The weight of obesity in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is one of the most frequently diagnosed primary conditions of the heart muscle. It is considered to be inherited, caused by genetic mutations encoding for sarcomere proteins. The marked heterogeneity in clinical manifestations and natural course of the disease, even among family members sharing the same genetic mutation, has raised the question of non-genetic environmental factors contributing to the phenotype. Obesity has been associated with worse cardiovascular outcomes in the general population. Its prevalence is increased in hypertrophic cardiomyopathy, and the two conditions share some similar pathophysiological and clinical characteristics. In this review, we aim to summarise the effects of obesity in the cardiac phenotype, the symptoms and management in patients with hypertrophic cardiomyopathy.

Novel Lesional Transcriptional Signature Separates Atherosclerosis With and Without Diabetes in Yorkshire Swine and Humans.

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Predicted Skeletal Muscle Mass and 4-Year Cardiovascular Disease Incidence in Middle-Aged and Elderly Participants of IKARIA Prospective Epidemiological Study: The Mediating Effect of Sex and Cardiometabolic Factors.

The sex-specific effect of skeletal muscle mass (SMM) index (SMI) on 4-year first fatal/non-fatal cardiovascular disease (CVD) event in free-of-disease individuals was examined. In 2009, n = 1411 inhabitants (mean age = 64(12)) from Ikaria were selected. Follow-up was performed in 2013. SMI was created to reflect SMM through appendicular skeletal muscle mass (indirectly calculated through formulas) divided by body mass index (BMI). Fifteen and six tenths percent of participants exhibited CVD (19.8% in men/12% in women, p = 0.002). Significant U-shape trends were observed in participants >65 years old and women irrespective to age confirmed through multi-adjusted Cox regression analysis; in age >65 years, Hazard Ratio (HR)(2nd vs. 1st SMI tertile) = 0.80, 95% Confidence Interval (95%CI) (0.45, 0.96) and in women HR(2nd vs. 1st SMI tertile) = 0.71, 95% CI (0.33, 0.95), while, as for the 3rd SMI tertile, no significant trends were observed. Mediation analysis revealed that mediators of the aforementioned associations in men were the arterial distensibility and total testosterone, while, in women, inflammation, insulin resistance, and arterial distensibility. High SMM accompanied by obesity may not guarantee lower CVD risk. Specific cardiometabolic factors seem to explain this need for balance between lean and fat mass.

Osteoprotegerin and Osteopontin Serum Levels are Associated with Vascular Function and Inflammation in Coronary Artery Disease Patients.

BACKGROUND: Osteoprotegerin and osteopontin have recently emerged as key factors in both vascular remodelling and atherosclerosis progression. Interleukin-6 (IL-6) is an inflammatory cytokine with a key role in atherosclerosis. The relationship of osteoprotegerin, osteopontin, and IL-6 serum levels with endothelial function and arterial stiffness was evaluated in patients with coronary artery disease (CAD). METHODS: We enrolled 219 patients with stable CAD and 112 control subjects. Osteoprotegerin, osteopontin and IL-6 serum levels were measured using an ELISA assay. Endothelial function was evaluated by flow-mediated dilation (FMD) in the brachial artery and carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. RESULTS: There was no significant difference between control subjects and CAD patients according to age and sex. Compared with control subjects, CAD patients had significantly impaired FMD (p<0.001) and increased PWV (p=0.009). CAD patients also had significantly higher levels of osteoprotegerin (p<0.001), osteopontin (p<0.001) and IL-6 (p=0.03), compared with control subjects. Moreover, IL-6 levels were correlated with osteoprotegerin (r=0.17, p=0.01) and osteopontin (r=0.30, p<0.001) levels. FMD was correlated with osteoprotegerin levels independent of possible confounders [b coefficient= - 0.79, 95% CI (-1.54, -0.05), p=0.04]. CONCLUSION: CAD patients have increased osteoprotegerin, osteopontin and IL-6 levels. Moreover, there is a consistent association between osteoprotegerin and osteopontin serum levels, vascular function and inflammation in CAD patients. These findings suggest another possible mechanism linking osteoprotegerin and osteopontin serum levels with CAD progression through arterial wall stiffening and inflammation.

