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Background Dobutamine stress echocardiography is an established diagnostic modality for assessing myocardial ischaemia in patients with known or suspected coronary artery disease. Dobutamine infusion causes dose-dependent increase in heart rate and contractility. However, in some cases, it induces paradoxical sinus deceleration, whose underlying mechanism and clinical significance are not fully understood. Case summary We present episodes of paradoxical sinus deceleration observed during dobutamine stress echocardiography in six (four males and two females) patients and described its patterns of occurrence and clinical and echocardiographic characteristics. Discussion Paradoxical sinus deceleration occurred mostly at maximal dobutamine infusion was accompanied with a decline in blood pressure and resolved spontaneously following cessation of dobutamine infusion. Individuals experiencing paradoxical sinus deceleration had in common abnormal left ventricle geometry but differed with regard to age, sex, and cardiometabolic risk factors.

Background The burden of non-obstructive coronary artery disease (CAD) in the society is high, and there is currently limited evidence-based recommendation for risk stratification and treatment. Previous studies have demonstrated an association between increasing extent of non-obstructive CAD and cardiovascular events. Whether hypertension, a modifiable cardiovascular risk factor, is associated with extensive non-obstructive CAD in patients with symptomatic chronic coronary syndrome (CCS) remains unclear. Methods We included 1138 patients (mean age 62±11 years, 48% women) with symptomatic CCS and non-obstructive CAD (1–49% lumen diameter reduction) by coronary computed tomography angiography (CCTA) from the Norwegian Registry for Invasive Cardiology (NORIC). The extent of non-obstructive CAD was assessed as coronary artery segment involvement score (SIS), and extensive non-obstructive CAD was adjudicated when SIS >4. Hypertension was defined as known hypertension or use of antihypertensive medication. Results Hypertension was found in 45% of patients. Hypertensive patients were older, with a higher SIS, calcium score, and prevalence of comorbidities and statin therapy compared to the normotensive (all p Conclusion In symptomatic CCS, hypertension was associated with extensive non-obstructive CAD by CCTA. Whether hypertension may be a new treatment target in symptomatic non-obstructive CAD needs to be explored in future studies. Clinical trial registration ClinicalTrials.gov: Identifier NCT 04009421.

Introduction: Myocardial ischemia is common among patients with chest pain and non-obstructive coronary artery disease (CAD). Epicardial adipose tissue (EAT) accumulation has been associated with inflammation, atherosclerosis and microvascular dysfunction. Accordingly, we hypothesised that EAT volume is associated with coronary plaque vulnerability and myocardial ischemia in patients with non-obstructive CAD. Methods: We included 125 patients with chest pain and non-obstructive CAD by coronary computed tomography angiography (CCTA). EAT volume was quantified on non-contrast cardiac computed tomography images by a semiautomatic analysis software. CCTA images were analysed with respect to plaque volume and composition. Plaque vulnerability was assessed as total coronary non-calcified plaque volume and positive remodelling index >1.10. Myocardial ischemia was detected by contrast dobutamine stress echocardiography. Patients were grouped in tertiles of EAT volume and high EAT volume was defined as volumes in the highest tertile (≥125 ml). Results: In the total study population (median age 63(58, 69) years and 58% women), the median EAT volume was 104 (77, 141) ml. High EAT volume was more common in men and associated with higher BMI, hypertension and positive remodelling (all p Conclusion: High EAT volume was associated with positive remodelling, but not with total non-calcified plaque volume or myocardial ischemia, and the association was attenuated after multivariable adjustments.

Introduction Increased left ventricular mass index (LVMi) and left ventricular hypertrophy (LVH) by echocardiography are common in obesity and important cardiovascular risk predictors associated with myocardial ischemia in non-obstructive coronary artery disease (CAD). Accumulation of epicardial adipose tissue (EAT) suggest a possible direct impact on LVMi and LVH. Purpose To explore the association between EAT volume, LVMi and LVH in patients with chest pain and non-obstructive CAD. Methods We included 129 patients with chest pain and non-obstructive CAD (46.7 g/m2.7 in women and >49.2 g/m2.7 in men. Coronary artery plaque burden was assessed as calcium score and segment involvement score on coronary CT angiography. Results High EAT volume was more common in men with higher BMI, waist circumference, serum triglycerides and higher prevalence of hypertension and obesity (all p Conclusion High EAT volume was associated with increased LVMi in patients with non-obstructive CAD, independent of hypertension and obesity, while there was no association with LVH. This suggest that direct infiltration of adipose tissue in the myocardium may contribute to the development of increased LVMi. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Western Norwegian Regional Health Authorities Table 1

