Marcello Chinali

Left ventricular mass predicts heart failure not related to previous myocardial infarction: the Cardiovascular Health Study

AIMS The relationship of left ventricular hypertrophy (LVH) to incident heart failure (HF) not attributable to myocardial infarction (MI) has not been defined. We assessed whether LVH is an independent predictor of MI-independent HF. METHODS AND RESULTS LVH was assessed by echocardiographic LV mass index (in g/m2.7) and excess of LV mass (eLVM, in % of the observed value) relative to the amount predicted by sex, stroke work, and height, using a prognostically validated equation in 2078 participants of Cardiovascular Health Study without prevalent MI and normal systolic function. Increasing eLVM was associated with progressively increasing left atrial dimension and concentric geometry, decreasing systolic (P < 0.0001), and diastolic function (P < 0.04). After adjustment for age, sex, obesity, diabetes, hypertension, and antihypertensive therapy, and accounting for by incident MI, hazard of HF increased by 1% for each 1% increase in eLVM and by 3% for each g/m2.7 increase in LV mass index (both P < 0.0001). The results were confirmed when also C-reactive protein and measures of systolic (endocardial shortening) and diastolic function (categories of E/A ratio) were added to the Cox models. CONCLUSION In an elderly population, LVH, measured as LV mass index or eLVM is an independent predictor of incident HF not related to prevalent or incident MI.

Evaluation of Concentric Left Ventricular Geometry in Humans: Evidence for Age-Related Systematic Underestimation

There might be limitations in identifying concentric left ventricular (LV) geometry by ratio of diastolic posterior wall thickness (WTp) to cavity radius, defined as relative wall thickness (RWTp). This study has been designed to evaluate age effects on RWTp. WTp, mean of septal thickness and WTp (WTm), and cavity radius were cross-sectionally evaluated in 766 1- to 85-year-old, normotensive, nonobese subjects and 331 hypertensive Italians (used as a test series). RWTp ≥0.43 defined “traditional” concentric LV geometry. The ratios WTm/radius (RWTm) and RWTp increased by 0.005 and 0.006 per year of age in the age stratum up to 17 years and by 0.002 in the older age stratum (18 years or older; all P<0.0001). Thus, RWTm and RWTp were normalized to average age in both age strata (10 and 46 years) by age-specific regression coefficients. The 90th and 95th percentiles of age-normalized RWTp or RWTm were 0.40 and 0.42 or 0.41 and 0.43, respectively, in adults and 0.36 and 0.39 or 0.36 and 0.38, respectively in young subjects. In hypertensive subjects, traditional RWTp cutoff identified 74 subjects (22%) with concentric LV geometry; by 95th or 90th normal percentiles, normalized RWTm identified 112 (34%), or 149 (45%) subjects with concentric LV geometry, and normalized RWTp 29% and 39%, respectively (all P<0.0001 versus unadjusted RWTp). Thus, prevalence of concentric LV geometry increases with age-normalized RWT. Accordingly, we suggest that concentric LV hypertrophy be defined by coexistence of high LV mass with age-normalized RWTm >0.41 or RWTp >0.40. Further studies are required to establish prognostic implications of our findings.

Risk Factors for Arterial Hypertension in Adults With Initial Optimal Blood Pressure: The Strong Heart Study

Whether metabolic factors and their change over time influence development of arterial hypertension in adults with initially optimal blood pressure (BP) is unknown. We analyzed associations of BP in the optimal range (<120/80 mm Hg), metabolic risk factors, and their changes over 4-year follow-up, with 8-year incident hypertension, in a cohort of American Indians with a high prevalence of obesity. At baseline, 967 participants with optimal BP and no prevalent cardiovascular disease (69.5% women; mean age, 54±7 years) were evaluated and reexamined after 4 (second examination) and 8 years to evaluate predictors of 8-year incident arterial hypertension. In participants with normal glucose tolerance, baseline BP and decrease in high-density lipoprotein cholesterol from baseline to the second examination were the most potent predictors of 8-year arterial hypertension (both P<0.0001), with additional effects of baseline waist circumference and its increase, increase in BP, and presence of diabetes at the second examination (all P<0.04). In participants with impaired glucose tolerance or diabetes, the most potent predictor of 8-year incident hypertension was diabetes at the second examination (P<0.0001) followed by a increase in BP and LDL cholesterol over the first 4 years (both P<0.001). Thus, incident arterial hypertension can be predicted by initial metabolic profile and unfavorable metabolic variations over time, in addition to initial BP. At optimal levels of initial BP, increasing abdominal obesity, and abnormal lipid profile are major predictors of development of arterial hypertension. Possible implications of these findings for primary cardiovascular prevention should be tested in prospective studies.

