Real-world walking behaviors are associated with early-stage heart failure: a Project Baseline Health Study.

BACKGROUND: Data collected via wearables may complement in-clinic assessments to monitor subclinical heart failure (HF). OBJECTIVES: Evaluate the association of sensor-based digital walking measures with HF stage and characterize their correlation with in-clinic measures of physical performance, cardiac function and participant reported outcomes (PROs) in individuals with early HF. METHODS: The analyzable cohort included participants from the Project Baseline Health Study (PBHS) with HF stage 0, A, or B, or adaptive remodeling phenotype (without risk factors but with mild echocardiographic change, termed RF-/ECHO+) (based on available first-visit in-clinic test and echocardiogram results) and with sufficient sensor data. We computed daily values per participant for 18 digital walking measures, comparing HF subgroups vs stage 0 using multinomial logistic regression and characterizing associations with in-clinic measures and PROs with Spearman's correlation coefficients, adjusting all analyses for confounders. RESULTS: In the analyzable cohort (N=1265; 50.6% of the PBHS cohort), one standard deviation decreases in 17/18 walking measures were associated with greater likelihood for stage-B HF (multivariable-adjusted odds ratios [ORs] vs stage 0 ranging from 1.18-2.10), or A (ORs vs stage 0, 1.07-1.45), and lower likelihood for RF-/ECHO+ (ORs vs stage 0, 0.80-0.93). Peak 30-minute pace demonstrated the strongest associations with stage B (OR vs stage 0=2.10; 95% CI:1.74-2.53) and A (OR vs stage 0=1.43; 95% CI:1.23-1.66). Decreases in 13/18 measures were associated with greater likelihood for stage-B HF vs stage A. Strength of correlation with physical performance tests, echocardiographic cardiac-remodeling and dysfunction indices and PROs was greatest in stage B, then A, and lowest for 0. CONCLUSIONS: Digital measures of walking captured by wearable sensors could complement clinic-based testing to identify and monitor pre-symptomatic HF.

Clinical and biochemical predictors of longitudinal changes in left atrial structure and function: A general population study.

PURPOSE: There is a need for better understanding the factors that modulate left atrial (LA) dysfunction. Therefore, we determined associations of clinical and biochemical biomarkers with serial changes in echocardiographic indexes of LA function in the general population. METHODS: We measured LA maximal and minimal volume indexes (LAVImax and LAVImin) by echocardiography and LA reservoir strain (LARS) by two-dimensional speckle-tracking in 627 participants (mean age 50.8 years, 51.2% women) at baseline and after 4.8 years. RESULTS: During follow-up, LARS decreased significantly in men (-.90%, P = .033) but not in women (-.23%, P = .60). In stepwise regression analysis, stronger decrease in LARS over time was associated with male sex, a higher age, body mass index (BMI), mean arterial pressure (MAP) and serum insulin at baseline and with a greater increase in BMI and MAP over time (P ≤ .018). Similarly, an increased risk of developing or retaining abnormal LARS was observed in older participants, in subjects with a higher baseline BMI, MAP, heart rate (HR), troponin T and ΔMAP, and in those who used ß-blockers at baseline. Both LAVImax and LAVImin increased significantly over time (P ≤ .0007). This increase was associated with a higher baseline age, pulse pressure and a lower HR at baseline and a greater increase in pulse pressure over time (P ≤ .029). Higher serum insulin and D-dimer were independently associated with a stronger increase in LAVImin (P ≤ .0034). CONCLUSION: Subclinical worsening in LA dysfunction was associated with older age, hypertension, obesity, insulin resistance and troponin T levels. Cardiovascular risk management strategies may delay LA deterioration.

Clinical and Echocardiographic Diversity Associated With Physical Fitness in the Project Baseline Health Study: Implications for Heart Failure Staging.

