Jennifer E. Liu

Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

Cardiac dysfunction resulting from exposure to cancer therapeutics was first recognized in the 1960s, with the widespread introduction of anthracyclines into the oncologic therapeutic armamentarium. Heart failure (HF) associated with anthracyclines was then recognized as an important side effect. As a result, physicians learned to limit their doses to avoid cardiac dysfunction. Several strategies have been used over the past decades to detect it. Two of them evolved over time to be very useful: endomyocardial biopsies and monitoring of left ven- tricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination of endomyocardial biopsies proved to be the most sensitive and spe- cific parameter for the identification of anthracycline-induced LV dysfunction and became the gold standard in the 1970s. However, the interest in endomyocardial biopsy has diminished over time because of the reduction in the cumulative dosages used to treat ma- lignancies, the invasive nature of the procedure, and the remarkable progress made in noninvasive cardiac imaging. The noninvasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially car- diotoxic cancer treatment.

Mitral Ratio of Peak Early to Late Diastolic Filling Velocity as a Predictor of Mortality in Middle-Aged and Elderly Adults: The Strong Heart Study

Background—With aging, left ventricular filling tends to decrease in early diastole, reducing the mitral ratio of peak early to late diastolic filling velocity (E/A). However, the prognostic significance of low or high E/A in older adults remains to be elucidated in population-based samples. Methods and Results—Doppler echocardiograms were analyzed in 3008 American Indian participants in the second Strong Heart Study examination who had no more than mild mitral or aortic regurgitation. Participants were followed for a mean of 3 years after Doppler echocardiography to assess risks of all-cause and cardiac death associated with E/A <0.6 or >1.5; 2429 (81%) participants had normal E/A ratio, 490 (16%) had E/A <0.6, and 89 (3%) had E/A >1.5. All-cause mortality was higher with E/A <0.6 or E/A >1.5 (12% and 13% versus 6%), as was cardiac mortality (4.5% and 6.5% versus 1.6%; both P <0.001). Adjusting for age, sex, body mass index, systolic blood pressure, HDL and LDL cholesterol, smoking, hypertension, diabetes, coronary heart disease, left ventricular hypertrophy, and low ejection fraction (<40%), the relative risk of all-cause death with E/A >1.5 was 1.73 (95% CI, 0.99 to 3.03;P =0.05); the relative risk of cardiac death was 2.8 (95% CI, 1.19 to 6.75;P <0.05). E/A <0.6 was not independently associated with increased all-cause or cardiac mortality (P =0.19 and 0.31, respectively) after adjusting for covariates. Conclusions—In a population-based sample of middle-aged and elderly adults, mitral E/A >1.5 at baseline Doppler echocardiography is associated with 2-fold increased all-cause and 3-fold increased cardiac mortality independent of covariates; mitral E/A <0.6 was also associated with 2-fold increased all-cause and cardiac mortality but not independent of covariates.

The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: the Strong Heart Study.

OBJECTIVES We sought to determine the effect of diabetes mellitus (DM) on left ventricular (LV) filling pattern in normotensive (NT) and hypertensive (HTN) individuals. BACKGROUND Diastolic abnormalities have been extensively described in HTN but are less well characterized in DM, which frequently coexists with HTN. METHODS We analyzed the transmitral inflow velocity profile at the mitral annulus in four groups from the Strong Heart Study: NT-non-DM (n = 730), HTN-non-DM (n = 394), NT-DM (n = 616) and HTN-DM (n = 671). The DM subjects were further divided into those with normal filling pattern (n = 107) and those with abnormal relaxation (AbnREL) (n = 447). RESULTS The peak E velocity was lowest in HTN-DM, intermediate in NT-DM and HT-non-DM and highest in the NT-non-DM group (p < 0.001), with a reverse trend seen for peak A velocity (p < 0.001). In multivariate analysis, E/A ratio was lowest in HTN-DM and highest in NT-non-DM, with no difference between NT-DM and HTN-non DM (p < 0.001). Likewise, mean atrial filling fraction and deceleration time were highest in HTN-DM, followed by HTN-non-DM or NT-DM and lowest in NT-non-DM (both p < 0.05). Among DM subjects, those with AbnREL had higher fasting glucose (p = 0.03) and hemoglobin A1C (p = 0.04). CONCLUSIONS Diabetes mellitus, especially with worse glycemic control, is independently associated with abnormal LV relaxation. The severity of abnormal LV relaxation is similar to the well-known impaired relaxation associated with HTN. The combination of DM and HTN has more severe abnormal LV relaxation than groups with either condition alone. In addition, AbnREL in DM is associated with worse glycemic control.