Prognostic Impact of Metabolic Syndrome by Different Definitions in a Population With High Prevalence of Obesity and Diabetes: The Strong Heart Study

OBJECTIVE— This study analyzed which definition of the metabolic syndrome is more predictive of cardiovascular events in both diabetic and nondiabetic members of a population-based sample. RESEARCH DESIGN AND METHODS— A 10-year, longitudinal follow-up of the Strong Heart Study cohort has been evaluated. The analysis included 3,945 participants (2,384 female) with complete data (1,700 with diabetes and 1,468 with arterial hypertension) for evaluation of metabolic syndrome. Those with prevalent cardiovascular disease were excluded (n = 287, of whom 127 were female). Prevalence of metabolic syndrome was assessed based on the World Health Organization (WHO), the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III, and International Diabetes Federation (IDF) definitions. The main outcome was 10-year incidence of combined fatal and nonfatal cardiovascular events, including stroke, coronary heart disease, and congestive heart failure. RESULTS— Fatal and nonfatal cardiovascular events occurred in 1,120 participants. After adjusting for age, sex, and diabetes, metabolic syndrome by all definitions was significantly associated with higher incidence of cardiovascular events (all P < 0.0001). In nondiabetic individuals, incident cardiovascular event rates were about 30–40% higher in those with metabolic syndrome, without a significant difference among definitions (0.03 < P < 0.001), and remained significant in WHO and NCEP ATP III definitions even after further adjustment for obesity, hypertension, and low HDL cholesterol. In the diabetic group, metabolic syndrome risk for cardiovascular events was greatest using the WHO definition (P < 0.002 vs. other models). CONCLUSIONS— In individuals without diabetes, metabolic syndrome is associated with incident cardiovascular disease, especially with WHO and NCEP ATP III definitions. Metabolic syndrome also predicts higher cardiovascular event rates in diabetic participants, a prediction that is greatest using the WHO definition.

Cardiac mechanics in mild hypertensive heart disease: a speckle-strain imaging study.

