In this longitudinal population study, we assessed in continuous and categorical analyses to what extent arterial properties predict alterations in echocardiographic indexes reflecting LV structure and function.status: publishe

Correlates of Peripheral Blood Mitochondrial DNA Content in a General Population

Accumulation of mitochondrial DNA (mtDNA) mutations leads to alterations of mitochondrial biogenesis and function that might produce a decrease in mtDNA content within cells. This implies that mtDNA content might be a potential biomarker associated with oxidative stress and inflammation. However, data on correlates of mtDNA content in a general population are sparse. Our goal in the present study was to describe in a randomly recruited population sample the distribution and determinants of peripheral blood mtDNA content. From 2009 to 2013, we examined 689 persons (50.4% women; mean age = 54.4 years) randomly selected from a Flemish population (Flemish Study on Environment, Genes, and Health Outcomes). Relative mtDNA copy number as compared with nuclear DNA was measured by quantitative real-time polymerase chain reaction in peripheral blood. There was a curvilinear relationship between relative mtDNA copy number and age. mtDNA content slightly increased until the fifth decade of life and declined in older subjects (Page (2) = 0.0002). mtDNA content was significantly higher in women (P = 0.007) and increased with platelet count (P < 0.0001), whereas it was inversely associated with white blood cell count (P < 0.0001). We also observed lower mtDNA content in women using estroprogestogens (P = 0.044). This study demonstrated in a general population that peripheral blood mtDNA content is significantly associated with sex and age. Blood mtDNA content is also influenced by platelet and white blood cell counts and estroprogestogen intake. Further studies are required to clarify the impact of chronic inflammation and hormone therapy on mitochondrial function.status: publishe