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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., (Copyright © 2024 Verily Life Sciences LLC. Published by Elsevier Inc. All rights reserved.)

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 ×age 2 and 11.5-0.87×10 -3 ×age 2 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., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Although up to 20% of people with type 2 diabetes (DM) have normal BMI (< 25 kg/m 2 ), it remains unclear whether there is a difference in the development of cardiac dysfunction between those with normal and higher BMI. Furthermore, little is known about the relationship of visceral fat with BMI or fitness in asymptomatic patients with DM., Methods: We prospectively enrolled asymptomatic patients with DM and divided into two groups: BMI ≥ 25kg/m 2 (overweight/obese group) versus < 25kg/m 2 (normal-weight group). Resting echocardiogram followed by exercise stress echocardiogram and exercise gas exchange analysis (in a subgroup) was performed. Cardiac function was evaluated using left ventricular longitudinal strain (LVLS), E/e', and relative wall thickness (RWT). In addition, epicardial fat thickness (EFT) was measured to estimate visceral fat., Results: Normal-weight patients with DM had more EFT compared with overweight/obese patients (0.66 ± 0.17 cm vs. 0.59 ± 0.22 cm, p < 0.05), despite the overlap between the groups. There was no significant difference in the prevalence of LV remodeling (p = 0.49), impaired LVLS (p = 0.22), or increased E/e' (p = 0.26), and these were consistently observed when matched for race. The majority of patients (63%) achieved ≥ 85% of percent peak-predicted VO 2 . At peak, there was no significant difference in peak VO 2 normalized by eLBM (36.4 ± 7.7 vs. 37.8 ± 7.1 ml/kg eLBM/min, p = 0.43) while VO 2 normalized by weight (23.6 ± 6.5 vs. 29.6 ± 6.7 ml/kg/min, p < 0.001) and VO 2 ratio (5.7 ± 1.7 vs. 7.3 ± 2.4 METs, p = 0.001) were significantly lower in patients with obese/overweight group. There was no significant difference between patients with higher and lower EFT., Conclusions: Patients with DM and normal BMI have excess epicardial fat compared to those with overweight/obese. Epicardial fat was not directly linked to prevalence of subclinical dysfunction., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

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., Competing Interests: Disclosures All authors acknowledge institutional research grants from Verily Life Sciences. FH received an institutional research grant from Actelion within the past 2 years and an institutional research grant from Precordior. KM reports grants from Verily, Afferent, AHA, Cardiva Medical, Gilead, Luitpold, Medtronic, Merck, Eidos, Ferring, Apple, Sanifit, and St. Jude; grants and personal fees from Amgen, AstraZeneca, Bayer, CSL Behring, Johnson & Johnson, Novartis, and Sanofi; and personal fees from Anthos, Applied Therapeutics, Elsevier, Inova, Intermountain Health, Medscape, Mount Sinai, Mundi Pharma, Myokardia, Novo Nordisk, Otsuka, Portola, SmartMedics, and Theravance outside the submitted work. AH reports grants from Verily; grants and personal fees from AstraZeneca, Amgen, Bayer, Merck, and Novartis, and personal fees from Boston Scientific outside the submitted work. NC reports grants from the Research Foundation Flanders. GB reports grants from the National Institutes of Health (U01-HL146382-03, Rx01-MD013493-03, D43TW009337, U01-HL123336-06, U01-HL142099-03, and D43 TW011625-01) and royalties or licensing fees from UpToDate. The other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2021. Published by Elsevier Inc.)

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., (© 2021 John Wiley & Sons Ltd.)