Role of local coronary blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and coronary plaque.

PURPOSE OF REVIEW: The natural history of coronary atherosclerosis is complex and atherosclerotic plaques exhibit large morphologic and functional variability within the same individual as well as over time. The purpose of this article is to review the role of blood flow patterns and shear stress on the development of microvascular and epicardial endothelial dysfunction and atherosclerosis progression. RECENT FINDINGS: Recent breakthroughs in cardiovascular imaging have facilitated in-vivo characterization of the anatomic and functional characteristics of atherosclerotic plaques and have highlighted the role of endothelial shear stress and epicardial and microvascular endothelial dysfunction in the natural history of coronary atherosclerosis. SUMMARY: There is an important need to identify individual lesions which may progress to vulnerable plaque in order to provide early therapeutic management. Evaluation of endothelial shear stress, local blood flow patterns, epicardial and microvascular endothelial dysfunction, as well as their complex associations might indicate those patients who have microvascular endothelial dysfunction and increased risk for upstream epicardial endothelial dysfunction and plaque progression. Such high-risk patients could potentially be targeted for more intensive therapeutic strategies to prevent the progression of both microvascular and epicardial atherosclerotic manifestations.

Local Low Shear Stress and Endothelial Dysfunction in Patients With Nonobstructive Coronary Atherosclerosis.

BACKGROUND: Local hemodynamic factors are important determinants of atherosclerotic plaque development and progression. OBJECTIVES: The goal of this study was to determine the association between low endothelial shear stress (ESS) and microvascular and epicardial endothelial dysfunction in patients with early atherosclerosis. METHODS: Sixty-five patients (mean age 52 ± 11 years) with nonobstructive coronary atherosclerosis (luminal diameter stenosis <30%) were included. Microvascular and epicardial coronary endothelial function was assessed by using intracoronary acetylcholine infusion. Vascular profiling, using 2-plane coronary angiography and intravascular ultrasound, was used to reconstruct the three-dimensional anatomy of the left anterior descending artery. Each reconstructed artery was divided into sequential 3-mm segments and analyzed for local ESS with computational fluid dynamics; that is, lower ESS levels at both a 3-mm regional level (average ESS and low ESS) and at a vessel level (lowest ESS per artery) and for plaque characteristics (plaque area, plaque thickness, and plaque burden). RESULTS: Coronary segments in arteries with abnormal microvascular function exhibited lower ESS compared with segments in arteries with normal microvascular function (average ESS: 1.67 ± 1.04 Pa vs. 2.03 ± 1.72 Pa [p = 0.050]; lowest ESS: 0.54 ± 0.25 Pa vs. 0.72 ± 0.32 Pa [p = 0.014]). Coronary segments in arteries with abnormal epicardial endothelial function also exhibited significantly lower ESS compared with segments in arteries with normal epicardial function (average ESS: 1.49 ± 0.89 Pa vs. 1.93 ± 1.50 Pa [p < 0.0001]; low ESS: 1.26 ± 0.81 Pa vs. 1.56 ± 1.30 Pa [p = 0.001]; lowest ESS: 0.51 ± 0.27 Pa vs. 0.65 ± 0.29 Pa [p = 0.080]). Patients with abnormal microvascular endothelial function exhibited a progressive decrease in average and low ESS, starting from patients with normal epicardial endothelial function to those with both microvascular and epicardial endothelial dysfunction (p < 0.0001 and p = 0.004, respectively). CONCLUSIONS: These data indicate an association between dysfunction of the microvascular and epicardial endothelium and local ESS at the early stages of coronary atherosclerosis in humans.

Role of Low Endothelial Shear Stress and Plaque Characteristics in the Prediction of Nonculprit Major Adverse Cardiac Events: The PROSPECT Study.

