Growth hormone administration reduces circulating proinflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy

Background Recent studies have shown that an abnormal proinflammatory cytokine expression and apoptotic process contribute to adverse left ventricular remodeling and progress of chronic heart failure. This study investigates the effects of growth hormone (GH) administration on serum levels of representative proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy (IDC). Methods Serum levels of tumor necrosis factor-α (TNF-α), its soluble receptors (sTNF-RI, sTNF-RII), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), soluble Fas (sFas) and soluble Fas Ligand (sFasL) were determined (enzyme-linked immunosorbent assay method) in 10 patients with IDC (New York Heart Association class III, ejection fraction 24% ± 2%) before and after a 3-month subcutaneous administration of 4 IU GH every other day (randomized crossover design). Peak oxygen consumption (Vo₂max) was also used to evaluate the functional status of patients with IDC. Results Treatment with GH produced a significant reduction in serum levels of TNF-α (8.2 ± 1.2 vs 5.7 ± 1.1 pg/mL, P < .05), sTNF-RI (3.9 ± 0.4 vs 3.2 ± 0.3 ng/mL, P < .05), sTNF-RII (2.6 ± 0.3 vs 2.2 ± 0.2 ng/mL, P < .05), IL-6 (5.5 ± 0.6 vs 4.4 ± 0.4 pg/mL, P = .05), sIL-6R (32.7 ± 3.0 vs 28.2 ± 3.0 ng/mL, P < .05), sFas (4.4 ± 0.8 vs 3.1 ± 0.6 ng/mL, P < .05), and sFasL (34.2 ± 11.7 vs 18.8 ± 7.3 pg/mL, P < .01). A significant improvement was also observed in Vo₂max after the completion of 3 months' treatment with GH (15.0 ± 0.8 vs 17.2 ± 1.0 mL/kg/min, P < .05). Good correlations were found between GH-induced reduction in TNF-α levels and increase in Vo₂max (r = −0.64, P < .05) as well as between GH-induced reduction in sFasL and increase in Vo₂max (r = −0.56, P = .08). Conclusions GH administration reduces serum levels of proinflammatory cytokines and soluble Fas/FasL system in patients with IDC. These immunomodulatory effects may be associated with improvement in clinical performance and exercise capacity of patients with IDC. (Am Heart J 2002;144:359-64.)     

Septal q waves as an indicator of risk of mortality in elderly patients with chronic heart failure

Background The absence of electrocardiographic septal q wave is a recognized marker of left ventricular disease. We aimed to investigate the prognostic significance of absent septal q waves in elderly (age >65 years) patients with chronic heart failure. Methods A total of 110 patients (mean age 73 ± 4 years) with New York Heart Association functional class II to IV and left ventricular ejection fraction of <45% were enrolled in the study. Standard 12-lead electrocardiograms were critically analyzed for the presence or absence of septal q waves in leads I, aVL, V₅, and V₆. Patient survival was determined from hospital and general practitioner records and National Statistics Registry at a mean follow-up of 4 years. Results Septal q waves were absent in 71 and present in 39 patients. The overall mortality rate was 47% (43 patients). The incidence of death was 49% (36 patients) in the group with no septal q waves and 18% (7 patients) in those who demonstrated septal q waves. On univariate analysis by Cox proportional hazard method, absence of septal q waves was found to be a strong marker of poor prognosis in CHF (P = .003, hazard ratio 1.40, 95% CI 1.10-1.67). Kaplan-Meier survival curves showed a significant difference in survival independent of age, New York Heart Association functional class, peak Vo₂, and QRS duration between these 2 groups. Conclusions Absence of the normal septal q wave on 12-lead electrocardiography, which may indicate structural heart disease and myocardial fibrosis, is an independent predictor of poor prognosis in elderly patients with CHF. (Am Heart J 2002;144:740-4.)     