Aims: Biomarkers may provide insights into molecular mechanisms underlying heart remodelling and dysfunction. Using a targeted proteomic approach, we aimed to identify circulating biomarkers associated with early stages of heart failure., Methods and Results: A total of 575 community-based participants (mean age, 57 years; 51.7% women) underwent echocardiography and proteomic profiling (CVD II panel, Olink Proteomics). We applied partial least squares-discriminant analysis (PLS-DA) and a machine learning algorithm [eXtreme Gradient Boosting (XGBoost)] to identify key proteins associated with echocardiographic abnormalities. We used Gaussian mixture modelling for unbiased clustering to construct phenogroups based on influential proteins in PLS-DA and XGBoost. Of 87 proteins, 13 were important in PLS-DA and XGBoost modelling for detection of left ventricular remodelling, left ventricular diastolic dysfunction, and/or left atrial reservoir dysfunction: placental growth factor, kidney injury molecule-1, prostasin, angiotensin-converting enzyme-2, galectin-9, cathepsin L1, matrix metalloproteinase-7, tumour necrosis factor receptor superfamily members 10A, 10B, and 11A, interleukins 6 and 16, and α1-microglobulin/bikunin precursor. Based on these proteins, the clustering algorithm divided the cohort into two distinct phenogroups, with each cluster grouping individuals with a similar protein profile. Participants belonging to the second cluster (n = 118) were characterized by an unfavourable cardiovascular risk profile and adverse cardiac structure and function. The adjusted risk of presenting echocardiographic abnormalities was higher in this phenogroup than in the other (P < 0.0001)., Conclusions: We identified proteins related to renal function, extracellular matrix remodelling, angiogenesis, and inflammation to be associated with echocardiographic signs of early-stage heart failure. Proteomic phenomapping discriminated individuals at high risk for cardiac remodelling and dysfunction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Patients with diabetes mellitus (DM) frequently present reduced exercise capacity. We aimed to explore the extent to which peripheral extraction relates to exercise capacity in asymptomatic patients with DM. We prospectively enrolled 98 asymptomatic patients with type-2 DM (mean age of 59 ± 11 years and 56% male sex), and compared with 31 age, sex and body mass index-matched normoglycemic controls. Cardiopulmonary exercise testing with resting followed by stress echocardiography was performed. Exercise response was assessed using peak oxygen uptake (peak VO 2 ) and ventilatory efficiency was measured using the slope of the relationship between minute ventilation and carbon dioxide production (VE/VCO 2 ). Peripheral extraction was calculated as the ratio of VO 2 to cardiac output. Cardiac function was evaluated using left ventricular longitudinal strain, E/e', and relative wall thickness. Among patients with DM, 26 patients (27%) presented reduced percent-predicted-peak VO 2 (<80%) and 18 (18%) presented abnormal VE/VCO 2 slope (>34). There was no significant difference in peak cardiac output; however, peripheral extraction was lower in patients with DM compared to controls. Higher peak E/e' (beta = -0.24, p = 0.004) was associated with lower peak VO 2 along with age, sex and body mass index (R 2  = 0.53). A cluster analysis found left ventricular longitudinal strain, E/e', relative wall thickness and peak VO 2 in different clusters. In conclusion, impaired peripheral extraction may contribute to reduced peak VO 2 in asymptomatic patients with DM. Furthermore, a cluster analysis suggests that cardiopulmonary exercise testing and echocardiography may be complementary for defining subclinical heart failure in patients with DM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: The Pooled Cohort Equations to Prevent Heart Failure (PCP-HF) estimate the 10-year risk for symptomatic heart failure (HF) from routine clinical data. The PCP-HF score should detect asymptomatic individuals with cardiac maladaptation preceding HF symptoms for it to be a useful HF prediction tool in primary prevention., Objective: To assess the concordance between PCP-HF risk scoring and the presence of subclinical cardiac maladaptation in the community., Design, Setting, and Participants: This cross-sectional analysis included participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes who underwent a clinical examination including echocardiography between May 2005 and January 2015. Participants younger than 30 years, older than 79 years, had prevalent cardiovascular disease, and/or had suboptimal echocardiographic imaging quality were excluded. Analysis began February 2020 and ended April 2020., Exposures: Ten-year HF risk as calculated from routine clinical data using the PCP-HF. Based on tertile limits, participants were categorized as having low (≤0.4%), intermediate (0.4%-2.4%), and high (≥2.4%) 10-year HF risk score., Main Outcomes and Measures: Echocardiographic profiles of subclinical heart remodeling and dysfunction., Results: A total of 1020 individuals were analyzed (mean [SD] age, 52.8 [11.4] years; 541 female [53.0%]). The prevalence of left ventricular (LV) remodeling and dysfunction was significantly higher from low to intermediate and high 10-year HF risk score. A doubling in 10-year HF risk score was associated with higher odds for LV concentric remodeling (odds ratio [OR], 1.48; 95% CI, 1.36-1.61; P < .001), LV hypertrophy (OR, 1.66; 95% CI, 1.51-1.83; P < .001), abnormal LV longitudinal strain (OR, 1.12; 95% CI, 1.05-1.19; P < .001), and LV diastolic dysfunction (OR, 2.28; 95% CI, 1.94-2.69; P < .001). Moreover, the PCP-HF score detected echocardiographic abnormalities with an accuracy of 74% (LV concentric remodeling), 78% (LV hypertrophy), 59% (abnormal LV longitudinal strain), and 87% (LV diastolic dysfunction). The likelihood of LV concentric remodeling, hypertrophy, and diastolic dysfunction were 3.1, 3.8, and 9.4 times higher in participants with high 10-year HF risk score than the average population risk, respectively (P < .001). Of all PCP-HF score components, age, body mass index, and systolic blood pressure were key correlates of echocardiographic abnormalities in multivariable-adjusted analysis., Conclusions and Relevance: PCP-HF risk scoring adequately detected individuals with subclinical heart maladaptation that precedes HF symptoms by years. Thus, it may be a valuable HF prediction tool in primary prevention.