OBJECTIVES: This study sought to determine whether low endothelial shear stress (ESS) adds independent prognostication for future major adverse cardiac events (MACE) in coronary lesions in patients with high-risk acute coronary syndrome (ACS) from the United States and Europe. BACKGROUND: Low ESS is a proinflammatory, proatherogenic stimulus associated with coronary plaque development, progression, and destabilization in human-like animal models and in humans. Previous natural history studies including baseline ESS characterization investigated low-risk patients. METHODS: In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, 697 patients with ACS underwent 3-vessel intracoronary imaging. Independent predictors of MACE attributable to untreated nonculprit (nc) coronary lesions during 3.4-year follow-up were large plaque burden (PB), small minimum lumen area (MLA), and thin-cap fibroatheroma (TCFA) morphology. In this analysis, baseline ESS of nc lesions leading to new MACE (nc-MACE lesions) and randomly selected control nc lesions without MACE (nc-non-MACE lesions) were calculated. A propensity score for ESS was constructed for each lesion, and the relationship between ESS and subsequent nc-MACE was examined. RESULTS: A total of 145 lesions were analyzed in 97 patients: 23 nc-MACE lesions (13 TCFAs, 10 thick-cap fibroatheromas [ThCFAs]), and 122 nc-non-MACE lesions (63 TCFAs, 59 ThCFAs). Low local ESS (<1.3 Pa) was strongly associated with subsequent nc-MACE compared with physiological/high ESS (≥1.3 Pa) (23 of 101 [22.8%]) versus (0 of 44 [0%]). In propensity-adjusted Cox regression, low ESS was strongly associated with MACE (hazard ratio: 4.34; 95% confidence interval: 1.89 to 10.00; p < 0.001). Categorizing plaques by anatomic risk (high risk: ≥2 high-risk characteristics PB ≥70%, MLA ≤4 mm2, or TCFA), high anatomic risk, and low ESS were prognostically synergistic: 3-year nc-MACE rates were 52.1% versus 14.4% versus 0.0% in high-anatomic risk/low-ESS, low-anatomic risk/low-ESS, and physiological/high-ESS lesions, respectively (p < 0.0001). No lesion without low ESS led to nc-MACE during follow-up, regardless of PB, MLA, or lesion phenotype at baseline. CONCLUSIONS: Local low ESS provides incremental risk stratification of untreated coronary lesions in high-risk patients, beyond measures of PB, MLA, and morphology.

Low Endothelial Shear Stress Predicts Evolution to High-Risk Coronary Plaque Phenotype in the Future: A Serial Optical Coherence Tomography and Computational Fluid Dynamics Study.

BACKGROUND: Low endothelial shear stress (ESS) is associated with plaque progression and vulnerability. To date, changes in plaque phenotype over time in relation to ESS have not been studied in humans. The aim of this study was to investigate whether local ESS can predict subsequent changes to plaque phenotype using optical coherence tomography. METHODS AND RESULTS: A total of 25 coronary arteries from 20 patients who underwent baseline and 6-month follow-up optical coherence tomography were included. Arteries were divided into serial 3-mm segments, and plaque characteristics were evaluated in each segment. A total of 145 segments were divided into low-ESS group (ESS <1 Pa) and higher-ESS group (ESS ≥1 Pa) based on baseline computational flow dynamics analyses. At baseline, low-ESS segments had significantly thinner fibrous cap thickness compared with higher-ESS segments (128.2±12.3 versus 165.0±12.0 µm; P=0.03), although lipid arc was similar. At follow-up, fibrous cap thickness remained thin in low-ESS segments, whereas it significantly increased in higher-ESS segments (165.0±12.0 to 182.2±14.1 µm; P=0.04). Lipid arc widened only in plaques with low ESS (126.4±15.2° to 141.1±14.0°; P=0.01). After adjustment, baseline ESS was associated with fibrous cap thickness (ß, 9.089; 95% confidence interval, 2.539-15.640; P=0.007) and lipid arc (ß, -4.381; 95% confidence interval, -6.946 to -1.815; P=0.001) at follow-up. CONCLUSIONS: Low ESS is significantly associated with baseline high-risk plaque phenotype and progression to higher-risk phenotype at 6 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01110538.

Heterogeneity of Coronary Plaque Morphology and Natural History: Current Understanding and Clinical Significance.