BACKGROUND: Clinical and echocardiographic features may carry diverse information about the development of heart failure (HF). Therefore, we determined heterogeneity in clinical and echocardiographic phenotypes and its association with exercise capacity. METHODS: In 2036 community-dwelling individuals, we defined echocardiographic profiles of left and right heart remodeling and dysfunction. We subdivided the cohort based on presence (+) or absence (-) of HF risk factors (RFs) and echocardiographic abnormalities (RF-/Echo-, RF-/Echo+, RF+/Echo-, RF+/Echo+). Multivariable-adjusted associations between subgroups and physical performance metrics from 6-minute walk and treadmill exercise testing were assessed. RESULTS: The prevalence was 35.3% for RF-/Echo-, 4.7% for RF-/Echo+, 39.3% for RF+/Echo-, and 20.6% for RF+/Echo+. We observed large diversity in echocardiographic profiles in the Echo+ group. Participants with RF-/Echo+ (18.6% of Echo+) had predominantly echocardiographic abnormalities other than left ventricular (LV) diastolic dysfunction, hypertrophy and reduced ejection fraction, whereas their physical performance was similar to RF-/Echo-. In contrast, participants with RF+/Echo+ presented primarily with LV hypertrophy or dysfunction, features that related to lower 6-minute walking distance and lower exercise capacity. CONCLUSIONS: Subclinical echocardiographic abnormalities suggest HF pathogenesis, but the presence of HF risk factors and type of echo abnormality should be considered so as to distinguish adverse from benign adaptation and to stratify HF risk.

Associations of long-term mortality with serum uric acid at admission in acute decompensated heart failure with different phenotypes.

BACKGROUND AND AIMS: It remains unclear whether the long-term prognostic value of serum uric acid (SUA) at admission differs in acute decompensated heart failure (HF) patients across the spectrum of left ventricular ejection fraction (EF). METHODS AND RESULTS: In 2375 patients (38.9% women; mean age, 68.8 years), we assessed the risk of long-term (>1 year) all-cause mortality associated with per 1-SD increase in SUA at admission, using multivariable Cox regression in HF with preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) EF. During a median follow-up of 4.1 years, the long-term mortality rate was 39.9%. In all patients, the multivariable-adjusted hazard ratio (HR) expressing the risk of long-term mortality associated with SUA was 1.18 (95% CI, 1.11-1.26; P < 0.001). Compared with the low tertile of the SUA distribution, the sex- and age-adjusted cumulative incidence of long-term mortality was higher in the top tertile. In patients with HFpEF and HFrEF, SUA predicted the risk of long-term mortality with HRs amounting to 1.12 (95% CI, 1.02-1.21; P = 0.012) and 1.28 (95% CI, 1.12-1.47; P < 0.001), respectively. However, there were no associations between the risk of mortality and SUA in HFmrEF. Furthermore, age, sex, NYHA class, and the prevalence of coronary heart disease interacted significantly with SUA for predicting long-term mortality. CONCLUSION: Higher levels of SUA at admission were associated with higher risk of long-term mortality in patients with different HF subtypes. The risk conferred by SUA was age and sex dependent. Our observations highlight that measuring SUA at admission may help to improve risk stratification.

Defining left ventricular remodeling using lean body mass allometry: a UK Biobank study.