Aims: Resting echocardiography is a valuable method for detecting subclinical heart failure (HF) in patients with diabetes mellitus (DM). However, few studies have assessed the incremental value of diastolic stress for detecting subclinical HF in this population., Methods and Results: Asymptomatic patients with Type 2 DM were prospectively enrolled. Subclinical HF was assessed using systolic dysfunction (left ventricular longitudinal strain <16% at rest and <19% after exercise in absolute value), abnormal cardiac morphology, or diastolic dysfunction (E/e' > 10). Metabolic equivalents (METs) were calculated using treadmill speed and grade, and functional capacity was assessed by percent-predicted METs (ppMETs). Among 161 patients studied (mean age of 59 ± 11 years and 57% male sex), subclinical HF was observed in 68% at rest and in 79% with exercise. Among characteristics, diastolic stress had the highest yield in improving detection of HF with 57% of abnormal cases after exercise and 45% at rest. Patients with revealed diastolic dysfunction during stress had significantly lower exercise capacity than patients with normal diastolic stress (7.3 ± 2.1 vs. 8.8 ± 2.5, P < 0.001 for peak METs and 91 ± 30% vs. 105 ± 30%, P = 0.04 for ppMETs). On multivariable modelling found that age (beta = -0.33), male sex (beta = 0.21), body mass index (beta = -0.49), and exercise E/e' >10 (beta = -0.17) were independently associated with peak METs (combined R2 = 0.46). A network correlation map revealed the connectivity of peak METs and diastolic properties as central features in patients with DM., Conclusion: Diastolic stress test improves the detection of subclinical HF in patients with diabetes mellitus., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