Background Inadequate intake of polyunsaturated fatty acids (PUFAs) is recognized as a modifiable risk factor for atherosclerotic cardiovascular disease (CVD) (1,2). The n-6 PUFA linoleic acid (LA) constitutes the predominant portion of total dietary PUFAs (3). However, whereas cardiometabolic effects of PUFAs belonging to the n-3 series have been studied for decades, less attention has been payed to potential health effects from n-6 PUFAs (4). Further, there has been concern regarding possible proinflammatory properties of several n-6 PUFA related metabolites. Purpose We explored correlations of serum total PUFAs, LA and the n-3 PUFA docosahexaenoic acid (DHA) with the inflammation marker GlycA. Further, we evaluated associations of total PUFAs, LA and DHA with the extension of atherosclerosis, as determined by the Agatston coronary artery calcium (CAC) score (5). Methods The study includes 250 patients who were hospitalized due to acute chest pain and referred to coronary CT angiography (CCTA) during in hospital stay. Exclusion criteria included diagnosis of acute myocardial infarction and/or revascularization within 24 hours after admittance. Serum levels of total PUFAs, LA, DHA and GlycA were analyzed by NMR technology in samples that had been frozen and stored at −80°C. After logarithmic transformation, relations of total PUFA, LA, and DHA with GlycA were evaluated by Pearson correlation analyses. The associations with CAC score were visualized in generalized additive regression plots and further evaluated in linear regression models including age, gender, body mass index, diabetes, hypertension and smoking status as independent covariables. Results Mean (SD) age was 57.6 (12.0) years, and 91 (36.4%) of the patients were women. Median (25th-75th percentiles) serum levels (in mmol/L) were for total PUFA 6.36 (5.76–7.06), LA 5.00 (4.51–5.55), DHA 0.36 (0.31–0.43) and GlycA 1.04 (0.94–1.13). Interestingly, GlycA was strongly, positively correlated with total PUFA (r=0.54). LA (r=0.53) and DHA (r=0.27), all P Conclusion In patients undergoing CCTA due to acute chest pain, serum levels of total PUFA and LA were strongly positively correlated with the pro-inflammatory marker GlycA. Still, total PUFA and LA were both inversely associated with the CAC score and the associations remained statistically significant after adjustments for CVD risk factors and GlycA levels. Future studies should further address the diverse effects of n-6 PUFAs on inflammatory pathways, atherogenesis and coronary calcification. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Western Norway Regional Health Authority

Background Although generally at lower risk than those with obstructive CAD, patients with non-obstructive CAD (NOCAD) are heterogeneous concerning long-term prognosis. Notably, reversible ischemia due to vascular dysfunction is a frequent finding in NOCAD patients (1). The endogenous, non-proteinogenic amino acid homoarginine (hArg) increases the availability of nitric oxide (NO) and thereby the NO-dependent vasodilatation (2). Several studies have reported a strong inverse relation between serum hArg levels and cardiovascular disease (CVD) risk among patients with obstructive CAD. However, the prognostic implications of serum hArg levels in NOCAD patients have not been explored previously. Purpose We evaluated serum hArg as a predictor of long-term risk of CVD mortality among patients with NOCAD. Methods 1046 patients with chronic coronary syndrome (CCS) underwent elective coronary angiography during 2000–2004, with the findings of NOCAD. Serum hArg was measured by liquid chromatography-tandem mass spectrometry in samples that had been frozen and stored at −80°C. The association of serum hArg to CVD mortality risk was visualized in a generalized additive regression plot and further explored using Cox regression. The models included age, sex, body mass index, hypertension, diabetes, smoking status, serum LDL cholesterol and estimated glomerular filtration rate as independent covariables. We evaluated model discrimination and risk classification by calculating C-statistics and net reclassification improvement (NRI >0), respectively. Results Median (25th-75th percentiles) age at inclusion was 57 (51–65) years, 48.5% were women and median (25th-75th percentiles) level of serum hArg was 1.87 (1.47–2.38) μmol/L. During median (25th- 75th percentiles) 14.1 (13.2–15.4) years of follow-up 5.7% of the patients died from CVD. The multivariable adjusted hazard ratio (95% confidence interval) per SD increment of (log transformed) hArg was 0.53 (0.40–0.70) in relation to CVD mortality. The multivariable model without biomarker provided a C- statistics for CVD mortality of 0.79 which increased to 0.82 by the addition of serum-hArg to the model (Δ area =0.03, P=0.01). Further, serum hArg provided a high NRI (95% CI) of 0.53 (0.40–0.70), P Conclusion We demonstrated a strong inverse relationship between serum hArg and long-term risk of CVD mortality among patients with NOCAD. Our study adds to previous literature linking low hArg with vascular dysfunction and adverse CVD prognosis. The potential clinical usefulness of serum hArg measurements for the identification of a high-risk phenotype in NOCAD warrants further evaluation. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): The Western Norway Regional Health Authority

Background: The underlying mechanisms causing myocardial ischemia in non-obstructive coronary artery disease (CAD) are still unclear. We explored whether left ventricular hypertrophy (LVH) was associated with myocardial ischemia in patients with stable angina and non-obstructive CAD. Methods: 132 patients (mean age 63 ± 8 years, 56% women) with stable angina and non-obstructive CAD diagnosed as 46.7 g/m2.7 in women and >49.2 g/m2.7 in men. Patients were grouped according to presence or absence of myocardial ischemia by myocardial contrast stress echocardiography. The number of LV segments with ischemia at peak stress was taken as a measure of the extent of myocardial ischemia. Results: Myocardial ischemia was found in 52% of patients, with on average 5 ± 3 ischemic LV segments per patient. The group with myocardial ischemia had higher prevalence of LVH (23 vs. 10%, p = 0.035), while age, sex and prevalence of hypertension did not differ between groups (all p > 0.05). In multivariable regression analyses, LVH was associated with presence of myocardial ischemia (odds ratio 3.27, 95% confidence interval [1.11–9.60], p = 0.031), and larger extent of myocardial ischemia (β = 0.22, p = 0.012), independent of confounders including age, hypertension, obesity, hypercholesterolemia, calcium score and segment involvement score by CCTA. Conclusions: LVH was independently associated with both presence and extent of myocardial ischemia in patients with stable angina and non-obstructive CAD by CCTA. These results suggest LVH as an independent contributor to myocardial ischemia in non-obstructive CAD. publishedVersion