PURPOSE: The geometric patterns of ventricular remodeling are determined using indexed left ventricular mass (LVM), end-diastolic volume (LVEDV) and concentricity, most often measured using the mass-to-volume ratio (MVR). The aims of this study were to validate lean body mass (LBM)-based allometric coefficients for scaling and to determine an index of concentricity that is independent of both volume and LBM. METHODS: Participants from the UK Biobank who underwent both CMR and dual-energy X-ray absorptiometry (DXA) during 2014-2015 were considered (n = 5064). We excluded participants aged ≥ 70 years or those with cardiometabolic risk factors. We determined allometric coefficients for scaling using linear regression of the logarithmically transformed ventricular remodeling parameters. We further defined a multiplicative allometric relationship for LV concentricity (LVC) adjusting for both LVEDV and LBM. RESULTS: A total of 1638 individuals (1057 female) were included. In subjects with lower body fat percentage (< 25% in males, < 35% in females, n = 644), the LBM allometric coefficients for scaling LVM and LVEDV were 0.85 ± 0.06 and 0.85 ± 0.03 respectively (R2 = 0.61 and 0.57, P < 0.001), with no evidence of sex-allometry interaction. While the MVR was independent of LBM, it demonstrated a negative association with LVEDV in (females: r = - 0.44, P < 0.001; males: - 0.38, P < 0.001). In contrast, LVC was independent of both LVEDV and LBM [LVC = LVM/(LVEDV0.40 × LBM0.50)] leading to increased overlap between LV hypertrophy and higher concentricity. CONCLUSIONS: We validated allometric coefficients for LBM-based scaling for CMR indexed parameters relevant for classifying geometric patterns of ventricular remodeling.

Insulin Growth Factor Phenotypes in Heart Failure With Preserved Ejection Fraction, an INSPIRE Registry and CATHGEN Study.

BACKGROUND: The insulin-like growth factor (IGF) axis emerged as an important pathway in heart failure with preserved ejection (HFpEF). We aimed to identify IGF phenotypes associated with HFpEF in the context of high-dimensional proteomic profiling. METHODS: From the INtermountain Healthcare Biological Samples Collection Project and Investigational REgistry for the On-going Study of Disease Origin, Progression and Treatment (Intermountain INSPIRE Registry), we identified 96 patients with HFpEF and matched controls. We performed targeted proteomics, including IGF-1,2, IGF binding proteins (IGFBP) 1-7 and 111 other proteins (EMD Millipore and ELISA). We used partial least square discriminant analysis (PLS-DA) to identify a set of proteins associated with prevalent HFpEF, pulmonary hypertension and 5-year all-cause mortality. K-mean clustering was used to identify IGF phenotypes. RESULTS: Patients with HFpEF had a high prevalence of systemic hypertension (95%) and coronary artery disease (74%). Using PLS-DA, we identified a set of biomarkers, including IGF1,2 and IGFBP 1,2,7, that provided a strong discrimination of HFpEF, pulmonary hypertension and mortality with an area under the curve of 0.91, 0.77 and 0.83, respectively. Using K mean clustering, we identified 3 IGF phenotypes that were independently associated with all-cause 5-year mortality after adjustment for age, NT-proBNP and kidney disease (P = 0.004). Multivariable analysis validated the prognostic value of IGFBP-1 and 2 in the CATHeterization GENetics (CATHGEN) biorepository. CONCLUSION: IGF phenotypes were associated with pulmonary hypertension and mortality in HFpEF.

Subclinical heart remodeling and dysfunction in relation to peripheral endothelial dysfunction: A general population study.

AIMS: Epidemiological studies should substantiate the paradigm that endothelial dysfunction contributes to the development of heart failure with preserved ejection fraction (HFpEF). We investigated the association of cardiac remodeling and dysfunction with peripheral vasoreactivity in the general population. METHODS: In 424 individuals, we echocardiographically assessed cardiac structure and function and determined digital vasomotor function by photoplethysmography (PPG) during reactive hyperemia (RH). We regressed echocardiographic indexes and abnormalities on RH ratios averaged for 30 s time intervals. We derived sex-specific peripheral vasoreactivity profiles from PPG time-series and compared their echocardiographic phenotypes. RESULTS: Higher left ventricular (LV) mass index and lower E/A ratio and e' peak and left atrial reservoir strain were independently related to lower RH ratios. Participants with LV hypertrophy or diastolic dysfunction presented significantly lower RH ratios during the 30 to 240s intervals than normal counterparts. Low RH responders (n = 250) presented higher odds for LV hypertrophy (adjusted OR: 2.60; p = .0040) and LV diastolic dysfunction (adjusted OR: 2.66; p = .0037) than moderate-to-high responders (n = 174). CONCLUSION: The association between subclinical heart maladaptation and decreased microvascular reactivity supports the involvement of endothelial dysfunction in HFpEF pathogenesis. Time-integrated profiling of microvascular vasoreactivity may enable early detection of HFpEF in the community.

