The pituitary tumor transforming gene in thyroid cancer.

The pituitary tumor transforming gene (PTTG) is a multifunctional proto-oncogene that is over-expressed in various tumors including thyroid carcinomas, where it is a prognostic indicator of tumor recurrence. PTTG has potent transforming capabilities in vitro and in vivo, and many studies have investigated the potential mechanisms by which PTTG contributes to tumorigenesis. As the human securin, PTTG is involved in critical mechanisms of cell cycle regulation, whereby aberrant expression induces aneuploidy. PTTG may further contribute to tumorigenesis through its role in DNA damage response pathways and via complex interactions with hormones and growth factors. Furthermore, PTTG over-expression negatively impacts upon the efficacy of radioiodine therapy in thyroid cancer, through repression of expression and function of the sodium iodide symporter. Given its various roles at all disease stages, PTTG appears to be an important oncogene in thyroid cancer. This review discusses the current knowledge of PTTG with particular focus on its role in thyroid cancer.

PTTG and PBF repress the human sodium iodide symporter.

The ability of the thyroid to accumulate iodide provides the basis for radioiodine ablation of differentiated thyroid cancers and their metastases. Most thyroid tumours exhibit reduced iodide uptake, although the mechanisms accounting for this remain poorly understood. Pituitary tumour transforming gene (PTTG) is a proto-oncogene implicated in the pathogenesis of thyroid tumours. We now show that PTTG and its binding factor PBF repress expression of sodium iodide symporter (NIS) messenger RNA (mRNA), and inhibit iodide uptake. This process is mediated at least in part through fibroblast growth factor-2. In detailed studies of the NIS promoter in rat FRTL-5 cells, PTTG and PBF demonstrated specific inhibition of promoter activity via the human upstream enhancer element (hNUE). Within this approximately 1 kb element, a complex PAX8-upstream stimulating factor 1 (USF1) response element proved critical both to basal promoter activity and to PTTG and PBF repression of NIS. In particular, repression by PTTG was contingent upon the USF1, but not the PAX8, site. Finally, in human primary thyroid cells, PTTG and PBF similarly repressed the NIS promoter via hNUE. Taken together, our data suggest that the reported overexpression of PTTG and PBF in differentiated thyroid cancer has profound implications for activity of the NIS gene, and hence significantly impacts upon the efficacy of radioiodine treatment.

Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF.

Pituitary tumor-transforming gene 1-binding factor (PTTG1IP; PBF) is a multifunctional glycoprotein, which is overexpressed in a wide range of tumours, and significantly associated with poorer oncological outcomes, such as early tumour recurrence, distant metastasis, extramural vascular invasion and decreased disease-specific survival. PBF transforms NIH 3T3 fibroblasts and induces tumours in nude mice, while mice harbouring transgenic thyroidal PBF expression show hyperplasia and macrofollicular lesions. Our assumption that PBF becomes an oncogene purely through increased expression has been challenged by the recent report of mutations in PBF within the Catalogue of Somatic Mutations in Cancer (COSMIC) database. We therefore sought to determine whether the first 10 PBF missense substitutions in human cancer might be oncogenic. Anisomycin half-life studies revealed that most mutations were associated with reduced protein stability compared to wild-type (WT) PBF. Proliferation assays narrowed our interest to two mutational events which significantly altered cell turnover: C51R and R140W. C51R was mainly confined to the endoplasmic reticulum while R140W was apparent in the Golgi apparatus. Both C51R and R140W lost the capacity to induce cellular migration and significantly reduced cell invasion. Colony formation and soft agar assays demonstrated that, in contrast to WT PBF, both mutants were unable to elicit significant colony formation or anchorage-independent growth. However, C51R and R140W retained the ability to repress radioiodide uptake, a functional hallmark of PBF. Our data reveal new insight into PBF function and confirm that, rather than being oncogenic, mutations in PBF are likely to be passenger effects, with overexpression of PBF the more important aetiological event in human cancer.

Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer.

The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4 × 10-4) compared with either PBF- (P=1.5 × 10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.8±2.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P=1.91 × 10-5) and disease-free survival (P=4.9 × 10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.

Improved left ventricular filling accompanies reduced left ventricular mass during therapy of essential hypertension.

