Elevated serum glucose from diabetes mellitus (DM) or impaired fasting glucose (IFG) shares many mechanisms with aging that decrease aortic distensibility (AD), such as glycation of the extra-cellular matrix. However, little data compares the simultaneous effects of elevated serum glucose and aging on AD. To study this, we examined the relationship between fasting glucose status, age, and AD in the Multi-Ethnic Study of Atherosclerosis (MESA): a multi-ethnic cohort of individuals aged 45-84 years without clinical cardiovascular disease. In MESA, participants with normal fasting glucose (NFG; n = 2270), IFG (n = 870), and DM (n = 412) underwent MRI assessment of proximal thoracic aortic distensibility. This sample was 46% male, 42% white, 30% AA, 11% Asian, and 17% Hispanic. The relationship between glucose status, age, and AD was analyzed with general linear models by adjusting for factors influential on AD. An interaction term was used to determine if age modified the effect of glucose status on AD. AD was lowest among those with DM. The interaction term was significant (p = 0.024). Comparing participants less than 65 years of age, AD was different between NFG and DM (p < 0.01), and between NFG and IFG (p = 0.02). In those older than 65, fasting glucose group was no longer a significant predictor of AD. Our data indicate that there are overall differences in AD between DM, IFG, and NFG. However, age modified the effect of glucose status such that differences between the groups diminished with advancing age.
aging; aorta; diabetes mellitus; glucose; magnetic resonance imaging
Background and Aims
Arterial stiffness is a prominent feature of vascular aging and a risk factor for cardiovascular disease (CVD). Fat around the heart and blood vessels (i.e. pericardial fat, Pfat) may contribute to arterial stiffness via a local paracrine effect of adipose tissue on the surrounding vasculature. Thus, we determined the association between Pfat and carotid stiffness in 5,770 participants (mean age 62 yrs, 53% female, 25% African American, 24% Hispanic, and 13% Chinese) from the Multi-Ethnic Study of Atherosclerosis.
Methods and Results
Pfat was measured by computed tomography, and ultrasonography of the common carotid artery was used to calculate the distensibility coefficient (DC) and young’s modulus (YM). Lower DC and higher YM values indicate stiffer arteries. Pfat quartile was highly associated with demographic, behavioral, anthropometric, hemodynamic, metabolic, and disease variables in both men and women. After adjusting for height, clinical site, CVD risk factors, and medications, a 1-standard deviation (41.91 cm3) increment in Pfat was associated with a 0.00007±0.00002 1/mmHg lower DC (p=0.0002) in men and a 48.1±15.1 mmHg/mm higher YM in women (p=0.002). Additional adjustment for C-reactive protein, coronary artery calcification, and carotid intima-media thickness had only modest effects. More importantly, adjusting for body mass index and waist circumference did not significantly change the overall results.
Higher Pfat is associated with higher carotid stiffness, independent of traditional CVD risk factors and obesity.
pericardial fat; arterial stiffness; distensibility; carotid artery
Serotonin and the serotonin transporter have been implicated in the development of pulmonary hypertension (PH). Selective serotonin reuptake inhibitors (SSRIs) may have a role in PH treatment, but the effects of SSRI use on right ventricular (RV) structure and function are unknown. We hypothesized that SSRI use would be associated with RV morphology in a large cohort without cardiovascular disease (N = 4114).
SSRI use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were assessed via cardiac magnetic resonance imaging. The cross-sectional relationship between SSRI use and each RV measure was assessed using multivariable linear regression; analyses for RV mass and end-diastolic volume (RVEDV) were stratified by sex.
After adjustment for multiple covariates including depression and left ventricular measures, SSRI use was associated with larger RV stroke volume (RVSV) (2.75 mL, 95% confidence interval [CI] 0.48–5.02 mL, p = 0.02). Among men only, SSRI use was associated with greater RV mass (1.08 g, 95% CI 0.19–1.97 g, p = 0.02) and larger RVEDV (7.71 mL, 95% 3.02–12.40 mL, p = 0.001). SSRI use may have been associated with larger RVEDV among women and larger RV end-systolic volume in both sexes.