The neutrophil to lymphocyte ratio (NLR) has been proposed as a simple and routinely obtained marker of inflammation. This study sought to determine whether the NLR on admission as well as NLR trajectory would be complementary to the Get with the Guidelines Heart Failure (GWTG-HF) risk score in patients hospitalized with acute heart failure with preserved ejection fraction (HFpEF).Using the Stanford Translational Research Database, we identified 443 patients between January 2002 and December 2013 hospitalized with acute HFpEF and with complete data of NLR both on admission and at discharge. The primary endpoint was all-cause mortality. Mean age was 77 ± 16 years, 58% were female, with a high prevalence of diabetes mellitus (35.4%), coronary artery disease (58.2%), systemic hypertension (96.6%) and history of atrial fibrillation (57.5%). Over a median follow-up of 2.2 years, 121 (27.3%) patients died. The median NLR on admission was 6.5 (IQR 3.6 - 11.1); a majority of patients decreased their NLR during the course of hospitalization. On multivariable Cox modeling, both NLR on admission (HR 1.18 95% CI (1.00 - .38), p = 0.04) and absolute NLR trajectory (HR 1.26 95% CI (1.10 - 1.45), p = 0.001) were shown to be incremental to GWTG-HF risk score (p < 0.05) for outcome prediction. Adding the NLR or absolute NLR trajectory to the GWTG-HF risk score significantly improved the area under the operator-receiver curve and the reclassification up to 3 years after admission.This simple, readily available marker of inflammation may be useful when stratifying the risk of patients hospitalized with HFpEF., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background Serial imaging studies in the general population remain important to evaluate the usefulness of pathophysiologically relevant biomarkers in predicting progression of left ventricular (LV) remodeling and dysfunction. Here, we assessed in a general population whether these circulating biomarkers at baseline predict longitudinal changes in LV structure and function. Methods and Results In 592 participants (mean age, 50.8 years; 51.4% women; 40.5% hypertensive), we derived echocardiographic indexes reflecting LV structure and function at baseline and after 4.7 years. At baseline, we measured alkaline phosphatase, markers of collagen turnover (procollagen type I, C-terminal telopeptide, matrix metalloproteinase-1) and high-sensitivity cardiac troponin T. We regressed longitudinal changes in LV indexes on baseline biomarker levels and reported standardized effect sizes as a fraction of the standard deviation of LV change. After full adjustment, a decline in LV longitudinal strain (-14.2%) and increase in E/e' ratio over time (+18.9%; P≤0.019) was associated with higher alkaline phosphatase activity at baseline. Furthermore, longitudinal strain decreased with higher levels of collagen I production and degradation at baseline (procollagen type I, -14.2%; C-terminal telopeptide, -16.4%; P≤0.029). An increase in E/e' ratio over time was borderline associated with lower matrix metalloproteinase-1 (+9.8%) and lower matrix metalloproteinase-1/tissue inhibitor of metalloproteinase-1 ratio (+11.9%; P≤0.041). Higher high-sensitivity cardiac troponin T levels at baseline correlated significantly with an increase in relative wall thickness (+23.1%) and LV mass index (+18.3%) during follow-up ( P≤0.035). Conclusions We identified a set of biomarkers predicting adverse changes in LV structure and function over time. Circulating biomarkers reflecting LV stiffness, injury, and collagen composition might improve the identification of subjects at risk for subclinical cardiac maladaptation.

The overall prevalence of symptomatic heart failure (HF) is similar in men and women and constitutes about a quarter of the first manifestation of cardiovascular disease in both sexes. However, there is an important difference between the sexes in the type of HF. Whereas men more frequently develop HF with reduced ejection fraction, HF with preserved ejection fraction is especially frequent in women. The major risk factors for symptomatic HF are high blood pressure and arterial stiffness, which evoke a complex network of functional and structural changes in the heart in both men and women. In this review, we will discuss the recent epidemiological data on sex discrepancies in cardiac maladaptation to hypertension and arterial stiffening.