Aim: Whether the total coronary atherosclerotic plaque burden is independently associated with myocardial ischemia in non-obstructive coronary artery disease (CAD) is not well established. We aimed to test the association of total plaque burden quantified by coronary computed tomography angiography (CCTA) with myocardial ischemia in patients with chronic coronary syndrome and non-obstructive CAD. Methods: We included 125 patients (age 62 ± 9 years, 58% women) with chronic coronary syndrome and non-obstructive CAD (stenosis 1.10. Results: Patients with myocardial ischemia (n = 66) had higher total plaque burden (847 ± 245 mm3 vs. 758 ± 251 mm3, p = 0.049) and higher left ventricular (LV) mass index (42.1 ± 9.9 g/m2.7 vs. 37.3 ± 8.0 g/m2.7, p = 0.004), while age, sex, prevalence of hypertension, diabetes, calcium score and positive remodelling did not differ between the groups (all p > 0.05). In multivariable regression analysis, total plaque burden remained associated with presence of myocardial ischemia (OR 1.02, 95% CI 1.00–1.04, p = 0.045) independent of age, sex, hypertension, diabetes, LV mass index, coronary calcium score and positive remodelling. Conclusion: Total coronary artery plaque burden by CCTA was independently associated with myocardial ischemia in patients with non-obstructive CAD. Whether plaque quantification is useful for clinical management of patients with non-obstructive CAD should be tested in prospective studies.ClinicalTrials.gov: Identifier NCT01853527.

Sex and gender are important modifiers of cardiovascular system physiology, pathophysiology, and disease development. The atherosclerosis process, together with the progressive loss of arterial elasticity with age, is a major factor influencing the development of overt cardiovascular, renal, and cerebrovascular disease. While differences between women and men in epidemiology and pathophysiology of vascular ageing are increasingly reported, sex-disaggregated data are still scarcely available for prospective studies. A better knowledge of sex differences in physiological ageing as well as in disease-related changes in vascular ageing trajectories is crucial to avoid misdiagnosis and mistreatment. This review presents key concepts and knowledge gaps identified in vascular ageing due to gonadal function, vascular physiology, pathophysiology, psychosocial factors, pregnancy, and prognostic relevance. Gender roles determine the effectiveness of any cardiovascular preventive strategy and acceptance for non-invasive or invasive diagnostics and therapeutics. Gender differences in health behaviour, also due to sociocultural norms conditioned by society, contribute to behaviours that may lead to premature arterial vascular ageing. These include differences in risk behaviours like smoking, diet, exercise, and in stress, but also conditions such as housing, noise pollution, poverty, disability, and any kind of stigmatisation. The VascAgeNet Gender Expert Group aims to advance the use of non-invasive vascular ageing measures in routine clinical settings by providing facts to fill in the gaps concerning sex and gender differences at each step of this process, and to search for solutions.

Background Ischemia with non-obstructive coronary arteries (INOCA) is incompletely understood. Depressed myocardial energetic efficiency index (MEEi), the ratio between external work and myocardial oxygen consumption, has been shown in heart failure. However, MEEi in INOCA has not been explored. Purpose To test whether MEEi is associated with INOCA. Methods We included 125 patients (56% women, age 62±9 years) with exercise-induced chest pain and non-obstructive coronary arteries (stenosis 46.7 g/m2.7 in women and >49.2 g/m2.7 in men. Myocardial ischemia was detected by myocardial contrast stress echocardiography. Coronary artery plaque burden was measured as plaque volume by CCTA. Results In univariable regression analysis, stress-induced ischemia, male sex, diabetes, hypertension, LV hypertrophy, lower LV ejection fraction and higher SBP were associated with MEEi (all p Conclusion MEEi is depressed in patients with INOCA. Our results suggest that myocardial ischemia negatively influences MEEi in patients with non-obstructive coronary arteries. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Western Norway Regional Health Authority, University of Bergen

Background Reduced serum levels of high density lipoprotein cholesterol (HDL-C) is a hallmark of the metabolic syndrome. Epidemiologic studies have reported an inverse correlation between HDL- C and cardiovascular disease (CVD) risk. However, recent works suggest that the association is strongest in healthy individuals. Changes in particle number and functional properties of HDL may more closely reflect CVD prognosis in patients with pre-existent disease. The majority of such patients receive statin treatment, which affects both HDL-C levels, and particle composition. Hence, serum apoA1 and the HDL-C:apoA1 ratio have been proposed as more sensitive indicators of cardio-metabolic prognosis. Purpose We studied the associations of serum HDL-C, apoA1 and the HDL-C: apoA1 ratio to long term risk of CVD mortality and incident type 2 diabetes (T2D) patients with suspected stable angina pectoris (SAP). Methods A total of 41064 patients underwent elective coronary angiography in 2000–2004 and were followed-up for CVD mortality throughout 2016. In a subgroup of 2519 participants without verified or possible diabetes at baseline, the associations to incident type 2 diabetes (T2D) were evaluated throughout 2014. Information on clinical endpoints was obtained through national health registries. Risk estimates are reported per 1 SD increment of (log transformed) biomarkers and were calculated by cox or logistic regression. We explored risk classification by calculating the continuous net reclassification improvement (NRI). Results At inclusion, median (25th-75th percentiles) age was 62 (55–70) years, 28% were women 76% had obstructive coronary artery disease and 80% received statins. During median (25th-75th percentiles) 13.9 (12.0–15.3) years of follow-up, 14.1% of the participants died from CVD. After multivariate adjustment (age, gender, body mass index, HbA1c, triglycerides, statin treatment, fasting status) HDL and apoA1, but not the HDL: apoA1 ratio, significantly predicted CVD mortality. The hazard ratio (HR) and 95% confidence interval (CI) was: 0.86 (0.78–0.94), 0.88 (0.80–0.98) and 0.96 (0.86–1.03) for HDL-C, apoA1 and the HDL-C:apoA1 ratio, respectively. HDL-C was the only of the evaluated biomarkers providing a significant NRI (95% CI) of 0.14 (0.04–0.19). In the subset evaluated for incdent T2D, HDL-C provided multivariate adjusted odds ratios (OR; 95% CI) and NRI (95% CI) of 0.69 (0.58–0.82) and 0.34 (0.21–0.47) for new onset TSD. The corresponding OR (95% CI) and NRI (95% CI) for apoA1 were: 0.85 (0.73–0.99) and 0.20 (0.06–0.33), respectively. The HDL:apo A1 ratio provided an OR (95% CI) of 0.66 (0.55–0.80) and NRI (95% CI) of 0.24 (0.11–0.37) for T2D. No significant effect modifications according to statin treatment were found (P≥0.22). Conclusion Among patients with suspected SAP, of which the majority received statins, HDL-C was non-inferior to apoA1 and the HDL:apoA1 ratio in predicting long term risk of CVD mortality and T2D. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Department of Heart Disease, Haukeland University Hospital; Department of Clinical Science, University of Bergen