SSRI use was associated with higher RVSV in cardiovascular disease-free individuals and, among men, greater RV mass and larger RVEDV. The effects of SSRI use in patients with (or at risk for) RV dysfunction and the role of sex in modifying this relationship warrant further study.
Pericardial fat has adverse effects on the surrounding vasculature. Previous studies suggest that pericardial fat may contribute to myocardial ischemia in symptomatic individuals. However, it is unknown if pericardial fat has similar effects in asymptomatic individuals.
We determined the association between pericardial fat and myocardial blood flow (MBF) in 214 adults with no prior history of cardiovascular disease from the Minnesota field center of the Multi-Ethnic Study of Atherosclerosis (43% female, 56% Caucasian, 44% Hispanic). Pericardial fat volume was measured by computed tomography. MBF was measured by MRI at rest and during adenosine-induced hyperemia. Myocardial perfusion reserve (PR) was calculated as the ratio of hyperemic to resting MBF.
Gender-stratified analyses revealed significant differences between men and women including less pericardial fat (71.9±31.3 vs. 105.2±57.5 cm3, p<0.0001) and higher resting MBF (1.12±0.23 vs. 0.93±0.19 ml/min/g, p<0.0001), hyperemic MBF (3.49±0.76 vs. 2.65±0.72 ml/min/g, p<0.0001), and PR (3.19±0.78 vs. 2.93±0.89, p = 0.03) in women. Correlations between pericardial fat and clinical and hemodynamic variables were stronger in women. In women only (p = 0.01 for gender interaction) higher pericardial fat was associated with higher resting MBF (p = 0.008). However, this association was attenuated after accounting for body mass index or rate-pressure product. There were no significant associations between pericardial fat and hyperemic MBF or PR after multivariate adjustment in either gender. In logistic regression analyses there was also no association between impaired coronary vasoreactivity, defined as having a PR <2.5, and pericardial fat in men (OR, 1.18; 95% CI, 0.82–1.70) or women (OR, 1.11; 95% CI, 0.68–1.82).
Our data fail to support an independent association between pericardial fat and myocardial perfusion in adults without symptomatic cardiovascular disease. Nevertheless, these findings highlight potentially important differences between asymptomatic and symptomatic individuals with respect to the underlying subclinical disease burden.
Biomarkers of inflammation and hemostasis have been associated with left ventricular (LV) mass. We studied relationships of C-reactive protein (CRP), interleukin-6 (IL6), D-dimer, soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor 1 (PAI-1), soluble thrombomodulin (sTM), soluble tumor necrosis factor type 1 receptor (sTNFR1), von Willebrand factor (vWF), soluble E-selectin (sE-selectin), factor VIII, fibrinogen, matrix metalloproteinase 3 (MMP3), and matrix metalloproteinase 9 (MMP9) with LV mass in an asymptomatic population. Multi-Ethnic Study of Atherosclerosis participants underwent magnetic resonance imaging to characterize LV mass; biomarkers were measured using standardized protocols (N = 763 to 4979). Adjusted models were used to associate each biomarker with LV mass while correcting for potential confounding.
LV mass was associated with many biomarkers after adjustment for demographic characteristics and traditional cardiovascular risk factors. Although the demographic and risk factor adjustments attenuated the association of CRP and IL6 with LV mass, further adjustment for weight changed regression coefficients from positive to negative for CRP and IL6 for LV mass. sTM, Factor VIII, and vWF were directly associated with LV mass in fully-adjusted models. For sTNFR1, sICAM-1, D-dimer, fibrinogen, and PAI-1, adjustment for risk factors and weight rendered associations with LV mass nonsignificant.