PURPOSE OF REVIEW: Despite the important progress in identifying high-risk atherosclerotic plaques, many key elements are elusive. Advanced imaging modalities provide valuable information about the anatomic and functional plaque characteristics and underscore the presence of multiple plaque morphologies. However, how the heterogeneity of atherosclerotic plaque can alter our current understanding of coronary artery disease is not fully understood. RECENT FINDINGS: Along the length of an individual plaque, the morphology patterns display marked heterogeneity. Contrary to previous beliefs, plaque morphology is also highly dynamic over time, with the vast majority of high-risk plaques becoming quiescent and mild plaques becoming severely obstructive in a short period of time. Endothelial shear stress, a local hemodynamic factor known for its critical effects in plaque initiation and progression, also displays longitudinal heterogeneity contributing to the arterial wall response in all time points. Risk stratification of plaques based on the morphological characteristics at one region of the plaque, usually the minimal lumen diameter, and at one point in time may be misleading. The evaluation of both morphological and hemodynamic characteristics along the length of a plaque will improve the risk assessment of individual plaques.

Intravascular hemodynamics and coronary artery disease: New insights and clinical implications.

Intracoronary hemodynamics play a pivotal role in the initiation and progression of the atherosclerotic process. Low pro-inflammatory endothelial shear stress impacts vascular physiology and leads to the occurrence of coronary artery disease and its implications.

The natural history of multifocal atrial rhythms in elderly outpatients: insights from the "Ikaria study".

BACKGROUND: Multifocal atrial tachycardias confer an adverse prognosis in hospitalized patients. We assessed the prognostic impact of multifocal atrial rhythms (MARs-either chaotic atrial rhythm or multifocal atrial tachycardia/bradycardia) in very elderly outpatients. METHODS: One hundred ten subjects aged 60-74 years, 112 aged 75-89 years, and 61 over 90 years old, were enrolled and prospectively evaluated. Several demographic and clinical characteristic were recorded in all individuals. RESULTS: A high prevalence of MARs was detected in the study population (namely, 6%), which in subjects >90 years was even higher (15%). Individuals with MARs were older, more often female and less active. In multivariate analysis, independent predictors of MARs were age (OR = 1.07, 95% CI: 1.02-1.13, P = 0.01) and female sex (OR = 4.77, 95% CI: 1.23-18.48, P = 0.02). The mortality rate during the follow-up period was 8.4% without differences between age groups (P = 0.209). In particular, mortality rate was 6% in individuals with MARs and 9% in those without (P = 0.72). Mortality was associated with age (OR 1.07, 95% CI: 1.02-1.12, P = 0.005) and history of cardiovascular disease at baseline (OR 4.57, 95% CI: 1.87-11.2 P = 0.001). CONCLUSIONS: Contrary to hospitalized individuals with multifocal atrial tachycardias, MARs were not associated with increased mortality in elderly outpatients in this study.

Fish Consumption Moderates Depressive Symptomatology in Elderly Men and Women from the IKARIA Study.

Background. The aim was to examine the association of depressive symptoms with fish eating habits, in elderly individuals. Methods. From June to October of 2009, we studied 330 men and 343 women, aged 65 to 100 years, permanent inhabitants of Ikaria Island. Among several characteristics, depression was assessed with the Geriatric Depression scale (GDS range 0-15), while dietary habits through a valid semiquantitative food frequency questionnaire. Results. Women had significantly higher values of the GDS compared to men (4.8 ± 3.5 versus 3.3 ± 3.1, P = .001). Participants in the upper tertile of depression scale ate less frequent fish and consumed higher quantities of alcohol, compared to those in the lowest tertile (all P < .05). Regarding fish consumption, 50% of the individuals reported consuming 1-2 times weekly, 32% 3 to 5 times weekly, 11% 2-3 times monthly, while the rest reported rare (4.5%) and everyday (1.2%) consumption. Logistic regression showed that increased fish consumption (>3 times/week versus never/rare) was inversely associated with the odds of having GDS greater the median value (i.e., 4) (odds ratio = 0.34, 95% CI: 0.19, 0.61), after controlling for several cofounders. Conclusion. Frequent fish consumption in elderly seems to moderate depression mood.