Background and aims Reduction of left ventricular mass index (LVMi) during antihypertensive treatment is less likely to occur in obese subjects. The aim of the study was to assess whether weight loss influences reduction of LVMi in treated, obese, hypertensive patients. Methods and results From the Campania Salute Network registry, we identified 1546 obese hypertensive patients (50 ± 9 years, 43% women) with more than 12 months follow-up. Echocardiographic reduction of LVMi was considered as achievement of normal values ( Conclusion In treated obese hypertensive patients, weight loss during follow-up promotes significant reduction of LVMi, independent of baseline characteristics and blood pressure control.

Background and aims Subclinical cardiac disease, like abnormal left ventricular (LV) geometry or left atrial (LA) dilatation, is common in obesity. Less is known about sex differences in the prevalence and type of subclinical cardiac disease in obesity. Methods and results Clinical and echocardiographic data from 581 women and men without established cardiovascular disease and body mass index (BMI) > 27.0 kg/m2 participating in the FAT associated CardiOvasculaR dysfunction (FATCOR) study was analyzed. LA dilatation was recognized as LA volume indexed for height2 ≥16.5 ml/m2 in women and ≥18.5 ml/m2 in men, and abnormal LV geometry as LV hypertrophy and/or increased relative wall thickness. On average, the participants were 48 years old, 60% women and mean BMI was 32.1 kg/m2. Overall, the prevalence of subclinical cardiac disease was higher in women than men (77% vs. 62%, p Conclusion The majority of overweight and obese participants in the FATCOR study had subclinical cardiac disease, which may contribute to the impaired prognosis observed in obesity. Women had a higher prevalence of subclinical cardiac disease than men. Clinical trial registration URL: http://www.clinicaltrials.gov NCT02805478 .

Strain rate imaging by tissue Doppler (TDI) is vulnerable to stationary reverberations and noise (clutter). Anatomic Doppler spectrum (ADS) presents retrospective spectral Doppler from ultra-high frame rate imaging (UFR-TDI) data for a region of interest, that is, ventricular wall or segment, at one time instance. This enables spectral assessment of strain rate (SR) without the influence of clutter. In this study, we assessed SR with ADS and conventional TDI in 20 patients with a recent myocardial infarction and 10 healthy volunteers. ADS-based SR correlated with fraction of scarred myocardium of the left ventricle (r = 0.68, p

The association of transaortic flow rate (FR) with outcomes was tested in 1,661 patients with aortic valve stenosis (AS) in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study.Low transaortic flow may complicate grading of AS. However, the association of lower transaortic FR with adverse outcomes has not been reported.Transaortic FR was calculated from Doppler-derived stroke volume in milliliters divided by systolic ejection time in seconds and considered low if 200 ml/s. The association of transaortic FR with cardiovascular and all-cause mortality during 4.3-year follow-up was tested in time-varying Cox regression models run with aortic valve replacement as competing risk and reported as hazard ratio (HR) and 95% confidence interval (CI).Low transaortic FR was found in 21% of patients at baseline. Patients with low transaortic FR were older, had lower systemic arterial compliance and left ventricular mass, and included more women and patients with inconsistently graded severe AS and low stroke volume index (35 ml/mIn patients with AS without known cardiovascular disease or diabetes, low transaortic FR was independently associated with higher rates of cardiovascular and all-cause mortality. (An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis (Narrowing of the Major Blood Vessel of the Heart) (MK-0653A-043 AM4); NCT00092677).

Background and aims Good cardiorespiratory fitness has been suggested to reduce the risk of cardiovascular disease in obesity. We explored the association of fitness with the prevalences of major cardiovascular risk factor like hypertension (HT), diabetes and metabolic syndrome (MetS) in overweight and obese subjects. Methods and results Clinical data from 491 participants in the FAT associated CardiOvasculaR dysfunction (FATCOR) study were analyzed. Physical fitness was assessed by ergospirometry, and subjects with at least good level of performance for age and sex were classified as fit. HT subtypes were identified from clinic and 24-h ambulatory blood pressure in combination. Diabetes was diagnosed by oral glucose tolerance test. MetS was defined by the American Heart Association and National Heart, Lung and Blood Institute criteria. The participants were on average 48 years old (60% women), and mean body mass index (BMI) was 32 kg/m 2 . 28% of study participants were classified as fit. Fitness was not associated with lower prevalences of HT or HT subtypes, diabetes, MetS or individual MetS components (all p > 0.05). In multivariable regression analysis, being fit was characterized by lower waist circumference, BMI 2 , non-smoking and a higher muscle mass (all p Conclusion In the FATCOR population, fitness was not associated with a lower prevalence of major cardiovascular risk factors like HT, diabetes or MetS. Given the strong association of cardiovascular risk factor burden with risk of clinical cardiovascular disease, these findings challenge the notion that fitness alone is associated with lower risk of cardiovascular disease in obesity.