Immune biomarkers link air pollution exposure to blood pressure in adolescents.

BACKGROUND: Childhood exposure to air pollution contributes to cardiovascular disease in adulthood. Immune and oxidative stress disturbances might mediate the effects of air pollution on the cardiovascular system, but the underlying mechanisms are poorly understood in adolescents. Therefore, we aimed to identify immune biomarkers linking air pollution exposure and blood pressure levels in adolescents. METHODS: We randomly recruited 100 adolescents (mean age, 16 years) from Fresno, California. Using central-site data, spatial-temporal modeling, and distance weighting exposures to the participant's home, we estimated average pollutant levels [particulate matter (PM), polyaromatic hydrocarbons (PAH), ozone (O3), carbon monoxide (CO) and nitrogen oxides (NOx)]. We collected blood samples and vital signs on health visits. Using proteomic platforms, we quantitated markers of inflammation, oxidative stress, coagulation, and endothelial function. Immune cellular characterization was performed via mass cytometry (CyTOF). We investigated associations between pollutant levels, cytokines, immune cell types, and blood pressure (BP) using partial least squares (PLS) and linear regression, while adjusting for important confounders. RESULTS: Using PLS, biomarkers explaining most of the variance in air pollution exposure included markers of oxidative stress (GDF-15 and myeloperoxidase), acute inflammation (C-reactive protein), hemostasis (ADAMTS, D-dimer) and immune cell types such as monocytes. Most of these biomarkers were independently associated with the air pollution levels in fully adjusted regression models. In CyTOF analyses, monocytes were enriched in participants with the highest versus the lowest PM2.5 exposure. In both PLS and linear regression, diastolic BP was independently associated with PM2.5, NO, NO2, CO and PAH456 pollution levels (P ≤ 0.009). Moreover, monocyte levels were independently related to both air pollution and diastolic BP levels (P ≤ 0.010). In in vitro cell assays, plasma of participants with high PM2.5 exposure induced endothelial dysfunction as evaluated by eNOS and ICAM-1 expression and tube formation. CONCLUSIONS: For the first time in adolescents, we found that ambient air pollution levels were associated with oxidative stress, acute inflammation, altered hemostasis, endothelial dysfunction, monocyte enrichment and diastolic blood pressure. Our findings provide new insights on pollution-related immunological and cardiovascular disturbances and advocate preventative measures of air pollution exposure.

Autoantibody profiling on a plasmonic nano-gold chip for the early detection of hypertensive heart disease.

The role of autoimmunity in cardiovascular (CV) diseases has been increasingly recognized. Autoimmunity is most commonly examined by the levels of circulating autoantibodies in clinical practices. Measurement of autoantibodies remains, however, challenging because of the deficiency of reproducible, sensitive, and standardized assays. The lack of multiplexed assays also limits the potential to identify a CV-specific autoantibody profile. To overcome these challenges, we developed a nanotechnology-based plasmonic gold chip for autoantibody profiling. This approach allowed simultaneous detection of 10 CV autoantibodies targeting the structural myocardial proteins, the neurohormonal regulatory proteins, the vascular proteins, and the proteins associated with apoptosis and coagulation. Autoantibodies were measured in four groups of participants across the continuum of hypertensive heart diseases. We observed higher levels of all 10 CV autoantibodies in hypertensive subjects (n = 77) compared with healthy participants (n = 30), and the autoantibodies investigated were related to each other, forming a highly linked network. In addition, we established that autoantibodies to troponin I, annexin-A5, and beta 1-adrenegic receptor best discriminated hypertensive subjects with adverse left ventricular (LV) remodeling or dysfunction (n = 49) from hypertensive subjects with normal LV structure and function (n = 28). By further linking these three significant CV autoantibodies to the innate and growth factors, we revealed a positive but weak association between autoantibodies to troponin I and proinflammatory cytokine IL-18. Overall, we demonstrated that this platform can be used to evaluate autoantibody profiles in hypertensive subjects at risk for heart failure.