Abnormal left ventricular diastolic performance, an early manifestation of hypertension in the heart, may precede the development of left ventricular hypertrophy. To assess effects of antihypertensive therapy on the heart, left ventricular mass (determined by echocardiography) and rapid left ventricular filling rate (determined by radionuclide ventriculography) were compared before and after 6 months of treatment of 16 patients. Nitrendipine (a dihydropyridine calcium channel blocker) was given alone or in combination with either propranolol or hydrochlorothiazide, or both, and significantly reduced blood pressure (156/103 +/- 12/7 to 137/89 +/- 10/6 mm Hg). In 6 of the 16 patients, left ventricular mass decreased by more than 10% (270 +/- 95 to 193 +/- 47 g, p less than 0.01); in the same patients, left ventricular filling rate increased (2.03 +/- 0.35 to 2.30 +/- 0.45 end-diastolic counts/s [EDC/s], p less than 0.01). In the one patient whose left ventricular mass increased (137 to 195 g), left ventricular filling rate decreased from 2.01 to 1.78 EDC/s. In the remaining nine patients who had no change in left ventricular mass, there was no significant changes in left ventricular filling. The changes in ventricular mass and filling could not be related to the extent of change in blood pressure or heart rate. These data suggest that regression of left ventricular mass during antihypertensive therapy with nitrendipine is accompanied by improved diastolic function.

Rapid ventricular filling in left ventricular hypertrophy: II. Pathologic hypertrophy.

To define the extent of left ventricular ejection and filling abnormalities in patients with mild hypertension, a non-imaging nuclear probe was used to generate high resolution time-activity curves in 25 patients with an average systolic blood pressure of 154 +/- 20 mm Hg and diastolic pressure of 98 +/- 8 mm Hg. The hypertensive patients did not meet electrocardiographic criteria for left ventricular hypertrophy, and none had evidence of ischemic or other cardiac disease. Compared with 25 age-matched normal subjects who had average systolic and diastolic pressures of 123 +/- 10 and 79 +/- 8 mm Hg, respectively, the hypertensive patients had a significantly lower ejection rate (2.00 +/- 0.20 versus 2.34 +/- 0.36 end-diastolic counts/s for the control group, p less than 0.05) and ejection fraction (58 +/- 4.9 versus 62 +/- 4.4) (p less than 0.05). The hypertensive patients had a markedly lower average rapid left ventricular filling rate (1.87 +/- 0.32 versus 2.69 +/- 0.41 counts/s for the control group, p less than 0.001). Although there was a modest inverse relation between echocardiographic left ventricular mass index and filling rate in the hypertensive patients (r = -0.59, p less than 0.01), 4 of 12 hypertensive patients with normal left ventricular mass index had a depressed filling rate. All of the hypertensive patients with increased left ventricular mass index had an abnormal left ventricular filling rate (less than 1.89 end-diastolic counts/s).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study.

OBJECTIVES: The aim of this study was to determine the prevalence of aortic sclerosis and stenosis in the elderly and to identify clinical factors associated with degenerative aortic valve disease. BACKGROUND: Several lines of evidence suggest that degenerative aortic valve disease is not an inevitable consequence of aging and may be associated with specific clinical factors. METHODS: In 5,201 subjects > or = 65 years of age enrolled in the Cardiovascular Health Study, the relation between aortic sclerosis or stenosis identified on echocardiography and clinical risk factors for atherosclerosis was evaluated by using stepwise logistic regression analysis. RESULTS: Aortic valve sclerosis was present in 26% and aortic valve stenosis in 2% of the entire study cohort; in subjects > or = 75 years of age, sclerosis was present in 37% and stenosis in 2.6%. Independent clinical factors associated with degenerative aortic valve disease included age (twofold increased risk for each 10-year increase in age), male gender (twofold excess risk), present smoking (35% increase in risk) and a history of hypertension (20% increase in risk). Other significant factors included height and high lipoprotein(a) and low density lipoprotein cholesterol levels. CONCLUSIONS: Clinical factors associated with aortic sclerosis and stenosis can be identified and are similar to risk factors for atherosclerosis.

Rapid ventricular filling in left ventricular hypertrophy: I. Physiologic hypertrophy.

