Thais Coutinho

Combining Body Mass Index With Measures of Central Obesity in the Assessment of Mortality in Subjects With Coronary Disease : Role of “Normal Weight Central Obesity”

OBJECTIVES This study sought to assess the mortality risk of patients with coronary artery disease (CAD) based ona combination of body mass index (BMI) with measures of central obesity. BACKGROUND In CAD patients, mortality has been reported to vary inversely with BMI (“obesity paradox”). In contrast,central obesity is directly associated with mortality. Because of this bidirectionality, we hypothesized that CAD patients with normal BMI but central obesity would have worse survival compared to individuals with other combinations of BMI and central adiposity. METHODS We included 15,547 participants with CAD who were part of 5 studies from 3 continents. Multivariate stratifiedCox-proportional hazard models adjusted for potential confounders were used to assess mortality risk according to different patterns of adiposity that combined BMI with measures of central obesity. RESULTS Mean age was 66 years, 60% were men. There were 5,507 deaths over a median follow-up of 2.4 years (IQR: 0.5 to 7.4 years). Individuals with normal weight central obesity had the worst long-term survival: a person with BMI of 22 kg/m2 and waist circumference (WC) of 101 cm had higher mortality than a person with similar BMI but WC of 85 cm (HR: 1.10[95% CI: 1.05 to 1.17]), than a person with BMI of 26 kg/m2 and WC of 85 cm (HR: 1.20 [95% CI: 1.09 to 1.31]), than a person with BMI of 30 kg/m2 and WC of 85 cm (HR: 1.61 [95% CI: 1.39 to 1.86]) and than a person with BMI of 30kg/m2 and WC of 101 cm (HR: 1.27 [95% CI: 1.18 to 1.39), p < 0.0001 for all). CONCLUSIONS In patients with CAD, normal weight with central obesity is associated with the highest risk of mortality [corrected].

Sex differences in arterial stiffness and ventricular-arterial interactions.

OBJECTIVES This study sought to assess sex differences in ventricular-arterial interactions. BACKGROUND Heart failure with preserved ejection fraction is more prevalent in women than in men, but the basis for this difference remains unclear. METHODS Echocardiography and arterial tonometry were performed to quantify arterial and ventricular stiffening and interaction in 461 participants without heart failure (189 men, age 67 ± 9 years; 272 women, age 65 ± 10 years). Aortic characteristic impedance (Z(c)), total arterial compliance (pulsatile load), and systemic vascular resistance index (steady load) were compared between men and women, and sex-specific multivariable regression analyses were performed to assess associations of these arterial parameters with diastolic dysfunction and ventricular-arterial coupling (effective arterial elastance/left ventricular end-systolic elastance [Ea/Ees]) after adjustment for potential confounders. RESULTS Z(c) was higher and total arterial compliance was lower in women, whereas systemic vascular resistance index was similar between sexes. In women but not men, higher log Z(c) was associated with mitral inflow E/A ratio (β ± SE: -0.17 ± 0.07), diastolic dysfunction (odds ratio: 7.8; 95% confidence interval: 2.0 to 30.2) and Ea/Ees (β ± SE: 0.13 ± 0.04) (p ≤ 0.01 for all). Similarly, total arterial compliance was associated with E/A ratio (β ± SE: 0.12 ± 0.04), diastolic dysfunction (odds ratio: 0.33; 95% confidence interval: 0.12 to 0.89), and Ea/Ees (β ± SE: -0.09 ± 0.03) in women only (p ≤ 0.03 for all). Systemic vascular resistance index was not associated with diastolic dysfunction or Ea/Ees. CONCLUSIONS Proximal aortic stiffness (Z(c)) is greater in women than men, and women may be more susceptible to the deleterious effects of greater pulsatile and early arterial load on diastolic function and ventricular-arterial interaction. This may contribute to the greater risk of heart failure with preserved ejection fraction in women.