Background—We hypothesized that abnormalities in regional systolic strain (ϵ) might be present among hypertensive subjects with normal ejection fraction, and, if present, could be used to identify patients at high risk for heart failure. The aim of the current case-control study was to use speckle tracking imaging to identify subclinical global and regional systolic function abnormalities in hypertensive subjects with normal ejection fraction. Methods and Results—Standard 2D Doppler echocardiography, tissue Doppler imaging, and 2D speckle strain imaging were performed in 52 hypertensive subjects with normal ejection fraction and 52 control subjects of similar age. Peak systolic (S′), and diastolic (E′) annular velocities were obtained by tissue Doppler imaging, whereas longitudinal myocardial systolic velocity (Vl) and circumferential, longitudinal, and radial strains (ϵc, ϵl, ϵr) were obtained by speckle tracking. Midwall shortening and peak basal longitudinal strain (ϵl) were used as indices of regional function. Hypertensive subjects had lower velocities—tissue Doppler imaging E′ and S′, and Vl—and evidence of reduced regional function. Surprisingly, however, global ϵ values did not differentiate hypertensive subjects from control subjects. Among hypertensive patients, significant inverse associations were found between left ventricular mass and global longitudinal and circumferential ϵ (both P<0.05). Conclusions—Hypertensive heart disease with normal ejection fraction is associated with reduced myocardial velocities and reduced regional function but normal global ϵ. Our data suggest that velocity abnormalities occur early in hypertension and may be an appropriate target for preventive strategies because they occur before abnormalities in global ϵ.Background— We hypothesized that abnormalities in regional systolic strain (e) might be present among hypertensive subjects with normal ejection fraction, and, if present, could be used to identify patients at high risk for heart failure. The aim of the current case-control study was to use speckle tracking imaging to identify subclinical global and regional systolic function abnormalities in hypertensive subjects with normal ejection fraction. Methods and Results— Standard 2D Doppler echocardiography, tissue Doppler imaging, and 2D speckle strain imaging were performed in 52 hypertensive subjects with normal ejection fraction and 52 control subjects of similar age. Peak systolic (S′), and diastolic (E′) annular velocities were obtained by tissue Doppler imaging, whereas longitudinal myocardial systolic velocity (Vl) and circumferential, longitudinal, and radial strains (ec, el, er) were obtained by speckle tracking. Midwall shortening and peak basal longitudinal strain (el) were used as indices of regional function. Hypertensive subjects had lower velocities—tissue Doppler imaging E′ and S′, and Vl—and evidence of reduced regional function. Surprisingly, however, global e values did not differentiate hypertensive subjects from control subjects. Among hypertensive patients, significant inverse associations were found between left ventricular mass and global longitudinal and circumferential e (both P <0.05). Conclusions— Hypertensive heart disease with normal ejection fraction is associated with reduced myocardial velocities and reduced regional function but normal global e. Our data suggest that velocity abnormalities occur early in hypertension and may be an appropriate target for preventive strategies because they occur before abnormalities in global e. Received September 26, 2008; accepted July 21, 2009. # CLINICAL PERSPECTIVE {#article-title-2}

Cardiovascular and Metabolic Predictors of Progression of Prehypertension Into Hypertension The Strong Heart Study

Prehypertension (defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) frequently evolves to hypertension (HTN) and increases cardiovascular risk. It is unclear whether metabolic and/or cardiac characteristics favor development of HTN in prehypertensive subjects. We evaluated baseline anthropometric, laboratory, and echocardiographic characteristics of 625 untreated prehypertensive participants in the Strong Heart Study, without prevalent cardiovascular disease (63% women; 22% with diabetes mellitus; mean age: 59±7 years) to identify predictors of the 4-year incidence of HTN. Diabetes mellitus was assessed by American Diabetic Association criteria, and a diabetes-specific definition of HTN was used. Four-year incidence of HTN was 38%. Incident HTN was independently predicted by baseline systolic blood pressure (odds ratio [OR]: 1.60 per 10 mm Hg; 95% CI: 1.30 to 2.00; P<0.0001), waist circumference (OR: 1.10 per 10 cm; 95% CI: 1.01 to 1.30; P =0.04), and diabetes mellitus (OR: 2.73; 95% CI=1.77 to 4.21; P<0.0001), with no significant effect for age, sex, hemoglobin A1c, homeostatic model assessment index, C-reactive protein, fibrinogen, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides, plasma creatinine, or urine albumin:creatinine ratio. Higher left ventricular mass index (OR: 1.15 per 5 g/m2.7; 95% CI: 1.01 to 1.25; P =0.03) or stroke volume index (OR: 1.25 per 5 mL/m2.04; 95% CI: 1.10 to 1.50; P =0.03) was also identified, together with baseline systolic blood pressure and the presence of diabetes mellitus, as an independent predictor of incident HTN, without an additional predictive contribution from other anthropometric, metabolic, or echocardiographic parameters (all P>0.10). Thus, progression to HTN in 38% of Strong Heart Study prehypertensive participants could be predicted by higher left ventricular mass and stroke volume in addition to baseline systolic blood pressure and prevalent diabetes mellitus.