The effects of endurance training on the diastolic properties of the left ventricle were examined by comparing left ventricular filling rates in 11 male distance runners and 12 age-matched nonathletic control subjects selected to have nearly similar heart rates at rest. Maximal oxygen consumption was 69 +/- 11 ml/kg-min for the athletes and 48 +/- 8 ml/kg X min for the control subjects (p less than 0.001). Left ventricular end-diastolic dimension, posterior wall thickness and mass were determined by echocardiography, and average left ventricular filling rate was determined with a nonimaging scintillation probe. Electrocardiographic voltage was significantly greater in the athlete group than in the control group (sums of the voltages of the S wave in lead V1 and the R wave in lead V5 were 40 +/- 10 and 26 +/- 7 mV, respectively) (p less than 0.001), whereas ejection fraction was similar in the two groups. Despite a modest degree of left ventricular hypertrophy in the athlete group compared with the control group (left ventricular mass index 127 +/- 30 and 82 +/- 13 g/m2, respectively) (p less than 0.001), the average left ventricular filling rate was similar in the two groups (2.53 +/- 0.34 versus 2.38 +/- 0.29 end-diastolic counts/s, p = NS). There was no trend for the athletes with a higher left ventricular mass to exhibit a slower filling rate. These findings demonstrate that unlike pathologic hypertrophy associated with chronic hemodynamic over-loading, physiologic left ventricular hypertrophy is not accompanied by slowed left ventricular diastolic filling.

Echocardiographic assessment of left ventricular diastolic performance in hypertensive subjects. Correlation with changes in left ventricular mass.

Left ventricular hypertrophy resulting from hypertension is accompanied by significant morbidity and mortality and in advanced stages may be irreversible. Hence, early detection of cardiac changes in hypertensive patients remains an important diagnostic goal. When the hypertrophy is mild or moderate, parameters of left ventricular diastolic function and measurements of left atrial size may facilitate the distinction between normal variation and pathologic increases in left ventricular mass. We measured left ventricular isovolumic relaxation time (IVRT, the time from aortic valve closure to mitral valve opening) and left atrial dimensions and correlated them to left ventricular mass index measured by M-mode echocardiography and rapid left ventricular filling by radionuclide ventriculography. In 20 subjects with untreated mild essential hypertension, IVRT was prolonged compared to a normotensive age-matched control group (91 +/- 23 vs 65 +/- 13 msec, p less than 0.0001). Left atrial dimension index was increased in patients compared to controls (1.9 +/- 0.4 vs 1.4 +/- 0.5 cm/m2, p less than 0.001), and this increase was related to prolonged IVRT (r = 0.46, p less than 0.001). Abnormal IVRT correlated with both increased left ventricular mass and decreased rapid ventricular filling in the hypertensive subjects. Thus, prolonged IVRT and borderline left atrial dimension may help identify subtle pathologic left ventricular mass increases in hypertensive subjects.

Effect of African-American race and hypertensive left ventricular hypertrophy on coronary vascular reactivity and endothelial function.

Excess cardiovascular morbidity and mortality among African (black) Americans remains an important yet unexplained public health problem. One possible explanation proposes that intrinsic or acquired abnormalities in coronary vascular reactivity and endothelial function result in excess ischemia among black Americans. To examine this hypothesis, we subjected 80 individuals with normal coronary arteries to invasive testing of coronary artery and microvascular relaxation using intracoronary infusions of acetylcholine and adenosine, a Doppler tipped intracoronary guide wire, and quantitative coronary angiography. We measured the percent increase in coronary blood flow and epicardial diameter after graded infusion of intracoronary acetylcholine and in coronary blood flow after intracoronary adenosine in 31 normotensive subjects (10 black, 21 white) and 49 hypertensive subjects with left ventricular hypertrophy (25 black, 24 white). Categorical and multivariate analyses revealed that in response to intracoronary adenosine and acetylcholine, the depression in endothelium-independent and -dependent microvascular relaxation during peak agonist effect was largely related to the presence of chronic hypertension and left ventricular hypertrophy. Normotensive subjects demonstrated no intrinsic racial differences in conduit and resistance vessel vasoreactivity. In response to maximal infusion of acetylcholine, epicardial coronary arteries constricted similarly in black and white subjects with hypertensive left ventricular hypertrophy and dilated similarly in normotensive black and white subjects. Thus, our study shows that in a cohort of black and white subjects referred for coronary arteriography because of chest pain, African American race is not associated with excess intrinsic or acquired depression in coronary vascular relaxation during the peak effect of the endothelium-dependent and -independent agonists acetylcholine and adenosine, after adjustment for the presence of left ventricular hypertrophy.

Effects of chronic nitrendipine on casual (office) and 24-hour ambulatory blood pressure.