Normal-Weight Central Obesity: Implications for Total and Cardiovascular Mortality

Context It is uncertain whether measures of central obesity, such as waist-to-hip ratio (WHR), provide additional information beyond body mass index (BMI) in defining mortality risks associated with obesity. Contribution This population-based cohort study found that normal BMI and central obesity (defined by WHR) were associated with the worst long-term survival compared with individuals with normal fat distribution regardless of BMI category. Caution Information on body fat distribution was based on anthropometric indicators alone. Implication Normal weight with central obesity may represent an important group for targeted lifestyle modifications and other preventive strategies. Obesity defined by body mass index (BMI) or measures of central obesity, such as waist-to-hip ratio (WHR) and waist circumference, is associated with increased total and cardiovascular mortality (13). However, a recent meta-analysis (4) showed that being overweight according to BMI was actually associated with lower total mortality, challenging the paradigm that BMI is linked to increased mortality. Further, whether measures of fat distribution provide any incremental risk information beyond BMI alone has been a major source of controversy (2, 3, 58). Indeed, the 2013 American Heart Association/American College of Cardiology/The Obesity Society guideline for the management of obesity (9) does not recommend measuring WHR and assumes that persons with normal BMI are not exposed to any obesity-related cardiovascular risk in view of the limited available data proving otherwise. A recent large study (6) showed that incorporating waist circumference information in prediction models did not increase the prognostic value already provided by BMI; however, for a given BMI category, subgroups of waist circumference or WHR were also associated with increased mortality risk. Other studies showed that measures of central obesity, such as WHR, waist-to-height ratio (10, 11), or waist circumference alone, may provide additional information beyond BMI on mortality risk among middle-aged adults, provided there is no adjustment for obesity-related cardiovascular risk factors (2, 3, 7). Further, a study (12) has shown that measures of central obesity are more strongly associated with total and cardiovascular disease mortality rates than BMI. Another study (13) showed that persons with normal body weight measured by BMI, but who had increased body fat measured by bioimpedance, have higher total and cardiovascular mortality rates and a higher prevalence of metabolic syndrome and its components than those with normal BMI and body fat content. In addition, a recent meta-analysis of individual-patient data in those with coronary artery disease (12) has shown that persons with normal BMI who are in the top tertile of central obesity measures had the highest total mortality rate. These results have been attributed to several factors. First, the diagnostic accuracy of BMI for obesity is not optimal, especially in persons with greater body fat percentages and normal or intermediate BMI (14). Second, those with normal body weight and higher body fat have less muscle mass, which is a factor associated with higher mortality risk and metabolic dysregulation (15, 16). Third, animal and human studies (17) have recently shown that adipose tissue in the legs and buttocks may have a favorable effect on glucose metabolism. Finally, persons with a central distribution of fat, particularly when measured with WHR, have less adipose tissue in the lower extremities (17). To our knowledge, no studies in the general U.S. population have specifically focused on assessing the mortality risk in persons with normal BMI and central obesity compared with those who are overweight or obese according to BMI. Thus, we hypothesized that persons with normal BMI and central obesity would have greater mortality risk than those who have any other combination of BMI and central obesity. We investigated the total and cardiovascular mortality risks associated with different patterns of body adiposity in a large cohort of participants in NHANES III (Third National Health and Nutrition Examination Survey) (1988 to 1994). Because hip circumference was not measured in the most recent National Health and Nutrition Examination Surveys (conducted yearly from 1999 to 2010) and WHR data to define central obesity were crucial to our primary hypothesis, we have used data from NHANES III instead. Methods Study Design and Participants NHANES III is a cross-sectional survey that produces generalizable health estimates for the U.S. population using a stratified, multistage, probability sampling design. From a sample of 39695 persons, 33994 were interviewed and 30818 were examined at mobile examination centers. The examination consisted of extensive anthropometric, physiologic, and laboratory testing. Waist and hip circumferences were measured by a trained examiner with