Urine albumin/creatinine ratio and echocardiographic left ventricular structure and function in hypertensive patients with electrocardiographic left ventricular hypertrophy: the LIFE study. Losartan Intervention for Endpoint Reduction

Background Albuminuria, reflecting systemic microvascular damage, and left ventricular (LV) geometric abnormalities have both been shown to predict increased cardiovascular morbidity and mortality. However, the relationship between these markers of cardiovascular damage has not been evaluated in a large hypertensive population. Methods The urine albumin/creatinine ratio (UACR) and echocardiographic measures of LV structure and function were obtained in 833 patients with stage I to III hypertension and LV hypertrophy determined by electrocardiogram (ECG) (Cornell voltage-duration or Sokolow-Lyon voltage criteria) after 14 days of placebo treatment. Results Patients' mean ages were 66 years, 42% were women, 23% had microalbuminuria, and 5% had macroalbuminuria. Patients with eccentric or concentric LV hypertrophy had higher prevalences of microalbuminuria (average 26%-30% vs 9%, P < .001) and macroalbuminuria (6%-7% vs <1%, P < .001). Furthermore, patients with microalbuminuria and macroalbuminuria had a significantly higher LV mass and lower endocardial and midwall fractional shortening. Patients with abnormal diastolic LV filling parameters had a significantly increased prevalence of microalbuminuria. In univariate analyses, UACR correlated positively to LV mass, systolic blood pressure, age (all P < .001) and pulse pressure/stroke volume and negatively to relative wall thickness (both P < .01) and endocardial (P < .05) and midwall shortening (P < .001) but not to diastolic filling parameters. In multiple regression analysis higher UACR was associated with higher LV mass (β = .169, P < .001) independently of older age (β = .095, P < .01), higher systolic pressure (β = .163), black race (β = .186), and diabetes (β = .241, all P < .001). Conclusions In hypertensive patients with ECG LV hypertrophy, abnormal LV geometry and high LV mass are associated with high UACR independent of age, systolic blood pressure, diabetes, and race, suggesting parallel cardiac and microvascular damage. (Am Heart J 2002;143:319-26.)     

Losartan treatment and left ventricular filling during volume loading in patients with dilated cardiomyopathy

Background Patients with mild heart failure show a reduction in preload reserve mechanism during volume expansion. At this time, the effects of volume expansion on left ventricular (LV) diastolic filling in this subset of patients have not been well characterized. Methods We evaluated the effects of acute volume loading on Doppler parameters of LV filling in 10 healthy control subjects and in 12 patients with idiopathic dilated cardiomyopathy (DCM). In patients with DCM, the effects of losartan on diastolic adaptation to volume load were also investigated. Results During volume loading, the healthy control subjects showed a decrease in isovolumic relaxation time (F = 5.3, P < .05) but an increase in the LV peak filling rate (F = 52.9, P < .001) and velocity time integral of both systolic (F = 72.8, P < .001) and diastolic (F = 4.6, P < .05) pulmonary venous flow. In patients with DCM, isovolumic relaxation time decreased more than in control subjects (F = 8.1, P < .01), and the deceleration time of the early mitral wave was reduced (F = 26.3, P < .001). Furthermore, the duration of pulmonary venous flow reversal exceeded that of mitral flow at atrial contraction (F = 28.5, P < .001). After treatment with losartan, the deceleration time of early mitral wave remained unchanged, and the duration of pulmonary venous flow reversal at atrial contraction did not exceed that of mitral flow; thus, a significant treatment effect was detectable (F = 5.6, P < .05; and F = 6.6, P <.05, respectively). Conclusions Control subjects respond to volume load with enhancement in early LV filling, whereas patients with DCM show an increase of LV filling pressure. Diastolic adaptation to volume load improves in patients with DCM after treatment with losartan. (Am Heart J 2002;143:433-40)     

Ventilatory response to exercise improves risk stratification in patients with chronic heart failure and intermediate functional capacity