Background In non-obstructive coronary artery disease (CAD), increasing extent of disease is associated with a worse prognosis. Statin therapy has been suggested to improve the prognosis. Whether hypertension, a modifiable CV risk factor, affects the extent of non-obstructive CAD in patients with stable angina is less explored. Purpose To assess the association between hypertension and extent of non-obstructive coronary artery disease. Methods We identified 1117 patients (mean age 62±10 years, 48% women) from the Norwegian Registry for Invasive Coronary angiography (NORIC). All subjects had stable angina and non-obstructive CAD defined as 1–49% stenosis in any coronary artery segment by coronary computed tomography angiography (CCTA). The extent of non-obstructive CAD was assessed as coronary artery segment involvement score (SIS) on CCTA. Extensive non-obstructive CAD was defined as SIS≥4. Results Hypertension was present in 44% and patients with hypertension were older with a higher prevalence of diabetes, obesity, smoking and statin therapy (all p Table 1. Covariables of extensive non-obstructive CAD in univariable and multivariable logistic regression analysis Univariable analysis Multivariable analysis OR 95% CI p-value OR 95% CI p-value Hypertension 1.57 1.21–2.04 0.001 1.47 1.03–2.10 0.035 Age 1.06 1.05–1.08 Conclusions Hypertension is associated with extensive non-obstructive CAD in patients with stable angina, suggesting that early and aggressive antihypertensive treatment may impact disease progression.

There is little information on left ventricular (LV) hypertrophy (LVH) development during antihypertensive treatment. We evaluate incident LVH in a treated hypertensive cohort, the Campania Salute Network registry. We analyzed prospectively 4290 hypertensives (aged 50.3±11.1 years, 40% women) with at least 1-year follow-up, without LVH at baseline. Incident LVH was defined as the first detection of echocardiographic LV mass index ≥47 in women or ≥50 g/m 2.7 in men. During a median 48-month follow-up, 915 patients (21.3%) developed LVH. They were older, more frequently women, and obese ( P P ++ -channel blockers and diuretics (both P P P =0.019; and obese versus nonobese women: hazard ratio, 1.34; confidence interval, 1.08–1.66; P =0.007). Despite more aggressive antihypertensive therapy, 21% of hypertensive patients develop clear-cut LVH. After adjusting for confounders, risk of incident LVH is particular relevant among women and is further increased by the presence of obesity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02211365.

OBJECTIVES The relation between aortic root dimension (ARD) and measures of arterial stiffness is uncertain. Accordingly, we studied the relation between ARD and an estimate of arterial stiffness in 12 392 hypertensive patients (age 53 ± 12 years, 43% women) free of prevalent cardiovascular disease and with ejection fraction at least 50%, from the Campania Salute Network Registry. METHODS Echocardiographic ARD was measured and compared with the value predicted by age, sex and height by using a z-score. Arterial stiffness was assessed by the pulse pressure/stroke index. The highest population tertile of pulse pressure/stroke index was considered 'high arterial stiffness'. RESULTS High arterial stiffness was more common in women than in men (P

ObjectiveHigh aortic stiffness may reduce myocardial perfusion pressure and contribute to development of myocardial ischaemia. Whether high aortic stiffness is associated with myocardial ischaemia in patients with stable angina and non-obstructive coronary artery disease (CAD) is less explored.MethodsAortic stiffness was assessed as carotid-femoral pulse wave velocity (PWV) by applanation tonometry in 125 patients (62±8 years, 58% women) with stable angina and non-obstructive CAD participating in the Myocardial Ischemia in Non-obstructive CAD project. PWV in the highest tertile (>8.7 m/s) was taken as higher aortic stiffness. Stress-induced myocardial ischaemia was detected as delayed myocardial contrast replenishment during stress echocardiography, and the number of left ventricular (LV) segments with delayed contrast replenishment as the extent of ischaemia.ResultsPatients with higher aortic stiffness were older with higher LV mass index and lower prevalence of obesity (all pConclusionsIn patients with stable angina and non-obstructive CAD, higher aortic stiffness was associated with stress-induced myocardial ischaemia. Consequently, assessment of aortic stiffness may add to the diagnostic evaluation in patients with non-obstructive CAD.Trial registration numberNCT01853527.

Background and aims Obesity is associated with reduced left ventricular (LV) systolic myocardial function. We aimed to explore by means of a cross-sectional study whether this effect is offset in the presence of good fitness. Methods and results We studied clinical and echocardiographic data from 469 overweight (body mass index [BMI] >27 kg/m2) and obese (BMI ≥30 kg/m2) women and men without known cardiovascular (CV) disease in the FAT associated CardiOvasculaR dysfunction (FATCOR) study. The participants were grouped according to obesity and sex- and age adjusted peak oxygen uptake, obtained by ergospirometry. LV systolic myocardial function was assessed by peak systolic global longitudinal strain (GLS) measured by speckle tracking echocardiography. The association of fitness with GLS was tested in logistic regression analyses and reported as odds ratio (OR) with 95% confidence interval (CI). In the total study population, participants were 47 years old, 60% were women, and mean BMI was 32.0 kg/m2. GLS did not differ between fit and unfit subjects within the overweight and obese groups (both p > 0.05), but the overweight fit group had higher GLS (more negative value) compared to the obese unfit group (−20.1 ± 2.6 vs. −19.0 ± 3.0, p Conclusion In obesity, fitness was independently associated with higher GLS, while no association was found in overweight. Clinical trial registration URL: http://www.clinicaltrials.gov NCT02805478 .