a measuring tape positioned at the high point of the iliac crest for the waist and at the greatest circumference of the buttocks. The design and methods for the survey are available elsewhere (18). In our study, 16124 adults aged 18 years or older had WHRs available. Because extremely thin persons and those with a history of nonskin cancer have a higher mortality risk, we further restricted our analysis to persons with a BMI greater than 18.5 kg/m2 and those without a history of nonskin cancer. The resulting sample was 15184 participants (7249 men and 7935 women). Total and Cardiovascular Mortality Assessment Identifier data were matched to the National Death Index to determine mortality status, with mortality follow-up from the date of the NHANES survey through 31 December 2006. A complete description of the methodology to link baseline NHANES III data to the National Death Index can be found elsewhere (19). International Classification of Diseases, Ninth Revision (ICD-9), codes from 1986 to 1998 and International Classification of Diseases, 10th Revision (ICD-10), codes from 1999 to 2000 were used to ascertain the underlying cause of death. Cardiovascular deaths were defined as those with ICD-9 codes 390 to 398, 402, and 404 to 429 and ICD-10 codes I00 to I09, I11, I13, and I20 to I51 (NHANES III codes 53 to 75). Statistical Analysis The overarching analytic goal was to estimate the influence of various magnitudes of central obesity and BMI on total mortality. To do this, we conducted weighted survival modeling that enabled the estimation of the relative risk for mortality, quantified by the hazard ratio (HR), and the expected survival for NHANES III participants. The NHANES III survey design and sampling weights were incorporated into the statistical analysis to calculate weighted means, SEs for continuous variables, and weighted percentages for categorical variables. To determine the total mortality associated with the different patterns of adiposity, we created multivariable Cox proportional hazards models and adjusted for potential confounders previously shown to be associated with obesity and mortality (4). These variables were age at examination, sex, education level, and smoking history. Although we considered adjusting for obesity-related cardiovascular risk factors in the models, we did not adjust our final estimates for these factors. Epidemiologic obesity research has shown that it might be inappropriate to control for factors in the causal pathway between obesity and death, such as diabetes, atherogenic dyslipidemia, and hypertension. In testing for differences in mortality risk for combinations of central obesity (defined by WHR) and BMI, we considered higher-order interactions of WHR with BMI and other covariates. The association pattern of WHR and BMI was found to be different for men versus women (that is, statistically significant higher-order interaction terms), so the final modeling was conducted using sex-stratified data to more clearly present the findings. The interaction terms allowed the potential quadratic risks (U-shaped risks) of values for these variables. The estimated model contains polynomial functions of BMI and WHR (for example, BMI2 and BMI2WHR2). These terms allow for relationships that are more sensitive to change in risk for mortality based on unique combinations (profiles) of WHR and BMI. The estimated risk function, when other covariates in the model are controlled for, will resemble a saddle with high- and low-risk areas. When possible, covariates were the grand mean centered to lessen the collinearity induced from quadratic effects. Likelihood ratio tests were used to determine whether these higher-order model terms could be removed. The proportional hazards assumption for all variables was assessed and satisfied for the final models. After these models were established, we estimated HRs with estimated model variables for different combinations of WHR and BMI stratified by sex. For these comparisons, we chose a BMI of 22 kg/m2 to represent persons with normal BMI, 27.5 kg/m2 to represent overweight persons, and 33 kg/m2 to represent obese persons. For WHR, we chose 0.89 and 1.00 for men and 0.80 and 0.92 for women as a measure of central obesity. Each of these sets of values were chosen either to reflect the approximate midpoint of standard clinical interpretationsto avoid issues with values at common thresholds (for example, BMI values at 30 kg/m2)or to be clinical targets we sought to better understand. Wald-based (or large sample-based) HR estimates and their SEs were assessed to provide significance tests among these representative patient profiles (20). Once the fitted Cox model was deemed satisfactory, we sought to estimate measures of absolute risk by means-adjusted 5- and 10-year survival estimates (21). In this analysis, we replicated observations to standardize (reweight) them and ensure balance across sex, age, WHR, and BMI categories. The expected survival was computed as a weighted estimate