To assess the clinical efficacy of chronic nitrendipine therapy in mild to moderate essential hypertension, we studied blood pressure (BP) and heart rate responses in 22 subjects receiving maintenance nitrendipine therapy. Ten subjects (45%) whose hypertension was controlled with chronic monotherapy had an 11/12 mm Hg decrease in supine BP (P less than 0.05) with a mean (+/- SD) dose of 71 +/- 15 mg/day. The 12 (55%) subjects whose hypertension was not controlled with monotherapy had a comparatively higher baseline BP than the other 10 (156/105 +/- 10/6 compared with 150/98 +/- 15/4 mm Hg; P less than 0.05). Eight of the 10 subjects demonstrating office BP control with chronic nitrendipine monotherapy who also had full-time employment underwent continuous ambulatory BP monitoring before and after maintenance monotherapy. Nitrendipine induced a reduction in the mean 24-hour BP and mean BP at home, but did not reduce the BP during work or while asleep. These data suggest that nitrendipine lowers BP when assessed by casual office methods. The ambulatory BP monitor data demonstrate that the hypotensive response to chronic nitrendipine is modified during work periods, which are generally associated with increased adrenergic activity. Ambulatory BP monitoring may be superior to office (casual) monitoring in the assessment of the overall efficacy of antihypertensive drugs.

Effect of the calcium channel blocker nitrendipine on left ventricular mass in patients with hypertension.

Reductions in left ventricular (LV) mass have been reported after antihypertensive therapy with certain sympatholytic agents and converting enzyme inhibitors, but little or no improvement has been noted after vasodilator therapy. In this study we evaluated the effect of the calcium channel blocker nitrendipine on echocardiographic LV mass. During a 12-month period, nitrendipine was used as monotherapy in 30 patients and in combination with propranolol or a diuretic in an additional 28 patients. Nitrendipine monotherapy lowered supine blood pressure from 148/97 to 136/83 mm Hg, but LV mass did not change significantly. Supine blood pressure decreased from 155/103 to 134/86 mm Hg in patients receiving combination therapy but, again, changes in LV mass were not significant. These data suggest that nitrendipine is effective in lowering blood pressure, but this is not associated with a significant decrease in LV mass in patients with mild hypertension.

Coronary vasomotor reactivity among normotensive African and white American subjects with chest pain.

BACKGROUND AND OBJECTIVES: Excess cardiovascular morbidity and mortality among African (black) Americans is the subject of intensive investigation but the etiology remains speculative. One hypothesis proposes that inherent, or intrinsic, differences in coronary vascular reactivity and endothelial function predispose African Americans to enhanced vasoconstriction and/or depressed vasodilation, resulting in excess ischemia. The objective of this study was to establish whether coronary vasoreactivity differs among normotensive, nondiabetic African and white Americans with normal arteries referred for coronary arteriography because of chest pain. PATIENTS AND METHODS: Eleven African American (8 female, 3 male) and 28 white American (9 female, 19 male) normotensive, euglycemic patients with normal coronary arteries were prospectively recruited for invasive testing of coronary artery and microvascular relaxation using the endothelium-dependent and -independent agents, acetylcholine and adenosine; a Doppler tipped intracoronary guidewire; and quantitative coronary angiography. RESULTS: The study cohort consisted of 17 women (44%) and 22 men (56%) with a mean age of 46 +/- 10 yrs. Of 8 African American women, 6 were premenopausal and 2 were postmenopausal on estrogen replacement therapy. Of 9 white American women, 2 were premenopausal, 1 was 46-year old with a previous history of hysterectomy without ovariectomy, 2 were postmenopausal on estrogen replacement therapy, 2 were perimenopausal and 44- and 54-year old, and 2 were postmenopausal without estrogen replacement therapy. In response to maximal infusion of acetylcholine, epicardial coronary arteries and resistance vessels dilated similarly in black and white subjects. Dose-response curves revealed no significant racial differences during submaximal graded infusion of acetylcholine. In response to peak effect of adenosine, there were no racial differences in dilation of the microcirculation. CONCLUSIONS: In the absence of hypertension, diabetes mellitus, and angiographic evidence of coronary artery disease, African American women demonstrate no evidence of intrinsic predisposition to enhanced coronary conduit vasoconstriction or depressed microcirculatory dilation in response to the endothelium-dependent and -independent vasodilator agonists-acetylcholine and adenosine-when compared with responses of similar white men and women. Because of low enrollment of black males, definitive conclusions cannot be drawn regarding this group.

Comparison of ambulatory left ventricular ejection fraction and blood pressure in systemic hypertension in patients with and without increased left ventricular mass.