Background/objectives: Heart failure (HF) is associated with disturbances in mitochondrial energy production. This mitochondrial dysfunction is reflected by depletion of mitochondrial DNA (mtDNA) in different tissues. Our aims were to determine if there was a correlation between mtDNA content measured in myocardial tissue and the easily accessible peripheral blood cells of patients with non-ischemic HF; and to determine if there was a correlation between myocardial mtDNA and left ventricular (LV) ejection fraction., Methods: We prospectively collected paired myocardial tissue and peripheral blood samples from 13 consecutive end-stage non-ischemic HF patients undergoing cardiac transplantation. mtDNA content was assessed with real-time quantitative PCR by calculating the relative ratio of two specific mitochondrial sequences and one nuclear control gene sequence., Results: HF patients with lower myocardial mtDNA content had a significantly lower LV ejection fraction (r = 0.65, p = 0.016). Peripheral blood mtDNA content correlated positively with right ventricular myocardial mtDNA content (r = 0.63, p = 0.021). We also observed that averaged myocardial DNA content tended to correlate with peripheral blood mtDNA content (r = 0.53, p = 0.061)., Conclusions: In non-ischemic HF patients, myocardial mtDNA content is positively correlated with peripheral blood mtDNA content and LV function as assessed by echocardiography.

Background In view of the increasing heart failure epidemic and awareness of the adverse impact of environmental pollution on human health, we investigated the association of left ventricular structure and function with air pollutants in a general population. Methods In 671 randomly recruited Flemish (51.7% women; mean age, 50.4 years) we echocardiographically assessed left ventricular systolic strain and strain rate and the early and late peak velocities of transmitral blood flow and mitral annular movement (2005-2009). Using subject-level data, left ventricular function was cross-sectionally correlated with residential long-term exposure to air pollutants, including black carbon, PM2.5, PM10 (particulate matter) and nitrogen dioxide (NO2), while accounting for clustering by residential address and confounders. Results Annual exposures to black carbon, PM2.5, PM10 and NO2 averaged 1.19, 13.0, 17.7, and 16.8 µg/m 3 . Systolic left ventricular function was worse ( p ≤ 0.027) with higher black carbon, PM2.5, PM10 and NO2 with association sizes per interquartile interval increment ranging from -0.339 to -0.458% for longitudinal strain and from -0.033 to -0.049 s -1 for longitudinal strain rate. Mitral E and a' peak velocities were lower ( p ≤ 0.021) with higher black carbon, PM2.5 and PM10 with association sizes ranging from -1.727 to -1.947 cm/s and from -0.175 to -0.235 cm/s, respectively. In the geographic analysis, the systolic longitudinal strain sided with gradients in air pollution. The path analysis identified systemic inflammation as a possible mediator of associations with black carbon. Conclusions Long-term low-level air pollution is associated with subclinical impairment of left ventricular performance and might be a risk factor for heart failure.

Background: Experimental studies have demonstrated that lead and cadmium have direct toxic effects on the myocardium, but the few human studies are limited by design, assessment of exposure, and use of heart failure as a late-stage endpoint., Methods and Results: In a prospective population study, we studied the association of left ventricular (LV) function with blood lead (BPb) and 24-hour urinary cadmium (UCd). In 179 participants randomly recruited from a Flemish population (50.3% women; mean age 39.1 years), geometric mean BPb and UCd at enrollment (1985-2000) were 0.20 μmol/L and 6.1 nmol, respectively. We assessed systolic and diastolic LV function 11.9 years (median) later (2005-2010) by using Doppler imaging of the transmitral blood flow and the mitral annular movement and speckle tracking. In multivariable-adjusted linear regression, LV systolic function decreased with BPb. For a doubling of exposure, estimates were -0.392% for global longitudinal strain (P=0.034), -0.618% and -0.113 s -1 for regional longitudinal strain (P=0.028) and strain rate (P=0.008), and -0.056 s -1 for regional radial strain rate (P=0.050). Regional longitudinal strain rate (-0.066 s -1 , P=0.009) and regional radial strain (-2.848%, P=0.015) also decreased with UCd. Models including both exposure indexes did not allow differentiating whether LV dysfunction was predominately related to BPb or UCd. Diastolic LV function was not associated with BPb or UCd (P≥0.159)., Conclusions: Although effect sizes were small, our results suggest that environmental exposure to lead, cadmium, or both might be a risk factor for systolic LV dysfunction, a condition often proceeding to heart failure., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)