Normal-weight central obesity

Context It is uncertain whether measures of central obesity, such as waist-to-hip ratio (WHR), provide additional information beyond body mass index (BMI) in defining mortality risks associated with obesity. Contribution This population-based cohort study found that normal BMI and central obesity (defined by WHR) were associated with the worst long-term survival compared with individuals with normal fat distribution regardless of BMI category. Caution Information on body fat distribution was based on anthropometric indicators alone. Implication Normal weight with central obesity may represent an important group for targeted lifestyle modifications and other preventive strategies. Obesity defined by body mass index (BMI) or measures of central obesity, such as waist-to-hip ratio (WHR) and waist circumference, is associated with increased total and cardiovascular mortality (13). However, a recent meta-analysis (4) showed that being overweight according to BMI was actually associated with lower total mortality, challenging the paradigm that BMI is linked to increased mortality. Further, whether measures of fat distribution provide any incremental risk information beyond BMI alone has been a major source of controversy (2, 3, 58). Indeed, the 2013 American Heart Association/American College of Cardiology/The Obesity Society guideline for the management of obesity (9) does not recommend measuring WHR and assumes that persons with normal BMI are not exposed to any obesity-related cardiovascular risk in view of the limited available data proving otherwise. A recent large study (6) showed that incorporating waist circumference information in prediction models did not increase the prognostic value already provided by BMI; however, for a given BMI category, subgroups of waist circumference or WHR were also associated with increased mortality risk. Other studies showed that measures of central obesity, such as WHR, waist-to-height ratio (10, 11), or waist circumference alone, may provide additional information beyond BMI on mortality risk among middle-aged adults, provided there is no adjustment for obesity-related cardiovascular risk factors (2, 3, 7). Further, a study (12) has shown that measures of central obesity are more strongly associated with total and cardiovascular disease mortality rates than BMI. Another study (13) showed that persons with normal body weight measured by BMI, but who had increased body fat measured by bioimpedance, have higher total and cardiovascular mortality rates and a higher prevalence of metabolic syndrome and its components than those with normal BMI and body fat content. In addition, a recent meta-analysis of individual-patient data in those with coronary artery disease (12) has shown that persons with normal BMI who are in the top tertile of central obesity measures had the highest total mortality rate. These results have been attributed to several factors. First, the diagnostic accuracy of BMI for obesity is not optimal, especially in persons with greater body fat percentages and normal or intermediate BMI (14). Second, those with normal body weight and higher body fat have less muscle mass, which is a factor associated with higher mortality risk and metabolic dysregulation (15, 16). Third, animal and human studies (17) have recently shown that adipose tissue in the legs and buttocks may have a favorable effect on glucose metabolism. Finally, persons with a central distribution of fat, particularly when measured with WHR, have less adipose tissue in the lower extremities (17). To our knowledge, no studies in the general U.S. population have specifically focused on assessing the mortality risk in persons with normal BMI and central obesity compared with those who are overweight or obese according to BMI. Thus, we hypothesized that persons with normal BMI and central obesity would have greater mortality risk than those who have any other combination of BMI and central obesity. We investigated the total and cardiovascular mortality risks associated with different patterns of body adiposity in a large cohort of participants in NHANES III (Third National Health and Nutrition Examination Survey) (1988 to 1994). Because hip circumference was not measured in the most recent National Health and Nutrition Examination Surveys (conducted yearly from 1999 to 2010) and WHR data to define central obesity were crucial to our primary hypothesis, we have used data from NHANES III instead. Methods Study Design and Participants NHANES III is a cross-sectional survey that produces generalizable health estimates for the U.S. population using a stratified, multistage, probability sampling design. From a sample of 39695 persons, 33994 were interviewed and 30818 were examined at mobile examination centers. The examination consisted of extensive anthropometric, physiologic, and laboratory testing. Waist and hip circumferences were measured by a trained examiner with a measuring tape positioned