ObjectiveLower systemic arterial compliance (SAC) is associated with increased cardiovascular morbidity and mortality in hypertension, but this has not been assessed in a prospective study in aortic valve stenosis (AS).MethodsData from 1641 patients (38% women) with initially asymptomatic mild-moderate AS enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study was used. Median follow-up was 4.3 years. SAC was assessed from Doppler stroke volume index to central pulse pressure ratio and considered low if ≤0.64 mL/m², corresponding to the lower tertile in the population. The association of SAC with outcome was assessed in Cox regression analysis and reported as HR and 95% CI.ResultsLow SAC at baseline was characterised by older age, female sex, hypertension, obesity, presence of a small aortic root, lower mean aortic gradient and more severe AS by effective aortic valve area (all pConclusionsIn patients with AS without diabetes and known cardiovascular disease, but a high prevalence of hypertension, low SAC was associated with higher cardiovascular and all-cause mortality independent of well-known prognosticators.Trial registration numberNCT00092677; Post-results.

Abnormal night-time blood pressure (BP) reduction is associated with increased cardiovascular risk in hypertension. Little is known about the prevalence and covariates of night-time BP reduction in ischemic stroke patients. Clinic and ambulatory BP measurements were recorded in 268 stroke survivors aged 15-60 years. The degree of night-time dipping was calculated from the difference between day-time and night-time mean BP, and defined as non-dipping if

Background: Women with non-ST elevation myocardial infarction (NSTEMI) have similar extent of myocardial ischemia but less obstructive coronary artery disease (CAD) than their male counterparts. We tested the impact of global coronary artery plaque area and artery tortuosity on myocardial perfusion in NSTEMI patients. Methods: Coronary artery plaque area was determined by quantitative angiography in 108 patients (32% women) with NSTEMI. Myocardial perfusion was assessed by contrast echocardiography in the 17 individual left ventricular segments. Artery tortuosity was defined as ‡ 3 curves > 45 in a main coronary artery. Results: Age, prevalence of hypertension, and diabetes did not differ between sexes (all nonsignificant). Women had lower prevalence of ‡ 50% coronary artery stenosis (74% vs. 91%, p < 0.05), while global coronary plaque area (35 – 22 vs. 43 – 21mm2) and the number of segments with hypoperfusion (6.9 – 3.7 vs. 7.2 – 3.4) did not differ between sexes (both p > 0.07). In multivariate analysis, larger coronary artery plaque area was associated with a 35% higher risk for having severe myocardial hypoperfusion (odds ratio 1.35 [95% confidence interval 1.01–1.80], p < 0.05) in the total study population, while no association between artery tortuosity and myocardial ischemia was found. Similar results were obtained in separate analysis among women and men. Conclusion: In women and men with NSTEMI, the global coronary artery plaque area was an important determinant of the severity of myocardial hypoperfusion at rest independent of presence of significant coronary stenoses. These findings may expand current understanding of NSTEMI in patients with nonobstructive CAD. publishedVersion

Background Regression of left ventricular ( LV ) hypertrophy ( LVH ) has been a goal in clinical trials. This study tests the external validity of results of clinical trials on LVH regression using a large registry from a tertiary care center, to identify phenotypes less likely to achieve regression of LVH . Methods and Results Patients from the Campania Salute Network, free of prevalent cardiovascular disease, but with echocardiographic LVH (defined as LV mass index [LVMi] >47 g/m 2.7 in women and >50 g/m 2.7 in men) were included. During a median follow‐up of 67 months, clear‐cut regression of LVH was documented in 14% of patients (13±8% reduction of initial LVMi ) or 23% when also considering those with a reduction of LVMi ≥5 g/m 2.7 . Patients with persistent LVH were older with longer duration of hypertension, suboptimal blood pressure (BP) control, larger body mass index, LV mass, and carotid intima‐media thickness and included more women and subjects with diabetes mellitus, isolated systolic hypertension, and metabolic syndrome (all P LVMi and carotid intima‐media thickness, and suboptimal BP control were significant covariates of persistent LVH (all P ≤0.01), independent of diabetes, duration of hypertension, isolated systolic hypertension, follow‐up time and number and class of antihypertensive drugs. Conclusions Early initiation of antihypertensive treatment, aggressive BP control, and attention to metabolic aspects are critical to avoid irreversible LVH .

Objective Women with severe aortic valve stenosis (AS) have better LV systolic function and more concentric LV geometry than their male counterparts. However, sex differences in cardiovascular (CV) outcome during progression of AS have not been reported from a longitudinal prospective study. Methods Doppler echocardiography and CV events were recorded during a median of 4.0 years in 979 men and 632 women aged 28–86 (mean 67±10) years in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. LV systolic function was assessed by EF and midwall shortening (MWS). Study outcomes were AS-related events, ischaemic CV events and total mortality. Results The annular cumulative incidence of AS events, ischaemic CV events and death was 8.1%, 3.4% and 2.8% in women, and 8.9%, 4.4% and 2.4% in men, respectively. Women and men had similar AS progression rate whether measured by peak jet velocity, mean gradient or valve area. In multivariate analyses, female sex independently predicted less reduction in LV MWS and EF during follow-up (both p

Objectives This study investigated whether overweight and obesity impacted outcome in patients with aortic valve stenosis (AS). Background Increased body mass index (BMI) is a strong predictor of h ...