Diabetes and incident heart failure in hypertensive and normotensive participants of the Strong Heart Study

Objectives Type 2 diabetes is accepted as a cause of heart failure, but direct cause–effect evidence independent of incident myocardial infarction (MI), hypertension and other coexisting risk factors is less well studied. We tested the hypothesis that diabetes predisposes to heart failure independently of hypertension and intercurrent MI. Methods We evaluated 12-year incident heart failure in 2740 participants (1781 women) without prevalent cardiovascular or severe kidney disease, at the time of the first exam of the Strong Heart Study cohort. Intercurrent MI was censored as a competing risk event. Results Diabetes was present in 1206 individuals (44%), and impaired fasting glucose (IFG) in 391 (14%). Diabetic participants more frequently had hypertension and/or central obesity (both P < 0.0001). Incident heart failure was ascertained in 64 participants with normal fasting glucose (NFG; 6%), 26 (7%) with IFG and 201 with diabetes (17%, hazard ratio = 4.04 vs. NFG, P < 0.0001). In Cox analysis adjusting for age, sex, obesity, central fat distribution, hypertension, antihypertensive medications, prevalent atrial fibrillation, glomerular filtration rate, urinary albumin/creatinine ratio, plasma cholesterol, Hb1Ac, smoking habit, alcohol use, educational level and physical activity, diabetes was associated with a two-fold greater risk of incident heart failure than NFG (hazard ratio = 2.45, P < 0.0001). Diabetes maintained 1.5-fold greater risk of heart failure than NFG (P < 0.03) even when intercurrent MI (n = 221) was censored as a competing risk event, similar to the adjusted hazard ratio for heart failure in hypertension. Conclusion Type 2 diabetes is a potent, independent risk factor for heart failure. Risk of heart failure in diabetic patients cannot be fully explained by incident MI and coexisting cardiovascular risk factors. Mechanisms directly related to diabetes and impairing cardiac function should be studied and identified.

Cardiac Markers of Pre-Clinical Disease in Adolescents With the Metabolic Syndrome: The Strong Heart Study

OBJECTIVES Our aim was to evaluate the impact of metabolic syndrome (MetS) on cardiac phenotype in adolescents. BACKGROUND A high prevalence of MetS has been reported in adolescents. METHODS Four hundred forty-six nondiabetic American Indian adolescents (age 14 to 20 years, 238 girls) underwent clinical evaluation, laboratory testing, and Doppler echocardiography. Age- and gender-specific partition values were used to define obesity and hypertension. Metabolic syndrome was defined according to Adult Treatment Panel III criteria, modified for adolescents. Left ventricular (LV) hypertrophy and left atrial (LA) dilation were identified using age- and gender-specific partition values. RESULTS One hundred eleven participants met criteria for MetS. They had a similar age and gender distribution as non-MetS participants. Analysis of covariance, controlling for relevant confounders, demonstrated that participants with MetS had higher LV, LA, and aortic root diameters, higher LV relative wall thickness, and greater LV mass index. Accordingly, MetS participants showed higher prevalences of LV hypertrophy (43.2% vs. 11.7%) and LA dilation (63.1% vs. 21.9%, both p < 0.001) compared with non-MetS participants. In addition, MetS was associated with a reduction in midwall shortening, lower transmitral mitral early to atrial peak velocity ratio, and mildly prolonged mitral early deceleration time (all p < 0.05). In multiple regression analysis, independently of demographics, obesity, blood pressure, and single metabolic components of MetS, clustered MetS was associated with a 2.6-fold higher likelihood of LV hypertrophy and a 2.3-fold higher likelihood of LA dilation (both p < or = 0.02). CONCLUSIONS In a population sample of adolescents, MetS is associated with higher prevalences of LV hypertrophy and LA dilation and with reduced LV systolic and diastolic function, independently of individual MetS components.

Left atrial volume and geometry in healthy aging: the Cardiovascular Health Study.