at the high point of the iliac crest for the waist and at the greatest circumference of the buttocks. The design and methods for the survey are available elsewhere (18). In our study, 16124 adults aged 18 years or older had WHRs available. Because extremely thin persons and those with a history of nonskin cancer have a higher mortality risk, we further restricted our analysis to persons with a BMI greater than 18.5 kg/m2 and those without a history of nonskin cancer. The resulting sample was 15184 participants (7249 men and 7935 women). Total and Cardiovascular Mortality Assessment Identifier data were matched to the National Death Index to determine mortality status, with mortality follow-up from the date of the NHANES survey through 31 December 2006. A complete description of the methodology to link baseline NHANES III data to the National Death Index can be found elsewhere (19). International Classification of Diseases, Ninth Revision (ICD-9), codes from 1986 to 1998 and International Classification of Diseases, 10th Revision (ICD-10), codes from 1999 to 2000 were used to ascertain the underlying cause of death. Cardiovascular deaths were defined as those with ICD-9 codes 390 to 398, 402, and 404 to 429 and ICD-10 codes I00 to I09, I11, I13, and I20 to I51 (NHANES III codes 53 to 75). Statistical Analysis The overarching analytic goal was to estimate the influence of various magnitudes of central obesity and BMI on total mortality. To do this, we conducted weighted survival modeling that enabled the estimation of the relative risk for mortality, quantified by the hazard ratio (HR), and the expected survival for NHANES III participants. The NHANES III survey design and sampling weights were incorporated into the statistical analysis to calculate weighted means, SEs for continuous variables, and weighted percentages for categorical variables. To determine the total mortality associated with the different patterns of adiposity, we created multivariable Cox proportional hazards models and adjusted for potential confounders previously shown to be associated with obesity and mortality (4). These variables were age at examination, sex, education level, and smoking history. Although we considered adjusting for obesity-related cardiovascular risk factors in the models, we did not adjust our final estimates for these factors. Epidemiologic obesity research has shown that it might be inappropriate to control for factors in the causal pathway between obesity and death, such as diabetes, atherogenic dyslipidemia, and hypertension. In testing for differences in mortality risk for combinations of central obesity (defined by WHR) and BMI, we considered higher-order interactions of WHR with BMI and other covariates. The association pattern of WHR and BMI was found to be different for men versus women (that is, statistically significant higher-order interaction terms), so the final modeling was conducted using sex-stratified data to more clearly present the findings. The interaction terms allowed the potential quadratic risks (U-shaped risks) of values for these variables. The estimated model contains polynomial functions of BMI and WHR (for example, BMI2 and BMI2WHR2). These terms allow for relationships that are more sensitive to change in risk for mortality based on unique combinations (profiles) of WHR and BMI. The estimated risk function, when other covariates in the model are controlled for, will resemble a saddle with high- and low-risk areas. When possible, covariates were the grand mean centered to lessen the collinearity induced from quadratic effects. Likelihood ratio tests were used to determine whether these higher-order model terms could be removed. The proportional hazards assumption for all variables was assessed and satisfied for the final models. After these models were established, we estimated HRs with estimated model variables for different combinations of WHR and BMI stratified by sex. For these comparisons, we chose a BMI of 22 kg/m2 to represent persons with normal BMI, 27.5 kg/m2 to represent overweight persons, and 33 kg/m2 to represent obese persons. For WHR, we chose 0.89 and 1.00 for men and 0.80 and 0.92 for women as a measure of central obesity. Each of these sets of values were chosen either to reflect the approximate midpoint of standard clinical interpretationsto avoid issues with values at common thresholds (for example, BMI values at 30 kg/m2)or to be clinical targets we sought to better understand. Wald-based (or large sample-based) HR estimates and their SEs were assessed to provide significance tests among these representative patient profiles (20). Once the fitted Cox model was deemed satisfactory, we sought to estimate measures of absolute risk by means-adjusted 5- and 10-year survival estimates (21). In this analysis, we replicated observations to standardize (reweight) them and ensure balance across sex, age, WHR, and BMI categories. The expected survival was computed as a weighted estimate