At a given level of left ventricular (LV) systolic function, LV pump performance (assessed by stroke index [SVi]) may differ, depending on LV size. We evaluated whether low SVi may be considered a marker of risk for incident congestive heart failure (HF), independent of LV geometry and systolic function, assessed by ejection fraction (EF) or midwall fractional shortening (MFS), in a large population-based sample with normal EF. Clinical and echocardiographic data from the second Strong Heart Study (SHS) examination, including 2,885 American Indians (59 ± 8 years; 63% women) with normal EF (EF ≥51% in men and EF ≥55% in women) and without prevalent HF or significant valve disease, were analyzed. Low SVi was defined as SVi ≤22 ml/m 2.04 . Low SVi was more common among men and associated with lower body mass index, systolic blood pressure, LV mass index, left atrial dimension, EF, and MFS and with higher relative wall thickness. During a mean 12-year follow-up, 209 participants developed HF and 246 had acute myocardial infarction. In Cox regression analysis, low SVi was associated with higher risk of incident HF (hazard ratio 1.38; 95% confidence interval 1.06 to 1.80), independently of age, gender, body mass index, heart rate, hypertension, prevalent cardiovascular disease, left atrial dimension index, LV mass index, LV concentric geometry, EF or MFS, and abnormal wall motion, also accounting for myocardial infarction as a competing risk event. In conclusion, in the SHS, low SVi was associated with higher incident rate of HF, independently of LV geometry and systolic function and other major confounders.

Objective In severe aortic valve stenosis (AS), low left ventricular (LV) stroke volume has been associated with increased cardiovascular (CV) mortality, but this association has not been explored during progression of AS in a large prospective study. Methods In 1671 patients from the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study, the association of stroke volume indexed for body surface area (SVI) with major CV events during a median of 4.3-year follow-up was assessed in Cox and time-varying Cox regression analyses. Low SVI was defined as Results Peak aortic jet velocity in the total study population was 3.1 ±0.7 m/s. Low SVI was found in 23% at baseline and associated with higher age, body mass index (BMI), heart rate and global LV load, and with lower mean aortic gradient, aortic valve area index, energy loss index, LV mass and ejection fraction and more often inconsistent AS grading (all p Conclusion In patients with AS in the SEAS study, lower baseline SVI was associated with higher HR of major CV events and total mortality independent of major confounders. Trial registration number NCT00092677: Results

Background: Masked hypertension (MHT), defined as normal office blood pressure (BP) but high ambulatory BP, has been associated with increased cardiovascular risk. Although MHT has been associated with obesity, there is limited knowledge on the prevalence and covariates of MHT in obese cohorts. Methods: Office and ambulatory BP recordings and other cardiovascular risk factors were assessed in 323 obese participants included in the fat-associated cardiovascular dysfunction study (mean age 48.9±9.0 years, 55% women, mean BMI 32.3±4.4 kg/m2). Office BP 130–139/85–89 mmHg was considered high-normal. Subclinical arterial damage was identified as carotid–femoral pulse wave velocity more than 10 m/s by applanation tonometry or carotid plaque by ultrasound (maximal intima–media thickness ≥1.5 mm). Results: MHT was present in 17.1% of the population. Patients with MHT had a higher prevalence of metabolic syndrome, high-normal office BP, and were more often male compared with the normotensive (NT) individuals (all P

We tested the prognostic impact of a marker of arterial stiffness, pulse pressure/stroke volume index (PP/SVi), in patients with hypertension and left ventricular (LV) hypertrophy. We used data from 866 patients randomized to losartan or atenolol-based antihypertensive treatment, over a median of 4.8 years, in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. The association of PP/SVi with outcomes was tested in Cox regression analyses and reported as hazard ratio (HR) and 95% confidence intervals (CI). In multivariate regression, reduction of PP/SVi was independently associated with male gender, reduction in systolic blood pressure (BP) and relative wall thickness and with an increase in left ventricular ejection fraction (all p

Asymmetric interventricular septum hypertrophy (ASH) has been associated with increased perioperative morbidity and mortality in patients with severe, symptomatic aortic valve stenosis (AS). Less is known about the prognostic impact of ASH during progression of AS. Clinical, echocardiographic, and outcome data from 1,691 patients with initially asymptomatic, mostly moderate AS, participating in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study was used. ASH was considered present if interventricular septum/posterior wall thickness ratio in end-diastole ≥1.5. The associations of ASH with hazard rate of ischemic cardiovascular events were tested in time-dependent Cox regression analyses. Based on the presence of ASH at study echocardiograms, the study population was grouped in to a no-ASH, nonpersistent ASH, persistent ASH, and new-onset ASH groups. During a median of 4.3 years of follow-up, ASH persisted or developed in 17% of patients. Persistent or new-onset ASH was characterized by higher left ventricular mass index and ejection fraction at baseline (both p0.05) but not with female gender or hypertension. In time-varying Cox regression analyses adjusting for these confounders, persistent or new-onset ASH was associated with higher hazard rate of ischemic cardiovascular events (hazard rate 1.45; 95% confidence interval 1.09 to 1.91, p = 0.01), in particular coronary artery bypass grafting (hazard rate 1.69; 95% confidence interval 1.17 to 2.47; p = 0.006), whereas no association with increased mortality was found. In conclusion, in patients with AS without diabetes or known renal or cardiovascular disease participating in the SEAS study, persistent or new-onset ASH during progression of AS was associated with higher rate of ischemic cardiovascular events.