Background—The left atrium is a validated marker of clinical and subclinical cardiovascular disease. Left atrial enlargement is often seen among older individuals; however, there are few population-based data regarding normal left atrial size among older persons, especially from those who are healthy, and from women. Furthermore, because the left atrium is a 3D structure, the commonly used parasternal long-axis diastolic diameter often underdiagnoses left atrial enlargement. Methods and Results—We evaluated left atrial size in 230 healthy participants (mean age, 76±5 years) free of prevalent cardiac disease, rhythm abnormality, hypertension, and diabetes selected from the Cardiovascular Health Study, a prospective community-based study of risk factors for cardiovascular disease in 5888 elderly participants. In addition to the standard long-axis measurement, we obtained left atrial superoinferior and lateral diameters and used these dimensions to estimate left atrial volume. These measurements were used to generate reference ranges for determining left atrial enlargement in older men and women, based on the 95% percentiles of the left atrial dimensions in healthy participants, both unadjusted, and after adjustment for age, height, and weight. In healthy elderly subjects, indices of left atrial size do not correlate with age or height but with weight and other measures of body build. Conclusions—These data provide normative reference values for left atrial size in healthy older women and men. The results should be useful for refining diagnostic criteria for left atrial dilation in the older population and may be relevant for cardiovascular risk stratification.Background— The left atrium is a validated marker of clinical and subclinical cardiovascular disease. Left atrial enlargement is often seen among older individuals; however, there are few population-based data regarding normal left atrial size among older persons, especially from those who are healthy, and from women. Furthermore, because the left atrium is a 3D structure, the commonly used parasternal long-axis diastolic diameter often underdiagnoses left atrial enlargement. Methods and Results— We evaluated left atrial size in 230 healthy participants (mean age, 76±5 years) free of prevalent cardiac disease, rhythm abnormality, hypertension, and diabetes selected from the Cardiovascular Health Study, a prospective community-based study of risk factors for cardiovascular disease in 5888 elderly participants. In addition to the standard long-axis measurement, we obtained left atrial superoinferior and lateral diameters and used these dimensions to estimate left atrial volume. These measurements were used to generate reference ranges for determining left atrial enlargement in older men and women, based on the 95% percentiles of the left atrial dimensions in healthy participants, both unadjusted, and after adjustment for age, height, and weight. In healthy elderly subjects, indices of left atrial size do not correlate with age or height but with weight and other measures of body build. Conclusions— These data provide normative reference values for left atrial size in healthy older women and men. The results should be useful for refining diagnostic criteria for left atrial dilation in the older population and may be relevant for cardiovascular risk stratification. Received October 7, 2008; accepted March 31, 2009. # CLINICAL PERSPECTIVE {#article-title-2}

Does Information on Systolic and Diastolic Function Improve Prediction of a Cardiovascular Event by Left Ventricular Hypertrophy in Arterial Hypertension

Left ventricular (LV) mass (LVM) is the most important information requested in hypertensive patients referred for echocardiography. However, LV function also predicts cardiovascular (CV) risk independent of LVM. There is no evidence that addition of LV function significantly improves model prediction of CV risk compared with LVM alone. Thus, composite fatal and nonfatal CV or cerebrovascular events were evaluated in 5380 hypertensive outpatients (2336 women, 298 diabetics, and 1315 obese subjects) without prevalent CV disease (follow-up: 3.5±2.8 years). We compared 5 risk models using Cox regression and adjusting for age and sex: (1) LV mass normalized for height in meters2.7 (LVMi); (2) LVMi, concentric LV geometry, by relative wall thickness (>0.43), ejection fraction, and transmitral diastolic pattern (by thirtiles of mitral deceleration index); (3) LVMi, LV geometry, midwall shortening, and mitral deceleration index thirtiles; (4) as No. 2 with the addition of left atrial dilatation (>23 mm); and (5) as No. 3 with the addition of left atrial dilatation. Individual hazard functions were compared using receiving operating characteristic curves and z statistics. Areas under the curves increased from 0.60 in the model with the sole LVMi to 0.62 in the others (all P values for differences were not significant). The additional information on systolic and diastolic function decreased the contribution (Wald statistics) of LVMi in the Cox model without improving the model ability to predict CV risk. We conclude that risk models with inclusion of information on LV geometry and systolic and diastolic function, in addition to LVMi, do not improve the prediction of CV events but rather redistribute the impact of individual predictors within the risk variance.