Area of the pressure-strain loop during ejection as non-invasive index of left ventricular performance: a population study.

BACKGROUND: Previous studies highlighted the usefulness of integrating left ventricular (LV) deformation (strain) and hemodynamic parameters to quantify LV performance. In a population sample, we investigated the anthropometric and clinical determinants of a novel non-invasive index of LV systolic performance derived from simultaneous registration of LV strain and brachial pressure waveforms. METHODS: Three hundred fifty-six randomly recruited subjects (44.7% women; mean age, 53.9 years; 47.5% hypertensive) underwent echocardiographic and arterial data acquisition. We constructed pressure-strain loops from simultaneously recorded two-dimensional LV strain curves and brachial pressure waveforms obtained by finger applanation tonometry. We defined the area of this pressure-strain loop during ejection as LV ejection work density (EWD). We reported effect sizes as EWD changes associated with a 1-SD increase in covariables. RESULTS: In multivariable-adjusted analyses, higher EWD was associated with age, female sex and presence of hypertension (P ≤ 0.0084). In both men and women, EWD increased independently with augmentation pressure (effect size: + 59.1 Pa), central pulse pressure (+ 65.7 Pa) and pulse wave velocity (+ 44.8 Pa; P ≤ 0.0006). In men, EWD decreased with relative wall thickness (- 29.9 Pa) and increased with LV ejection fraction (+ 23.9 Pa; P ≤ 0.040). In women, EWD increased with left atrial (+ 76.2 Pa) and LV end-diastolic (+ 43.8 Pa) volume indexes and with E/e' ratio (+ 51.1 Pa; P ≤ 0.026). CONCLUSION: Older age, female sex and hypertension were associated with higher EWD. Integration of the LV pressure-strain loop during ejection might be a useful tool to non-invasively evaluate sex-specific and interdependent effects of preload and afterload on LV myocardial performance.

Temporal changes in left ventricular longitudinal strain in general population: Clinical correlates and impact on cardiac remodeling.

BACKGROUND: Recent studies in patients and general population have reported the role of left ventricular (LV) longitudinal strain (LS) as an independent predictor of outcome. However, there are few data on changes in LS over time. We therefore investigated in a general population clinical correlates of temporal changes in LS. We also explored the potential correlation between temporal changes in LV volumes and LS. METHODS AND RESULTS: We measured LV end-systolic (ESV) and end-diastolic (EDV) volumes by conventional echocardiography and LS by 2D speckle tracking in 627 participants (mean age 50.6 years, 51.4% women; 41.3% hypertensives) at baseline and after 4.7 years. For statistical analysis, we used the absolute values of LS. In stepwise regression, the magnitude of the decrease in all LV LS indexes over time was greater in men than in women (P < 0.0001). Higher baseline mean arterial pressure (MAP), a larger longitudinal increase in MAP, and stopping diuretic treatment during follow-up were related to larger decreases in LS indexes. In multivariable-adjusted analysis, we observed an inverse correlation between baseline ESV and LV LS (P ≤ 0.0017). Similarly, lower baseline LS and a larger decrease in LS over time were correlated with a lesser longitudinal decrease in ESV (P ≤ 0.0004). CONCLUSIONS: A significant decrease in LS over time was associated with male sex, higher baseline MAP, ∆MAP, and alteration in antihypertensive treatment. We suggested an interaction between a longitudinal decrease in LV deformation and adverse cardiac remodeling, while underscoring the importance of deformation analysis based on LS assessment in patients at risk.

The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population.

Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results. Conclusion: Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established.

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population.

BACKGROUND: Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population. METHODS: In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus. RESULTS: Over a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056). CONCLUSIONS: In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.

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.

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

BACKGROUND: In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). RESULTS: In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25-2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16-3.31), 1.87 (1.20-2.91) and 3.16 (1.41-7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). CONCLUSIONS: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

Exercise Systolic Blood Pressure Response During Cycle Ergometry is Associated with Future Hypertension in Normotensive Individuals.

AIMS: We aimed to investigate the association between the exercise systolic blood pressure (SBP) response and future hypertension (HTN) in normotensive individuals referred for cycle ergometry, with special regard to reference exercise SBP values, and exercise capacity. METHODS: In this longitudinal cohort study, data from 14,428 exercise tests were cross-linked with Swedish national registries on diagnoses and medications. We excluded individuals with a baseline diagnosis of cardiovascular disease or HTN. The peak exercise SBP (SBPpeak) was recorded and compared to the upper limit of normal (ULN) derived from SBPpeak reference equations incorporating age, sex, resting SBP and exercise capacity. To evaluate the impact of exercise capacity, three SBP to work rate slopes (SBP/W-slopes), were calculated, relative to either supine or seated SBP at rest or to the first exercise SBP. Adjusted hazard ratios (HRadjusted [95% Confidence interval, CI]) for incident HTN during follow-up, in relation to SBP response metrics, were calculated. RESULTS: We included 3,895 normotensive individuals (49±14 years, 45% females) with maximal cycle ergometer tests. During follow-up (median 7.5 years) 22% developed HTN. Higher SBPpeak and SBPpeak>ULN were associated with incident HTN (HRadjusted 1.19 [1.14-1.23] per 10 mmHg, and 1.95 [1.54-2.47], respectively). All three SBP/W-slopes were positively associated to incident HTN, particularly the SBP/W-slope calculated as supine-to-peak SBP (HRadjusted 1.25 [1.19-1.31] per 1 mmHg/10W). CONCLUSION: Both SBPpeak>ULN based on reference values and high SBP/W-slopes were associated with incident HTN in normotensive individuals and should be considered in the evaluation of the cycle ergometry SBP response.

We examined the systolic blood pressure response during maximal bicycle exercise testing in individuals without hypertension or established cardiovascular disease, and found that: When applying reference values for peak systolic blood pressure during cycling exercise, accounting for age, sex, resting blood pressure and exercise capacity, exceeding the upper limit of normal was associated with twice as high relative risk of future hypertension, compared to having a peak systolic blood pressure within normal limits. A steep increase in exercise blood pressure in relation to the increase in work rate was also associated with future hypertension but did not always coincide with elevated peak systolic blood pressure.

Quantifying assumptions underlying peak oxygen consumption equations across the body mass spectrum.

The goal of this study is to quantify the assumptions associated with the Wasserman-Hansen (WH) and Fitness Registry and the Importance of Exercise: A National Database (FRIEND) predictive peak oxygen consumption (pVO2) equations across body mass index (BMI). Assumptions in pVO2 for both equations were first determined using a simulation and then evaluated using exercise data from the Stanford Exercise Testing registry. We calculated percent-predicted VO2 (ppVO2) values for both equations and compared them using the Bland-Altman method. Assumptions associated with pVO2 across BMI categories were quantified by comparing the slopes of age-adjusted VO2 ratios (pVO2/pre-exercise VO2) and ppVO2 values for different BMI categories. The simulation revealed lower predicted fitness among adults with obesity using the FRIEND equation compared to the WH equations. In the clinical cohort, we evaluated 2471 patients (56.9% male, 22% with BMI >30 kg/m2, pVO2 26.8 mlO2/kg/min). The Bland-Altman plot revealed an average relative difference of -1.7% (95% CI: -2.1 to -1.2%) between WH and FRIEND ppVO2 values with greater differences among those with obesity. Analysis of the VO2 ratio to ppVO2 slopes across the BMI spectrum confirmed the assumption of lower fitness in those with obesity, and this trend was more pronounced using the FRIEND equation. Peak VO2 estimations between the WH and FRIEND equations differed significantly among individuals with obesity. The FRIEND equation resulted in a greater attributable reduction in pVO2 associated with obesity relative to the WH equations. The outlined relationships between BMI and predicted VO2 may better inform the clinical interpretation of ppVO2 values during cardiopulmonary exercise test evaluations.