To evaluate whether lower stroke volume during antihypertensive treatment is a predictor of cardiovascular events independent of left ventricular geometric pattern.The association between left ventricular stroke volume and combined cardiovascular death, stroke and myocardial infarction, the prespecified primary study endpoint, was assessed in Cox regression analysis using data from baseline and annual follow-up visits in 855 patients during 4.8 years of randomized losartan-based or atenolol-based treatment in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy.During follow-up, a total of 91 primary endpoints occurred. At baseline, lower left ventricular stroke volume was associated with smaller body size, female sex, lower left ventricular mass and stress-corrected midwall shortening, higher relative wall thickness and total peripheral resistance, more concentric left ventricular geometry and impaired diastolic relaxation (all P 0.01). Baseline stroke volume did not predict outcome. However, in time-varying multivariable Cox regression analysis, lower in-treatment left ventricular stroke volume indexed for height was associated with higher risk of cardiovascular events {hazard ratio 1.69 per 1 SD (6 ml/m) lower stroke volume [95% confidence interval (CI) 1.35-2.11], P 0.001} independent of in-treatment left ventricular mass and concentric geometry and in a secondary model also independent of stress-corrected midwall shortening, impaired diastolic relaxation, heart rate, new-onset atrial fibrillation and study treatment [hazard ratio 1.46 per 1 SD (6 ml/m) lower stroke volume (95% CI 1.13-1.88)].Assessment of in-treatment left ventricular stroke volume may reflect cardiac and vascular remodeling and impairment and, hence, adds information on cardiovascular risk in treated hypertensive patients beyond assessment of left ventricular structure alone.NCT 00338260.

Quantitative contrast stress echocardiography (CSE) can assess regional myocardial perfusion. The aim of this study was to evaluate the performance of quantitative CSE in the detection of restenosis after percutaneous coronary intervention (PCI).Thirty-three patients with stable coronary artery disease, scheduled for PCI, underwent CSE and quantitative coronary angiography (QCA) before and 9 months after PCI. Regional myocardial perfusion was analysed blinded to QCA results. QCA identified 38 significant stenoses (or =50% diameter reduction). Before PCI, perfusion during stress was significantly reduced in regions supplied by stenotic arteries; blood flow velocity (Deltabeta) -3.9 (-9.0 to 0.5) s(-1), perfusion rate (DeltaA x beta) -175.0 (-518.0 to 58.5) s(-1), and refilling time (Deltart) 210 (-22 to 452)ms, compared with the perfusion increase seen in regions supplied by non-stenotic arteries; Deltabeta 1.6 (-0.7 to 4.4) s(-1), DeltaA x beta 151.7 (-67.0 to 300.5) s(-1), and Deltart -47 (-195 to 89) ms, all P0.05. At follow-up, regional stress-induced perfusion improved in 29 regions with successful PCI; Deltabeta 0.1 (-2.7 to 3.6), DeltaA x beta 30.5 (-133.3 to 232.1), and Deltart -99 (-247 to 125), all Por = 0.01, although there was no improvement in nine regions with restenosis; Deltabeta 0.9 (-1.5 to 5.3), DeltaAxbeta 65.7 (-40.8 to 412.6), and Deltart -79 (-268 to 163), P = NS.Quantitative CSE has the potential to detect angiographically significant coronary artery stenoses as well as angiographic success after PCI.

Background: Myocardial contrast stress echocardiography (stress MCE) is a novel method for diagnosing coronary artery disease (CAD). Few studies have compared the diagnosis of ischemia by stress MCE to angiographic CAD. Methods: Dobutamine stress MCE and SonoVue contrast infusion were performed before an elective percutaneous coronary intervention in 37 patients (8 women) aged 45–75 years with symptomatic CAD and at least one significant coronary artery stenosis measured by quantitative coronary angiography (QCA). The total and regional perfusion and wall motion (WM) were scored as normal or abnormal and attributed to the three main epicardial coronary arteries using a 17-segment left ventricular model. Results: An intermediate stress level was obtained in 29 (78%) patients, and 2 (5%) patients obtained peak stress. A perfusion defect was detected in 92% and WM abnormality in 57% of the patients at peak stress (P < 0.01). By perfusion, 70% of stenoses were both detected and correctly anatomically located, compared to 42% by WM (P < 0.01). All 21 patients with multivessel disease and/or proximal left anterior descending (LAD) stenosis measured by QCA were identified by stress-induced perfusion defects, while only 11 of them were identified by WM abnormalities (P < 0.01). Conclusion: Perfusion scoring is superior to WM scoring during stress MCE for diagnosing significant CAD in patients obtaining intermediate stress level, in particular, when multivessel disease or proximal LAD stenosis is present.

Background— The prognostic importance of left ventricular (LV) mass in nonsevere asymptomatic aortic stenosis has not been documented in a large prospective study. Methods and Results— Cox regression analysis was used to assess the impact of echocardiographic LV mass on rate of major cardiovascular events in 1656 patients (mean age, 67 years; 39.6% women) with mild-to-moderate asymptomatic aortic stenosis participating in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. Patients were followed during 4.3 years of randomized treatment with combined simvastatin 40 mg and ezetimibe 10 mg daily or placebo. At baseline, LV mass index was 45.9 + 14.9 g/m 2.7 , and peak aortic jet velocity was 3.09 + 0.54 m/s. During follow-up, 558 major cardiovascular events occurred. In Cox regression analyses, 1 SD (15 g/m 2.7 ) higher baseline LV mass index predicted increases in hazards of 12% for major cardiovascular events, 28% for ischemic cardiovascular events, 34% for cardiovascular mortality, and 23% for combined total mortality and hospitalization for heart failure (all P P Conclusions— Higher LV mass index is independently associated with increased cardiovascular morbidity and mortality during progression of aortic stenosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00092677.