In this large cohort free of clinical cardiovascular disease, several hemostasis and inflammation markers were associated with LV mass. The unusual finding of a negative relationship of CRP and IL6 with LV mass only after adjustment for weight suggests that the effects of inflammation on LV mass are strongly influenced by obesity.
Left ventricle; biomarker; hemostasis; inflammation
To determine if cardiovascular magnetic resonance (CMR) measures of gadolinium (Gd) signal intensity (SI) within the left ventricular (LV) myocardium are associated with future changes in LV ejection fraction (LVEF) after receipt of doxorubicin (DOX).
Methods and Results
Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of: normal saline (NS) (n=7), 1.5 mg/kg DOX (n=19), or 2.5 mg/kg DOX (n=14). MR determinations of LVEF and myocardial Gd-SI were performed before and then at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were sacrificed at different time points so that histopathological assessments of the LV myocardium could be obtained. Within group analyses were performed to examine time-dependent relationships between Gd-SI and primary events (a deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg of DOX and 10/14 animals receiving 2.5 mg/kg of DOX experienced a primary event; no NS animals experienced a primary event. In animals with a primary event, histopathological evidence of myocellular vacuolization occurred (p=0.04), and the Gd-SI was elevated relative to baseline at the time of the event (p<0.0001) and during the measurement period prior to the event (p=0.0001). In all animals (including NS) without an event, measures of Gd-SI did not differ from baseline.
After DOX, low serial measures of Gd-SI predict an absence of a LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity.
cardiotoxicity; chemotherapy; congestive heart failure; doxorubicin
Background. The association between plasma omega-6 fatty acids and cardiovascular disease (CVD) is unclear, and discrepancy remains concerning the cardiovascular benefit of the omega-3 fatty acid alpha-linolenic acid. Methods. Associations of plasma phospholipid fatty acid levels (arachidonic acid, linoleic acid, eicosapentaenoic acid, docosahexaenoic acid (DHA), and alpha-linolenic acid) with cardiac magnetic resonance imaging measures of left ventricular (LV) mass, LV volume, ejection fraction, stroke volume, and aortic distensibility were investigated in 1,274 adults. Results. Results of multivariate analysis showed no statistically significant associations of plasma omega-6 or omega-3 levels with cardiac magnetic resonance imaging measures. Stratification by gender revealed a positive association between DHA and LV mass in women (β = 1.89, P = 0.02; P interaction = 0.003) and a trend for a positive association between DHA and ejection fraction in men (β = 0.009, P = 0.05; P interaction = 0.03). Conclusion. Additional research is warranted to clarify the effects of plasma DHA on cardiac structure and function in women versus men.
The impact of cardiovascular risk factors on the left ventricle is well known but their impact on right ventricle has not been studied using advanced imaging techniques. The purpose of this study was to determine the relation between cardiovascular risk factors and right ventricular (RV) structure and function and its interaction with the left ventricle. Cardiac magnetic resonance images were analyzed in 4204 participants free of clinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression models were used to study the cross sectional association between individual RV parameters and risk factors. All RV parameters except ejection fraction decreased with age (p<0.0001). RV mass was positively associated with systolic blood pressure (+0.4g, p<0.0001) and high density lipoprotein (HDL) cholesterol (+0.2g, p<0.0001); inversely with diastolic blood pressure (−0.3g, p<0.0001) and total cholesterol (−0.2g, p<0.01). RV end diastolic volume was positively associated with systolic blood pressure (+1.6ml, p<0.01) and HDL cholesterol (+1.8ml, p<0.0001); and inversely with diastolic blood pressure (−2.2 ml, p<0.0001), total cholesterol (−1.4ml, p<0.0001), current smoking (−2.7ml, p<0.05) and diabetes mellitus (−3.1ml, p<0.01). RV ejection fraction was positively related with systolic blood pressure (+1.0%, p<0.0001), HDL cholesterol (+0.4%, p<0.0001) and inversely with diastolic blood pressure (−0.7%, p<0.0001). In conclusion, the mass and volumes of the right ventricle decrease with age. Cardiovascular risk factors, especially blood pressure and HDL cholesterol are associated with subclinical changes in RV mass and volumes.