Improving Reporting of Exercise Capacity Across Age Ranges Using Novel Workload Reference Equations.

Exercise capacity (EC) is an important predictor of survival in the general population and in subjects with cardiopulmonary disease. Despite its relevance, considering the percent-predicted workload (%pWL) given by current equations may overestimate EC in older adults. Therefore, to improve the reporting of EC in clinical practice, our main objective was to develop workload reference equations (pWL) that better reflect the relation between workload and age. Using the Fitness Registry and the Importance of Exercise National Database (FRIEND), we analyzed a reference group of 6,966 apparently healthy participants and 1,060 participants with heart failure who underwent graded treadmill cardiopulmonary exercise testing. For the first group, the mean age was 44 years (18 to 79); 56.5% of participants were males and 15.4% had obesity. Peak oxygen consumption was 11.6 ± 3.0 METs in males and 8.5 ± 2.4 METs in females. After partition analysis, we first developed sex-specific pWL equations to allow comparisons to a healthy weight reference. For males, pWL (METs) = 14.1-0.9×10-3×age2 and 11.5-0.87×10-3×age2 for females. We used those equations as denominators of %pWL, and based on their distribution, we determined thresholds for EC classification, with average EC defined by the range corresponding to 85% to 115%pWL. Compared with %pWL using current equations, the new equations yielded better-calibrated %pWL across different age ranges. We also derived body mass index-adjusted pWL equations that better assessed EC in subjects with heart failure. In conclusion, the novel pWL equations have the potential to impact the report of EC in practice.

Unsupervised Time-Series Clustering of Left Atrial Strain for Cardiovascular Risk Assessment.

BACKGROUND: Early identification of individuals at high risk for developing cardiovascular (CV) events is of paramount importance for efficient risk management. Here, the authors investigated whether using unsupervised machine learning methods on time-series data of left atrial (LA) strain could distinguish clinically meaningful phenogroups associated with the risk for developing adverse events. METHODS: In 929 community-dwelling individuals (mean age, 51.6 years; 52.9% women), clinical and echocardiographic data were acquired, including LA strain traces, at baseline, and cardiac events were collected on average 6.3 years later. Two unsupervised learning techniques were used: (1) an ensemble of a deep convolutional neural network autoencoder with k-medoids and (2) a self-organizing map to cluster spatiotemporal patterns within LA strain curves. Clinical characteristics and cardiac outcome were used to evaluate the validity of the k clusters using the original cohort, while an external population cohort (n = 378) was used to validate the trained models. RESULTS: In both approaches, the optimal number of clusters was five. The first three clusters had differences in sex distribution and heart rate but had a similar low CV risk profile. On the other hand, cluster 5 had the worst CV profile and a higher prevalence of left ventricular remodeling and diastolic dysfunction compared with the other clusters. The respective indexes of cluster 4 were between those of clusters 1 to 3 and 5. After adjustment for traditional risk factors, cluster 5 had the highest risk for cardiac events compared with clusters 1, 2, and 3 (hazard ratio, 1.36; 95% CI, 1.09-1.70; P = .0063). Similar LA strain patterns were obtained when the models were applied to the external validation cohort, and clinical characteristics revealed similar CV risk profiles across all clusters. CONCLUSION: Unsupervised machine learning algorithms used in time-series LA strain curves identified clinically meaningful clusters of LA deformation and provide incremental prognostic information over traditional risk factors.