Background Peak oxygen consumption (VO₂) has an important prognostic role in chronic heart failure (CHF), but its discriminatory power is limited in patients with intermediate exercise capacity (peak VO₂ between 10-18 mL/kg/min). Thus, supplementary exertional indexes are greatly needed. Methods Six hundred patients with CHF with left ventricular ejection fraction (LVEF) ≤40% who performed a symptom-limited cardiopulmonary exercise testing were screened and followed up for 780 ± 450 days. Results Eighty-seven patients had major cardiac events (77 cardiac deaths and 10 urgent heart transplantations). Multivariate analysis revealed the rate of increase of minute ventilation per unit of increase of carbon dioxide production (VE/VCO₂ slope) (χ², 79.3, P < .0001), LVEF (χ², 24.6, P < .0001), and peak VO₂ (χ², 9.4, P < .0001) as independent and additional predictors of major cardiac events. VE/VCO₂ slope was the strongest independent predictor of outcome (χ², 20.9, P = .0001) in patients with intermediate peak VO₂ (n = 403), and the best cutoff value was 35 (χ², 25.8; relative risk = 3.2, 95% CI 2.0-5.1, P < .0001). Total mortality rate was 30% in patients with VE/VCO₂ slope ≥35 (n = 103, 26%) and 10% in those with VE/VCO₂ slope <35 (n = 300, 74%) (P < .0001). Patients with VE/VCO₂ slope ≥35 had a similar total mortality rate to those with peak VO₂ ≤10 mL/kg/min (30% vs 37%, P not significant). Conclusions A rational and pragmatic risk stratification process with symptom-limited cardiopulmonary exercise testing in CHF should include both peak VO₂ and VE/VCO₂ slope, the latter index effectively predicting outcome in almost one fourth of patients with intermediate exercise capacity. (Am Heart J 2002;143:418-26.)     

Left ventricular remodeling in the first year after acute myocardial infarction and the predictive value of N-terminal pro brain natriuretic peptide

Background Left ventricular (LV) remodeling after myocardial infarction (MI) has received much attention because of its severe impact on morbidity and mortality rates. However, the incidence and extent of LV remodeling in a modern infarct population who were offered antiremodeling treatment in compliance with daily clinical practice is unknown. The purpose of this study was to clarify this issue and to evaluate the predictive value of N-terminal pro brain natriuretic peptide (NT-proBNP). Methods Forty-two patients with a first transmural MI were examined after 1 week, 1 month, 3 months, 6 months, and 1 year with blood samples and magnetic resonance imaging. Results In 12 patients (29%), LV end-diastolic volume index (LVEDVI) and LV end-systolic volume index (LVESVI) increased by 24% and 22% (P <.0001; P = .01). In 12 patients (29%), LVEDVI and LVESVI decreased by 19% and 23% (P <.0001; P = .0005), whereas the remaining 18 patients (43%) had stable conditions regarding these LV measures. LV ejection fraction at baseline was significantly reduced in all patient categories but was unchanged over time. Elevated NT-proBNP level at baseline was identified as an independent predictor of increase in LVEDVI during follow-up examination (P = .007). A baseline level of NT-proBNP >115 pmol/L identified patients who later had LV dilatation develop with a sensitivity and specificity of 89% and 68% (area under curve = 0.77). Conclusion In this 1-year follow-up study of patients with a first transmural MI, approximately 30% had significant increments develop in LVEDVI and LVESVI, and LV ejection fraction remained unchanged. Patients in whom LV dilatation developed could be identified early after the MI with elevated plasma levels of NT-proBNP. (Am Heart J 2002;143:696-702.)     

Treatment of acromegaly improves myocardial abnormalities

Background Treatment for acromegaly decreases left ventricular (LV) mass, but it is not clear whether diastolic dysfunction is also reversible. With Doppler echocardiography, before and after effective therapy, we assessed the LV morphology and function of patients with acromegaly who were free of complications. Methods In 15 patients with active acromegaly (age range, 33.4 ± 9.3 years), we compared LV Doppler echocardiographic indices, before and after transsphenoidal surgery or radiotherapy or before and after both procedures, noting a significant drop in plasma levels of growth hormone (<2.0 ng/mL after oral glucose tolerance testing). Patients did not have arterial hypertension, diabetes mellitus, thyroid dysfunction, or coronary artery disease. Occasionally, in this series, patients had no symptoms of heart failure, and patients who underwent treatment with somatostatin analog drugs were not included because they did not have a significant hormonal drop. The follow-up period after hormonal control was 2.7 ± 1.7 years. We also studied 15 healthy control subjects matched for age, sex, and body surface area. Results Patients with acromegaly compared with healthy control subjects had increased LV mass index, relative wall thickness, and deteriorated diastolic function. After therapy, most of the abnormalities improved: LV mass index (104 ± 21 g/m² × 87 ± 21 g/m²; P <.01), LV relative wall thickness (0.40 ± 0.06 × 0.35 ± 0.04; P <.01), proto/telediastolic transmitral peak flow velocity ratio (1.17 ± 0.33 × 1.49 ± 0.34; P <.001), and isovolumetric relaxation period (126 ± 18 ms × 113 ± 13 ms; P <.05). Conclusion Treatment of acromegaly in patients without clinical heart failure improves both LV morphology and diastolic function. Avoidance of progression to more advanced forms of acromegalic cardiomyopathy should be possible. (Am Heart J 2002;143:873-6).     