Combined effect of cardiorespiratory fitness and adiposity on mortality in patients with coronary artery disease

BACKGROUND High cardiorespiratory fitness and body mass index (BMI) are associated with decreased mortality in patients with coronary artery disease. Our objective was to determine the joint impact of fitness and adiposity measures on all-cause mortality in this subgroup. METHODS Coronary artery disease patients (n = 855) enrolled in the Mayo Clinic cardiac rehabilitation program from 1993 to 2007 were included. Fitness levels were determined by cardiopulmonary exercise testing. Patients were divided into low and high fitness by sex-specific median values of peak oxygen consumption and total treadmill time. Adiposity was measured through BMI and waist-to-hip ratio (WHR). RESULTS There were 159 deaths during 9.7 ± 3.6 years of mean follow-up. After adjusting for potential confounding factors, low fitness, shorter treadmill time, low BMI, and high WHR were significantly associated with increased mortality. Using low WHR-high fitness group as reference, significantly increased mortality was noted in low WHR-low fitness (hazard ratio 4.2, 95% CI, 1.8-9.8), centrally obese-high fitness (2.3, 1.0-5.4), and centrally obese-low fitness (6.1, 2.7-13.6) groups. Overweight-high fitness (2.2, 0.63-7.4), obese-high fitness (3.2, 0.88-11.4), and obese-low fitness (3.3, 0.96-11.4) subjects did not have a significantly different mortality as compared with the reference group of normal weight-high fitness subjects, whereas normal weight-low fitness (9.6, 2.9-31.8) and overweight-low fitness (6.8, 2.1-22.2) groups had significantly increased mortality. CONCLUSIONS Low fitness and central obesity were independently and cumulatively associated with increased mortality in coronary artery disease patients attending cardiac rehabilitation. The association of BMI with mortality is complex and altered by fitness levels.

Aortic Pulse Wave Velocity Is Associated With Measures of Subclinical Target Organ Damage

OBJECTIVES Our goal was to evaluate the associations of central arterial stiffness, measured by aortic pulse wave velocity (aPWV), with subclinical target organ damage in the coronary, peripheral arterial, cerebral, and renal arterial beds. BACKGROUND Arterial stiffness is associated with adverse cardiovascular outcomes. We hypothesized that aPWV is associated with subclinical measures of atherosclerosis-coronary artery calcification (CAC) and ankle-brachial index (ABI) and arteriolosclerosis-brain white matter hyperintensity (WMH) and urine albumin-creatinine ratio (UACR). METHODS Participants (n = 812; mean age 58 years; 58% women, 71% hypertensive) belonged to hypertensive sibships and had no history of myocardial infarction or stroke. aPWV was measured by applanation tonometry, CAC by electron beam computed tomography, ABI using a standard protocol, WMH volume by brain magnetic resonance, and UACR by standard methods. WMH was log-transformed, whereas CAC and UACR were log-transformed after adding 1 to reduce skewness. The associations of aPWV with CAC, ABI, WMH, and UACR were assessed by multivariable linear regression using generalized estimating equations to account for the presence of sibships. Covariates included in the models were age, sex, body mass index, history of smoking, hypertension and diabetes, total and high-density lipoprotein cholesterol, estimated glomerular filtration rate, use of aspirin and statins, and pulse pressure. RESULTS The mean ± SD aPWV was 9.8 ± 2.8 m/s. After adjustment for age, sex, conventional cardiovascular risk factors, and pulse pressure, higher aPWV (1 m/s increase) was significantly associated with higher log (CAC + 1) (β ± SE = 0.14 ± 0.04; p = 0.0003), lower ABI (β ± SE = -0.005 ± 0.002; p = 0.02), and greater log (WMH) (β ± SE = 0.03 ± 0.009; p = 0.002), but not with log (UACR + 1) (p = 0.66). CONCLUSIONS Higher aPWV was independently associated with greater burden of subclinical disease in coronary, lower extremity, and cerebral arterial beds, highlighting target organ damage as a potential mechanism underlying the association of arterial stiffness with adverse cardiovascular outcomes.

Vancomycin-Resistant Enterococcus faecalis Endocarditis: Linezolid Failure and Strain Characterization of Virulence Factors

ABSTRACT Infective endocarditis due to vancomycin-resistant (VR) Enterococcus faecalis has only rarely been reported. We report a case of VR E. faecalis endocarditis that failed to respond to linezolid therapy, outline the virulence traits of the isolate, and review previously published cases of VR E. faecalis endocarditis.

Arterial dysfunction and functional performance in patients with peripheral artery disease: a review.