This study was performed to determine the utility of dobutamine stress test results for predicting myocardial infarction (MI) and cardiac death in patients with chest pain and left ventricular hypertrophy (LVH).
Methods and Results
Three hundred fifty-three (353) participants, aged 64±12 years (54% men) underwent dobutamine cardiovascular magnetic resonance (DCMR) stress testing and then were followed for 6±2 (range 0.5 to 11.5) years to assess the post-DCMR occurrence of MI or cardiac death. Left ventricular mass and the presence or absence of ischemia were determined; LVH was defined as > 96 g/m2 in men and > 77 g/m2 in women. LVH was present in 62 participants (18 % of the men and 17% of the women, p=0.90). Seventy-one (20%) participants experienced a MI or cardiac death during follow-up. The MI and cardiac death rate was more frequent in those with versus without LVH (32% vs. 17%, p=0.009). In multivariable analysis that accounted for the presence of pre-existing coronary artery disease, hypertension, diabetes, stress induced ischemia, and reduced LVEF, LVH was an independent predictor of MI and cardiac death (hazard ratio = 1.99, 95% confidence interval = 1.13-3.50; p=0.02).
Left ventricular hypertrophy is predictive of future MI and cardiac death in patients with or without inducible ischemia during dobutamine cardiac stress testing. As a result, LVH should be reported in those referred for dobutamine cardiac stress tests, particularly those without inducible ischemia, in whom otherwise one would assume a favorable cardiac prognosis.
hypertrophy; magnetic resonance imaging; myocardial infarction
Methods to index left ventricular (LV) mass, measured by cardiovascular magnetic resonance (CMR), for body size have not been investigated. The purposes of this study were to develop allometric indices for LV mass measured by CMR and compare estimates of the prevalence and predictive value of LV hypertrophy defined by a new allometric height-weight index, LV mass/body surface area (BSA), height indices (a new allometric height index; and previously derived indices from echocardiographic measurements: LV mass/height2, LV mass/height2.7), and non-indexed LV mass. 5,004 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with CMR measurements of LV mass and no clinical cardiovascular disease at baseline were followed for a median of 4.1 years. The new indices and limits for hypertrophy (95th percentile) were derived from 822 normal-weight, normotensive, non-diabetic MESA participants. 107 events (coronary heart disease or stroke) were observed. The estimated prevalence of hypertrophy at baseline and hazard ratio for event associated with hypertrophy were 8% and 2.4 with the new allometric height-weight index, 11% and 2.2 with LV mass/BSA, 23–24% and 2.0–2.1 with height indices, and 20% and 1.7 with non-indexed LV mass. A statistically significant difference was detected between the hazard ratios based on the new height-weight index and non-indexed LV mass. The prevalence of hypertrophy is higher for indices that do not account for weight. The predictive value of hypertrophy is significantly better with the new allometric height-weight index than with non-indexed LV mass and may be better than indices without weight.
Cardiovascular risk; Hypertension; Hypertrophy; LV mass index; Magnetic resonance imaging; Obesity
Cancer survivors exposed to anthracyclines experience an increased risk of cardiovascular (CV) events. We hypothesized that anthracycline use may increase aortic stiffness, a known predictor of CV events.
Patients and Methods
We performed a prospective, case-control study involving 53 patients: 40 individuals who received an anthracycline for the treatment of breast cancer, lymphoma, or leukemia (cases), and 13 age- and sex-matched controls. Each participant underwent phase-contrast cardiovascular magnetic resonance measures of pulse wave velocity (PWV) and aortic distensibility (AoD) in the thoracic aorta at baseline, and 4 months after initiation of chemotherapy. Four one-way analyses of covariance models were fit in which factors known to influence thoracic aortic stiffness were included as covariates in the models.