To evaluate the effects of long-standing systemic hypertension on left ventricular (LV) function during daily activities, ambulatory radionuclide monitoring of LV ejection fraction (EF) and blood pressure was performed during exercise and other structured activities in 31 hypertensive patients. Patients were divided into 3 groups based on the absence of LV hypertrophy (group 1 [n = 16], LV mass 107 +/- 12 g/m2), presence of LV hypertrophy without electrocardiographic changes (group 2 [n = 10], LV mass 141 +/- 8 g/m2) and LV hypertrophy with associated electrocardiographic changes (group 3 [n = 5], LV mass 158 +/- 9 g/m2). The groups were similar with respect to age, baseline medication, treated and untreated blood pressure, resting EF and treadmill exercise time. Patients in group 3 had the longest history of hypertension. Peak filling rate was normal in group 1 (2.9 +/- 0.4 end-diastolic volume/s), but reduced at rest in groups 2 (2.4 +/- 0.4) and 3 (2.1 +/- 0.3). Patients in group 1 had normal EF responses to exercise and mental stress testing, as well as during routine ambulatory activities. Patients in group 2 had a blunted EF response to exercise, and those in group 3 had a significantly abnormal response. Both group 2 and 3 patients demonstrated abnormal EF responses to mental stress, as well as cold pressor testing in association with significant increases in mean arterial pressure and marked reduction in diastolic filling rate. Decreases in EF were also observed during routine patient monitoring in 3 group 3 patients and 4 group 2 patients. These events were associated with significantly increased blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Carotid artery measures are strongly associated with left ventricular mass in older adults (a report from the Cardiovascular Health Study).

Associations of carotid artery diameter and intimal-medial thickness by ultrasound with echocardiographic left ventricular (LV) structure were examined in 3,409 participants in the Cardiovascular Health Study, a population-based study of risk factors for coronary heart disease and stroke in men and women aged > or = 65 years. At baseline, sector-guided M-mode echocardiography and B-mode ultrasound were used to evaluate the left ventricle and carotid arteries, respectively. Common carotid artery diameter and intimal-medial thickness were significantly related to LV mass in correlational analysis (r=0.40 and 0.20, respectively, p<0.01), and each was independently associated with LV mass after adjustment for age, gender, weight, systolic and diastolic blood pressure, antihypertensive medication use, prior coronary heart disease, electrocardiographic abnormalities, high-density lipoprotein, and factor VII. We speculate that changes in the arterial wall affect impedance to LV ejection leading to increases in LV mass. Further follow-up of this cohort is in progress and will help to determine whether such carotid artery measures could, by exacerbating LV hypertrophy, constitute another important risk factor for adverse cardiovascular outcomes.

Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study).

Atrial fibrillation (AF) is a common arrhythmia in elderly persons and a common cause of embolic stroke. Most studies of the prevalence and correlates of AF have used selected, hospital-based populations. The Cardiovascular Health Study is a population-based, longitudinal study of risk factors for coronary artery disease and stroke in 5,201 men and women aged > or = 65 years. AF was diagnosed in 4.8% of women and in 6.2% of men at the baseline examination, and prevalence was strongly associated with advanced age in women. Prevalence of AF was 9.1% in men and women with clinical cardiovascular disease, 4.6% in patients with evidence of subclinical but no clinical cardiovascular disease, and only 1.6% in subjects with neither clinical nor subclinical cardiovascular disease. A history of congestive heart failure, valvular heart disease and stroke, echocardiographic evidence of enlarged left atrial dimension, abnormal mitral or aortic valve function, treated systemic hypertension, and advanced age were independently associated with the prevalence of AF. The low prevalence of AF in the absence of clinical and subclinical cardiovascular disease calls into question the existence and clinical usefulness of the concept of so-called "lone atrial fibrillation" in the elderly.

Coronary vasomotor function in a normotensive, nondiabetic referral population with normal coronary arteriograms.

In a referral normal cardiac population, endothelium-independent coronary relaxation is nearly always normal, but endothelium-dependent relaxation may be depressed in a significant proportion of patients. Further study of the natural history of referral subjects with endothelial dysfunction is necessary to assess the potential cardiovascular risk of this finding in a presumed low-risk population.

Left ventricular diastolic filling in the elderly: the cardiovascular health study.