Detection of left ventricular enlargement and impaired systolic function with plasma N-terminal pro brain natriuretic peptide concentrations

Background Brain- and N-terminal pro brain natriuretic peptide (NT-proBNP) have been identified as promising markers for heart failure. However, previous studies have revealed that they may hold insufficient diagnostic power for implementation into clinical practice because of a significant overlap in the range of plasma levels between healthy subjects and subjects with heart failure. We hypothesized that imprecision of the reference method (ie, the echocardiographic evaluation of left ventricular [LV] function) may have affected results from those earlier studies. We therefore wanted to investigate the diagnostic potential of NT-proBNP with magnetic resonance imaging as the reference method for the cardiac measurements. Methods Forty-eight patients with stable symptomatic heart failure in New York Heart Association functional classifications II to IV were examined once with blood samples and magnetic resonance imaging along with 20 age-matched and gender-matched healthy control subjects. Results NT-proBNP was associated with LV end-diastolic (r = 0.69; P < .0001) and end-systolic (r = 0.73; P < .0001) volume indices, LV mass index (r = 0.69; P < .0001), and LV ejection fraction (r = −0.75; P < .0001). Receiver operating characteristic curves were calculated for the ability of NT-proBNP to detect LV end-diastolic volume index (>105 mL · m⁻²[cut-off]; sensitivity/specificity, 82%/87%), LV end-systolic volume index (>35 mL · m⁻²; sensitivity/specificity, 86%/86%), LV mass index (>152 g · m⁻²; sensitivity/specificity, 85%/86%), and LV ejection fraction (<58%; sensitivity/specificity, 84%/85%) deviating more than 2 standard deviations from control values. Conclusion NT-proBNP is a powerful marker for LV dimensions and systolic function in patients with heart failure and discriminates well between healthy subjects and subjects with impaired LV systolic function or increased LV dimensions. (Am Heart J 2002;143:923-9.)     

Prognostic importance of systolic and diastolic function after acute myocardial infarction

Background Although risk stratification after acute myocardial infarction (AMI) often is focused on systolic left ventricular (LV) function, it appears that a more complete study of ventricular function including assessment of LV filling would be useful. Doppler echocardiography allows assessment of LV filling, and with the use of the Tei index (sum of isovolumic relaxation and contraction times divided by ejection time), a global estimate of ventricular function may be obtained. Therefore, the aim of this study was to determine the prognostic importance of LV systolic, diastolic, and overall LV function in a large consecutive population with AMI.Methods Echocardiography was performed within 6 days of AMI. LV systolic, diastolic, and global function was assessed by means of wall motion index (WMI), mitral flow pattern, and Tei index. The primary end point was all-cause death.Results Of 799 enrolled patients, 197 died during a median follow-up of 34 months. In a multivariate model including WMI and clinical parameters, WMI had important prognostic information. When mitral filling pattern and quartiles of Tei index were added to the model, restrictive filling (mitral deceleration time <140 ms) was associated with a risk ratio of 1.9 (95% CI 1.3-2.7, P < .0001, Tei index values of >0.68/0.56-0.68/0.46-0.55/<0.46 were associated with risks of 4.0 [2.1-6.9]/2.3 [1.5-3.9]/2.1 [1.2-3.6]/1.0, P < .001). In this model, WMI had no prognostic value (P = .18).Conclusions Mitral deceleration time and the Tei index have independent and important prognostic value after AMI. (Am Heart J 2003;145:147-153.)     