At the 4-month follow-up visit, aortic stiffness remained similar to baseline in the control participants. However, in the participants receiving anthracyclines, aortic stiffness increased markedly (relative to baseline), as evidenced by a decrease in AoD (P < .0001) and an increase in PWV (P < .0001). These changes in aortic stiffness persisted after accounting for age, sex, cardiac output, administered cardioactive medications, and underlying clinical conditions known to influence aortic stiffness, such as hypertension or diabetes (P < .0001).
A significant increase in aortic stiffness occurs within 4 months of exposure to an anthracycline which was not seen in an untreated control group. These results indicate that previously regarded cardiotoxic cancer therapy adversely increases thoracic aortic stiffness, a known independent predictor of adverse cardiovascular events.
To determine the effect of statins and hormone replacement therapy on submaximal exercise induced coronary artery blood flow in postmenopausal women without a history of coronary artery disease.
Hormone replacement or statin therapy in early postmenopausal women without coronary artery disease have been shown to enhance arterial endothelial function; we hypothesized that these agents would improve submaximal exercise induced coronary artery blood flow.
Sixty-four postmenopausal women, aged 50–65 years without documented coronary artery disease, were randomized in a double blinded, cross-over fashion to receive 8 weeks of hormone replacement therapy versus placebo, with or without 80 mg/day of atorvastatin. Prior to receipt of any therapy and after each treatment period, each woman underwent measures of coronary artery blood flow at rest and stress.
The combination of hormone replacement therapy and atorvastatin increased submaximal exercise induced coronary artery blood flow (p=0.04). In the subgroups of women compliant with treatment, resting coronary artery blood flow increased in those receiving hormone replacement therapy (p=0.03) or statin therapy (p=0.02).
In postmenopausal women aged 50–65 years without documented coronary artery disease, rest and submaximal exercise induced coronary artery blood flow improve after receipt of high dose atorvastatin and conjugated estrogen therapy.
estrogen; statins; exercise; magnetic resonance imaging; coronary artery flow
Over the past 20 years, investigators world-wide have developed and utilized dobutamine magnetic resonance stress testing procedures for the purpose of identifying ischemia, viability, and cardiac prognosis. This article traces these developments and reviews the data utilized to substantiate this relatively new noninvasive imaging procedure.
There are a number of imaging tests that are used in the setting of acute myocardial infarction and acute coronary syndrome. Each has their strengths and limitations. Experts from the European Society of Cardiac Radiology and the North American Society for Cardiovascular Imaging together with other prominent imagers reviewed the literature. It is clear that there is a definite role for imaging in these patients. While comparative accuracy, convenience and cost have largely guided test decisions in the past, the introduction of newer tests is being held to a higher standard which compares patient outcomes. Multicenter randomized comparative effectiveness trials with outcome measures are required.
Acute myocardial infarction; Acute coronary syndrome; Cardiac imaging
Exercise intolerance is the primary symptom in older patients with heart failure and preserved ejection fraction (HFPEF); however, little is known regarding its mechanisms and therapy.
Methods and Results
Seventy-one stable elderly (70±1 years) patients (80% women) with compensated HFPEF and controlled blood pressure were randomized into a 12-month follow-up double-blind trial of enalapril 20 mg/d versus placebo. Assessments were peak exercise oxygen consumption; 6-minute walk test; Minnesota Living with HF Questionnaire; MRI; Doppler echocardiography; and vascular ultrasound. Compliance by pill count was excellent (94%). Twenty-five patients in the enalapril group versus 34 in the placebo group completed the 12-month follow-up. During follow-up, there was no difference in the primary outcome of peak exercise oxygen consumption (enalapril, 14.5±3.2 mL/kg/min; placebo, 14.3±3.4 mL/kg/min; P=0.99), or in 6-minute walk distance, aortic distensibility (the primary mechanistic outcome), left ventricle mass, or neurohormonal profile. The effect size of enalapril on peak exercise oxygen consumption was small (0.7%; 95% CI, 4.2% to 5.6%). There was a trend toward improved Minnesota Living with HF Questionnaire total score (P=0.07), a modest reduction in systolic blood pressure at peak exercise (P=0.02), and a marginal improvement in carotid arterial distensibility (P=0.04).