Effect of Type 2 Diabetes Mellitus on Left Ventricular Geometry and Systolic Function in Hypertensive Subjects Hypertension Genetic Epidemiology Network (HyperGEN) Study

Background—Type 2 diabetes is a cardiovascular risk factor. It remains to be elucidated in a large, population-based sample whether diabetes is associated with changes in left ventricular (LV) structure and systolic function independent of obesity and systolic blood pressure (BP). Methods and Results—Among 1950 hypertensive participants in the HyperGEN Study without overt coronary heart disease or significant valve disease, 20% (n=386) had diabetes. Diabetics were more likely to be women, black, older, and have higher BMI and waist/hip ratio than were nondiabetics. After adjustment for age and sex, diabetics had higher systolic BP, pulse pressure, and heart rate; lower diastolic BP; and longer duration of hypertension than nondiabetics. LV mass and relative wall thickness were higher in diabetic than nondiabetic subjects independent of covariates. Compared with nondiabetic hypertensives, diabetics had lower stress-corrected midwall shortening, independent of covariates, without difference in LV EF. Insulin levels and insulin resistance were higher in non–insulin-treated diabetics (n=195) than nondiabetic (n=1439) subjects (both P <0.01). Insulin resistance positively but weakly related to LV mass and relative wall thickness. Conclusions—In a relatively healthy, population-based sample of hypertensive adults, type 2 diabetes was associated with higher LV mass, more concentric LV geometry, and lower myocardial function, independent of age, sex, body size, and arterial BP.

Congestive Heart failure despite normal left ventricular systolic function in a population-based sample : The Strong Heart study

In selected clinical series, > or = 50% of adults with congestive heart failure (CHF) do not have left ventricular (LV) systolic dysfunction. Little is known of the prevalence of this phenomenon in population samples. Therefore, clinical examination and echocardiography were used in the second examination of the Strong Heart Study (3,184 men and women, 47 to 81 years old) to identify 95 participants with CHF, 50 of whom had normal LV ejection fraction (EF) (> 54%), 19 of whom had mildly reduced EF (40% to 54%), and 26 of whom had EF < or = 40%. Compared with those with no CHF, participants with CHF and no, mild, or severe decrease in EF had higher creatinine levels (2.34 to 2.85 vs 1.01 mg/dl, p < 0.001) and higher prevalences of diabetes (60% to 70% vs 50%) and hypertension (75% to 96% vs 46%, p < 0.05). Compared with those with no CHF, participants with CHF and normal EF had prolonged deceleration time (233 vs 204 ms, p < 0.05) and a reduced E/A, whereas those with CHF and EF < or = 40% had short deceleration time (158 ms, p < 0.05) and high E/A (1.70, p < 0.001); patients with CHF and normal EF had higher LV mass (98 vs 84 g/m2, p < 0.001) and relative wall thickness (0.37 vs 0.35, p < 0.05) than those without CHF. Patients with CHF with normal EF were, compared with those without CHF or with CHF and EF < or = 40%, disproportionately women (mean 84% vs 63% and 42%, p < 0.001), older (mean 64 vs 60 years and 63 years, respectively, p < 0.01), had higher body mass index (mean 33.1 vs 31.0 and 27.7 kg/m2, p < 0.05), and higher systolic blood pressure (mean 137 vs 130 and 128 mm Hg, both p < 0.05). Thus, in a population-based sample, patients with CHF and normal LV EF were older and overweight, more often women, had renal dysfunction, impaired early diastolic LV relaxation, and concentric LV geometry, whereas patients with CHF and severe LV dysfunction were more often men, had lower body mass index, a restrictive pattern of LV filling, and eccentric LV hypertrophy.

Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

### A. Definition, classification, and mechanisms of toxicity Cardiac dysfunction resulting from exposure to cancer therapeutics was first recognized in the 1960s, with the widespread introduction of anthracyclines into the oncological therapeutic armamentarium.1 Heart failure (HF) associated with anthracyclines was then recognized as an important side effect. As a result, physicians learned to limit their doses to avoid cardiac dysfunction.2 Several strategies have been used over the past decades to detect it. Two of them evolved over time to be very useful: endomyocardial biopsies and monitoring of left ventricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination of endomyocardial biopsies proved to be the most sensitive and specific parameter for the identification of anthracycline-induced LV dysfunction and became the gold standard in the 1970s. However, the interest in endomyocardial biopsy has diminished over time because of the reduction in the cumulative dosages used to treat malignancies, the invasive nature of the procedure, and the remarkable progress made in non-invasive cardiac imaging. The non-invasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially cardiotoxic cancer treatment.3–5 The timing of LV dysfunction can vary among agents. In the case of anthracyclines, the damage occurs immediately after the exposure;6 for others, the time frame between drug administration and detectable cardiac dysfunction appears to be more variable. Nevertheless, the heart has significant cardiac reserve, and the expression of damage in the form of alterations in systolic or diastolic parameters may not be overt until a substantial amount of cardiac reserve has been exhausted. Thus, cardiac damage may not become apparent until years or even decades after receiving the cardiotoxic treatment. This is particularly applicable to …

Differences in Left Ventricular Structure Between Black and White Hypertensive Adults The Hypertension Genetic Epidemiology Network Study

The degree to which ethnic differences in left ventricular structure among hypertensive adults are independent of clinical and hemodynamic factors remains uncertain. We assessed whether left ventricular mass and geometry differ between black and white hypertensives after accounting for differences in such factors. Our study group comprised 1060 black and 580 white hypertensive participants free of valvular or coronary disease in a population-based cohort. Blood pressure was measured during a clinic visit and echocardiography was performed using standardized protocols. After controlling for clinical and hemodynamic parameters (cardiac index, peripheral resistance index, and pulse pressure/ stroke index), both left ventricular mass and relative wall thickness were higher in blacks than whites (173.9±30.9 versus 168.3±24.3 grams, P =0.006, and 0.355±0.055 versus 0.340±0.055 grams, P <0.001). Similarly, the adjusted risk of having left ventricular hypertrophy, whether indexed by height2.7 or by body surface area, was greater for blacks than for whites (odds ratio: 1.80; 95% CI: 1.29 to 2.51; and odds ratio: 2.50; 95% CI: 1.58 to 3.96, respectively), and this was also true for concentric geometry (odds ratio: 2.28; 95% CI: 1.22 to 4.25). Further adjustment for relatedness in this genetic epidemiological study did not attenuate these differences. Our findings confirm the strong association between black ethnicity and increased left ventricular mass and relative wall thickness in hypertensive adults and demonstrate that these differences are independent of standard clinical and hemodynamic parameters. Whether such differences relate to distinct ambulatory pressure profiles or an ethnic propensity to cardiac hypertrophy requires further investigation.

Separate and joint effects of systemic hypertension and diabetes mellitus on left ventricular structure and function in American Indians (the Strong Heart Study).