Functional performance influences quality of life in individuals with peripheral artery disease (PAD) and is also a powerful prognostic marker in these patients. The pathophysiology of impaired functional performance in patients with PAD is incompletely understood. The severity of atherosclerotic burden, non-invasively assessed by the ankle—brachial index (ABI), does not reliably predict the degree of functional impairment observed in PAD patients. We review associations of measures of arterial function (arterial stiffness and endothelial dysfunction) with functional performance in PAD patients, and also review potential therapies for arterial stiffness and endothelial dysfunction that could improve functional performance in PAD. Recent studies suggest that measures of arterial function, such as arterial stiffness and endothelial function, are associated with exercise performance in the setting of PAD. These studies have provided new insights into (1) the pathophysiology of functional impairment in PAD, (2) mechanisms of strategies known to be effective such as walking programs, and (3) potential new therapeutic interventions for improving functional performance. Thus, therapies aimed at arterial ‘de-stiffening’ and improving endothelial function (such as aerobic exercise, statins and angiotensin-converting enzyme inhibitors) may improve functional performance in patients with PAD; however, further investigations are needed.

Arterial Stiffness and Its Clinical Implications in Women

The burden of cardiovascular disease (CVD) in women is increasing, and CVD presently kills more North American women than men, highlighting the need for sex-specific research aimed at disentangling the complex interactions between sex, aging, and cardiovascular health. In the past decade, arterial stiffness has emerged as an independent predictor of adverse cardiovascular events and mortality, and its noninvasive, safe evaluation makes it an attractive tool for a snapshot assessment of cardiovascular health. An increasing number of reports have documented greater aortic stiffness in older women than men, which appears to have close relationships with blood pressure control, diastolic dysfunction, impaired ventricular coupling, and left ventricular remodelling in women. Thus, arterial stiffness is thought to play a role in the female predominance of several diseases such as isolated systolic hypertension, refractory hypertension, heart failure with preserved ejection fraction, and paradoxical low-flow, low-gradient, normal ejection fraction severe aortic stenosis. Furthermore, greater arterial stiffness is a common characteristic of women who develop hypertensive complications of pregnancy. Thus, better understanding sex differences in arterial stiffness and aging might provide valuable insights into CVD in women, and help identify novel risk stratification tools and therapeutic targets. To this end, the present review aims at describing sex differences in arterial stiffness, exploring the potential role of sex hormones and menopause on arterial aging, and highlighting the role of arterial stiffness in specific CVDs that preferentially affect women.

Reduced Myocardial Flow in Heart Failure Patients With Preserved Ejection Fraction

Background—There remains limited insight into the pathophysiology and therapeutic advances directed at improving prognosis for patients with heart failure with preserved ejection fraction (HFpEF). Recent studies have suggested a role for coronary microvascular dysfunction in HFpEF. Rb-82 cardiac positron emission tomography imaging is a noninvasive, quantitative approach to measuring myocardial flow reserve (MFR), a surrogate marker for coronary vascular health. The aim of this study was to determine whether abnormalities exist in MFR in patients with HFpEF without epicardial coronary artery disease. Methods and Results—A total of 376 patients with ejection fraction ≥50%, no known history of obstructive coronary artery disease, and a confirmed diagnosis of heart failure (n=78) were compared with patients with no evidence of heart failure (n=298), further stratified into those with (n=186) and without (n=112) hypertension. Global and regional left ventricular MFR was calculated as stress/rest myocardial blood flow using Rb-82 positron emission tomography. Patients with HFpEF were more likely to be older, female, and have comorbid hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, anemia, and renal dysfunction. HFpEF was associated with a significant reduction in global MFR (2.16±0.69 in HFpEF versus 2.54±0.80 in hypertensive controls; P<0.02 and 2.89±0.70 in normotensive controls; P<0.001). A diagnosis of HFpEF was associated with 2.62 times greater unadjusted odds of having low global MFR (defined as <2.0) and remained a significant predictor of reduced global MFR after adjusting for comorbidities. Conclusions—HFpEF, in the absence of known history for obstructive epicardial coronary artery disease, is associated with reduced MFR independent of other risk factors.