In stable, older patients with compensated HFPEF and controlled blood pressure, 12 months of enalapril did not improve exercise capacity or aortic distensibility. These data, combined with those from large clinical event trials, suggest that angiotensin inhibition does not substantially improve key long-term clinical outcomes in this group of patients. This finding contrasts sharply with observations in HF with reduced EF and highlights our incomplete understanding of this important and common disorder.
aging; exercise; heart failure; diastole; vasculature
To determine the prognostic utility of dobutamine cardiovascular magnetic resonance (DCMR) stress test results in women.
To date, the preponderance of studies reporting the utility of DCMR stress results for predicting cardiac prognosis have been performed in men. We sought to determine the utility of DCMR results for predicting cardiac prognosis in women.
Two hundred sixty-six consecutively referred women underwent DCMR in which left ventricular wall motion (LVWM) was assessed at rest and after intravenous dobutamine and atropine. Inducible LVWM abnormalities were identified during testing. Women were contacted to determine the post DCMR occurrence of a cardiac event. All events were substantiated according to defined criteria, and then verified after a thorough medical record review by individuals blinded to testing data.
Women were contacted an average of 6.2 ± 1.6 (median 6.2, range 0.8 to 10.4) years after DCMR; 27% of the women experienced an inducible LVWM abnormality during testing. In those with and without inducible LVWM abnormalities, the proportion of women with cardiac events were 63% versus 30%, respectively, (hazard ratio [HR] of 2.7 [CI 1.8 – 4.3] for the presence of inducible LVWM abnormalities p<0.0001). The proportion of women with myocardial infarction (MI) and cardiac death were 33.3% and 7.5%, respectively. This resulted in a HR for MI and cardiac death of 4.1 [CI 2.2 – 9.4] for those with versus without inducible LVWM abnormalities; p<0.0001. A subgroup analysis was performed in women without a history of coronary artery disease and in those with LVWM abnormalities, DCMR remained an adverse predictor of cardiac events (HR 4.0, CI 1.8 – 9.0, p=0.003).
Inducible LVWM abnormalities during DCMR predict cardiac death and MI in women. Similar to men, these results indicate DCMR is a valuable noninvasive stress imaging modality for identifying cardiac risk in women with known or suspected ischemic heart disease.
Women; Prognosis; Magnetic Resonance
To determine myocardial infarct (MI) size during cardiovascular magnetic resonance (CMR) at 1.5 Tesla using 0.1 mmol/kg bodyweight of gadobenate dimeglumine (Gd-BOPTA) and 0.2 mmol/kg bodyweight of gadopentetate dimeglumine (Gd-DTPA).
Twenty participants (16 men, 4 women), aged 58 ± 12 years, with a prior chronic MI were imaged in a cross-over design. Participants received 0.2 mmol/kg bodyweight of Gd-DTPA, and 0.1 mmol/kg bodyweight of Gd-BOPTA on 2 occasions separated by 3 to 7 days
The correlations were high between Gd-DTPA and Gd-BOPTA measures of infarct volume (r=0.93) and the percentage of infarct relative to LV myocardial volume (r=0.85). The size and location of the infarcts were similar (p=0.9) for the 2 contrast agents. Interobserver correlation of infarct volume (r=0.91) was high.
In chronic myocardial infarction, late gadolinium enhancement identified with a single 0.1 mmol/kg bodyweight dose of Gd-BOPTA is associated in volume and location to a double (0.2 mmol/kg body weight) dose of Gd-DTPA. Lower doses of higher relaxivity contrast agents should be considered for determining LV myocardial infarct size.
myocardial infarction; contrast; ischemic heart disease