Although the association of systemic hypertension (SH) with diabetes mellitus (DM) is well established, the cardiac features and hemodynamic profile of patients with SH and DM diagnosed by American Diabetes Association criteria have not been elucidated. To address this issue, echocardiograms were analyzed in 1,025 American Indian participants of the Strong Heart Study with neither DM nor SH, 642 with DM alone, 614 with SH alone, and 874 with SH and DM. In analyses that adjusted for age, gender, body mass index, and heart rate, DM and SH were associated with increased left ventricular (LV) wall thicknesses, with the greatest impact of DM on LV relative wall thickness and of the combination of DM and SH on LV mass (both p <0.001). LV fractional shortening was reduced with SH and SH + DM, midwall shortening was reduced with DM, SH, and their combination, and was reduced in both diabetic groups compared with their nondiabetic counterparts (p <0.001). DM alone was associated with lower measures of LV pump performance (stroke volume, cardiac output, and their indexes) than SH alone. Pulse pressure/stroke index, an indirect measure of arterial stiffness, was elevated in participants with DM or SH alone and most in those with both conditions. There were progressive increases from the reference group to DM alone, SH alone, and DM + SH with regard to prevalences of LV hypertrophy (12% to 19%, 29% and 38%) and subnormal LV myocardial function (7% to 10%, 11% and 18%, both p <0.001). In conclusion, DM and SH each have adverse effects on LV geometry and function, and the combination of SH and DM results in the greatest degree of LV hypertrophy, myocardial dysfunction, and arterial stiffness.

Prevalence and correlates of mitral regurgitation in a population-based sample (the Strong Heart Study) ∗

Evidence suggesting that mitral regurgitation (MR) may be induced by appetite suppressant medications heightens the importance of understanding the prevalence and correlates of MR, especially its relation to obesity, in population-based samples. MR was assessed by color Doppler echocardiography in 3,486 American Indian participants in the Strong Heart Study. Mild (1+) MR was present in 19.2%, moderate (2+) MR in 1.6%, moderately severe (3+) in 0.3%, and severe (4+) in 0.2% of participants. In univariate analyses, MR was unrelated to gender, diabetes, or lipid levels, but was more frequent in North/South Dakota (28.3%) than in Oklahoma (21.6%) or Arizona (14.3%) (p <0.001). MR was related to lower body mass index (BMI) (p <0.001), older age (p <0.001), higher systolic blood pressure (p = 0.003), higher serum creatinine (p <0.001), and higher urine albumin/creatinine ratio (p <0.001). In multivariate analyses, the presence and severity of MR were independently associated with higher serum creatinine, lower BMI, mitral stenosis, prior myocardial infarction, female gender, mitral valve prolapse and, variably, older age. In conclusion, MR, mostly mild, is detected by color Doppler echocardiography in >20% of middle-aged and older adults. MR is independently associated with female gender, lower BMI, older age, and renal dysfunction, as well as with prior myocardial infarction, mitral stenosis, and mitral valve prolapse. It is not related to dyslipidemia or diabetes.

Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes: the Strong Heart Study.

OBJECTIVES We sought to compare systolic and diastolic function in American Indians with diabetes mellitus (DM) based on albuminuria status. BACKGROUND Albuminuria has been shown to predict cardiovascular disease (CVD) in populations with DM. However, the mechanism of the association of albuminuria and CVD is unclear. METHODS We compared echo-derived indices of left ventricular (LV) systolic and diastolic function in three groups of American Indians with DM based on albuminuria status: I = no albuminuria (<30 mg albumin/g creatinine); II = microalbuminuria (30 to 300 mg/g); and III = macroalbuminuria (>300 mg/g). RESULTS Group II and III were slightly older than Group I with no significant gender difference between groups. Systolic blood pressure increased and body mass index decreased from Group I to Group III. Left ventricular systolic function was lower in the groups with albuminuria with step-wise decreases in ejection fraction and stress-corrected midwall shortening (MWS) from Group I to Group III. Similar findings were noted in diastolic LV filling with lower mitral E/A ratios and longer deceleration times in groups with albuminuria. The proportion of participants with abnormal MWS and abnormal LV diastolic relaxation showed step-wise increases from no albuminuria to macroalbuminuria. In multivariate analysis, albuminuria status remained independently associated with both systolic and diastolic dysfunction after adjusting for age, gender, body mass index, systolic blood pressure, duration of diabetes, coronary artery disease, and LV mass. CONCLUSIONS Albuminuria is independently associated with LV systolic and diastolic dysfunction in type 2 DM; this may explain in part the relationship of albuminuria to increased cardiovascular (CV) events in the DM population. Screening for albuminuria identifies individuals with high CV risk and possible cardiac dysfunction.