Outcome of significant functional tricuspid regurgitation after percutaneous mitral valvuloplasty

Background The outcome of significant functional tricuspid regurgitation (TR) associated with mitral stenosis (MS) after percutaneous mitral valvuloplasty (PMV) remains to be clarified. Methods From 265 patients who underwent PMV at our institution from 1995 to 2000 and who were regularly observed, we selected 71 patients (55 women, mean age 43 ± 11 years) who showed significant moderate to severe functional TR before PMV. We analyzed data from the echocardiograms performed before, 24 hours after, and long after the intervention (29 ± 12 months) and analyzed clinical outcomes. Resolution of TR was defined as trace or mild TR on the follow-up color Doppler study. Results Patients with moderate to severe TR showed more severe MS and pulmonary hypertension and more atrial fibrillation than patients with less than moderate TR. TR was resolved on the follow-up echocardiography in 23 of the 71 patients with significant TR before PMV (32%). The TR jet area before PMV (P < .05) and the late decrement of peak transmitral pressure gradient (P < .01) were independent determinants of resolution. TR was resolved in only 6.7% of patients (1/15) with an unsuccessful long-term PMV result, but was resolved in 39% of patients (22/56) with a successful long-term result (P < .05). During the clinical follow-up period (mean length 38 ± 20 months), 4 patients underwent open heart surgery 24 to 39 months after PMV, and there was no overall mortality. Conclusions Significant functional TR was associated with more severe MS, and it could be diminished when the transmitral pressure gradient was sufficiently relieved with PMV. (Am Heart J 2003;145:371-6.)     

Impact of disease activity on left ventricular performance in patients with acromegaly

Background In patients with acromegaly, abnormalities of systolic and diastolic left ventricular (LV) performance, mostly associated with hypertension or LV hypertrophy, have been reported. We used 2-dimensional/Doppler echocardiographic methods and tissue Doppler imaging (TDI) to elucidate the impact of disease activity on LV function in patients with acromegaly. Methods In a prospective study design, 15 patients with active acromegaly (AA group; mean age-adjusted serum insuline-like growth factor-I [IGF-I] level, 420 ± 170 ng/mL, mean growth hormone nadir during 75-g oral glucose load, 12.3 ± 30.1 μg/L), 18 patients with cured (n = 14, mean IGF-I level 205 ± 115 ng/mL, mean growth hormone nadir during glucose load 0.72 ± 0.34 μg/L) or well-controlled (n = 4, normal age-adjusted ranges of IGF-I levels with medication with somatostatin analogues 354 ± 88 ng/mL) acromegaly (CA group), and 24 control subjects (control group) underwent 2-dimensional/Doppler echocardiographic measurements, including assessment of the Tei index (isovolumic contraction time and isovolumic relaxation time divided by ejection time). Systolic and diastolic mitral annular velocities (peak systolic velocity, peak early diastolic velocity [E′], peak late diastolic velocity [A′], E′/A′ ratio) were derived from pulsed TDI. Results No significant differences between study groups were observed with respect to muscle mass and systolic parameters, such as ejection fraction, fractional shortening, and peak systolic velocity. In patients with AA, E′ and the E′/A′ ratio were lower than in control and CA subjects (AA 6.8 ± 1.7 cm/s, control 10.0 ± 1.7 cm/s, CA 9.1± 3.0 cm/s, P < .01 AA vs control, P < .05 AA versus CA, AA 0.68 ± 0.22, control 0.98 ± 0.16, CA 0.89 ± 0.37, P < .01 AA vs control and CA, respectively). In comparison with control subjects and patients with CA, patients with AA had a reduced mitral peak velocity of early/late filling ratio (AA 0.78 ± 0.22 m/s, control 1.12 ± 0.33 m/s, CA 1.11 ± 0.36 m/s, P < .05 AA vs control and CA) and a prolonged deceleration time (AA 223 ± 41 ms, control 188 ± 26 ms, CA 185 ± 25 ms, P < .05 AA vs control and CA). The Tei index was significantly elevated in patients with AA in comparison with control subjects and patients with CA (AA 0.54 ± 0.13, control 0.40 ± 0.09, CA 0.44 ± 0.10, P < .05 AA vs control and CA). No significant differences were observed between control subjects and patients with CA with respect to mitral flow-derived variables, TDI parameters, and the Tei index. Conclusion Disease activity has a significant impact on LV performance in patients with acromegaly. In subjects with active disease, diastolic dysfunction and beginning impairment of overall LV performance are present. In patients with cured/well-controlled disease, systolic and diastolic function appear normal. (Am Heart J 2002;144:538-43.)     