Changes in left ventricular (LV) diastolic function (e.g., as measured by transmitral flow velocity) are known to occur with aging. In addition, impaired LV diastolic function plays an important role in such cardiovascular disorders common in the elderly as hypertension, ischemic heart disease, and congestive heart failure (CHF). Participants in the Cardiovascular Health Study, a multicenter study of community-dwelling men (n=2,239) and women (n=2,962) > or = 65 years of age, underwent an extensive baseline evaluation, including echocardiography. Early diastolic LV Doppler (transmitral) peak filling velocity decreased, and peak late diastolic (atrial) velocity increased with age in multivariate analyses (all p <0.001). Early and late diastolic peak filling velocities were both significantly higher in women than in men, even after adjustment for body surface area (or height and weight). In multivariate models in the entire cohort and a healthy subgroup (n=703), gender, age, heart rate, and blood pressure (BP) were most strongly related to early and late diastolic transmitral peak velocities. Early and late diastolic peak velocities both increased with increases in systolic BP and decreased with increases in diastolic BP (p <0.001). Doppler transmitral velocities were compared among health status subgroups. In multiple regression models adjusted for other covariates, and in analysis of variance models examining differences across subgroups adjusted only for age, the subgroup with CHF had the highest early diastolic peak velocities. All clinical disease subgroups had higher late diastolic peak velocities than the healthy subgroup, with the subgroups with either CHF or hypertension having the highest age-adjusted means. The subgroup with hypertension had the lowest ratio of early-to-late diastolic peak velocity, and men with CHF had the highest ratio. These findings are consistent with previous reports that hypertensive subjects exhibit an abnormal relaxation pattern, whereas patients with CHF develop a pattern suggestive of an increased early diastolic left atrial-LV pressure gradient.

M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (the Cardiovascular Health Study).

Previous studies have identified a number of echocardiographic variables that predict cardiovascular disease (CVD) events and mortality, but have not focused on a large elderly cohort. The purpose of this study was to determine whether M-mode echocardiographic variables predicted all-cause mortality, incident coronary heart disease (CHD), congestive heart failure (CHF), and stroke in a large prospective, multicenter, population-based study. In the Cardiovascular Health Study, a biracial cohort of 5,888 men and women (mean age 73 years) underwent 2-dimensional M-mode echocardiographic measurements of left ventricular (LV) internal dimensions, wall thickness, mass and geometry, as well as measurement of left atrial dimension and assessment for mitral annular calcium. Participants were followed for 6 to 7 years for incident events; analyses excluded subjects with prevalent disease. One or more echocardiographic measurements were independent predictors of all-cause mortality and incident CHD, CHF, and stroke. After adjustment for anthropometric and traditional CVD risk factors, LV mass was significantly related to incident CHD, CHF, and stroke. The highest quartile of LV mass conferred a hazards ratio of 3.36, compared with the lowest quartile, for incident CHF. Furthermore, incident CHF-free survival was significantly lower for participants with LV mass in the highest versus the 2 lowest quartiles (86% vs 97%, respectively, at 2,500 days). Eccentric and concentric LV hypertrophy, respectively, conferred adjusted hazards ratios, compared with normal LV geometry, of 2.05 and 1.61 for incident CHD, and 2.95 and 3.32 for incident CHF. Thus, in an elderly biracial population, selected 2-dimensional M-mode echocardiographic measurements were important markers of subclinical disease and conferred independent prognostic information for incident CVD events, especially CHF and CHD.

Reduced vital capacity in elderly persons with hypertension, coronary heart disease, or left ventricular hypertrophy. The Cardiovascular Health Study.

The Cardiovascular Health Study provided the opportunity to determine the association of subclinical and clinical cardiovascular disease with pulmonary function in a population sample of elderly adults. Included were 2,955 women and 2,246 men over age 64 years who were recruited for this observational study from four communities and completed extensive examinations that included spirometry, echocardiograms, and blood pressure. Current smokers, past smokers with >20 pack-years of smoking, and persons with a history of asthma, chronic bronchitis, or emphysema were excluded from this analysis, leaving 2,784 (55%) of the cohort. Systolic hypertension or coronary artery disease was associated with 40- to 100-mL decrements in FEV1, and 50- to 150-mL decrements in FVC, while a history of congestive heart failure was associated with 200 to 300 mL lower FEV1 and FVC values (p < 0.0001), after correcting for age, height, and waist size. Higher left ventricular (LV) mass was also significantly associated with a decrease in FEV1 and FVC in multivariate models. This relationship was strongest with the end-diastolic LV posterior wall thickness component of LV mass. In summary, FEV1 and FVC are reduced in elderly persons with hypertension, ischemic heart disease, higher disease, higher LV mass, and congestive heart failure, though the magnitude of these associations is relatively small unless heart failure supervenes. Substantial decrements in percent predicted FEV1 and FVC should not be attributed to the presence of uncomplicated ischemic heart disease or hypertension alone.