Chronotropic incompetence and its relation to exercise intolerance in hypertrophic cardiomyopathy

Background

Diminished functional capacity is common in hypertrophic cardiomyopathy (HCM), although the underlying mechanisms are complicated. We studied the prevalence of chronotropic incompetence and its relation to exercise intolerance in patients with HCM.

Methods

Cardiopulmonary exercise testing was performed in 68 patients with HCM (age 44.8 ± 14.6 years, 45 males). Chronotropic incompetence was defined by chronotropic index (heart rate reserve)/(220-age-resting heart rate) and exercise capacity was assessed by peak oxygen consumption (peak Vo₂).

Results

Chronotropic incompetence was present in 50% of the patients and was associated with higher NYHA class, history of atrial fibrillation, higher fibrosis burden on cardiac MRI, and treatment with β-blockers, amiodarone and warfarin. On univariate analysis, male gender, age, NYHA class, maximal wall thickness, left atrial diameter, peak early diastolic myocardial velocity of the lateral mitral annulus, history of atrial fibrillation, presence of left ventricular outflow tract obstruction (LVOTO) at rest, and treatment with beta-blockers were related to peak Vo₂. Peak heart rate during exercise, heart rate reserve, chronotropic index, and peak systolic blood pressure were also related to peak Vo₂. On multivariate analysis male gender, atrial fibrillation, presence of LVOTO and heart rate reserve were independent predictors of exercise capacity (R² = 76.7%). A cutoff of 62 bpm for the heart rate reserve showed a negative predictive value of 100% in predicting patients with a peak Vo₂ < 80%.

Conclusions

Blunted heart rate response to exercise is common in HCM and represents an important determinant of exercise capacity.     

Change of left ventricular geometric pattern after 1 year of antihypertensive treatment: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study

Background Patients with hypertension have different types of left ventricular (LV) geometry, but the impact of blood pressure (BP) reduction on LV geometry change during antihypertensive treatment remains unclear. Methods Two-dimensional and M-mode echocardiograms were recorded at baseline in 853 unmedicated patients with stage II to III hypertension and LV hypertrophy determined by electrocardiography (Cornell voltage duration ≥2440 mV × ms or modified Sokolow-Lyon criteria: SV1 + RV5/RV6 >38 mV) after 14 days of placebo treatment. Follow-up echocardiography was done after 1 year of blinded treatment with either losartan or atenolol, in some cases supplemented with thiazide and calcium antagonist to reach target a BP of 140/90 mm Hg. Results Baseline systolic/diastolic BP were reduced from 174 ± 20/95 ± 11 to 151 ± 19/84 ± 11 mm Hg. LV mass was reduced from 234 ± 56 to 207 ± 51 g and relative wall thickness from 0.41 ± 0.07 to 0.38 ± 0.06 (all P < .001). Prevalence of concentric LV hypertrophy decreased from 24% to 6%, eccentric LV hypertrophy from 46% to 37%, and concentric LV remodeling from 10% to 6%; normal geometry increased from 20% to 51%. A shift toward lower LV mass and relative wall thickness was found, as approximately 73% of those with concentric LV remodeling at baseline shifted to normal geometric pattern, whereas only 7% of those with normal pattern at baseline shifted to concentric LV remodeling. Of patients with concentric LV hypertrophy at baseline, 34% shifted to eccentric LV hypertrophy, whereas only 3% with eccentric LV hypertrophy at baseline had concentric LV hypertrophy. Furthermore, multiple regression analysis showed that Doppler stroke volume reduction was a significant correlate of LV mass reduction (β = 0.108, P < .001) independent of BP, heart rate change, and assigned drug treatment. Conclusions Antihypertensive treatment reduces LV mass and decreases the prevalence of LV hypertrophy and concentric LV remodeling. Additional control of Doppler stroke volume potentiates the effect of BP reduction on LV mass regression independent of the BP reduction per se. (Am Heart J 2002;144:1057-64.)     

Associations between angiotensinogen gene variants and left ventricular mass and function in the HyperGEN study

Background The angiotensinogen M235T polymorphism is positively associated with plasma angiotensinogen, hypertension, and coronary heart disease. However, the association of M235T polymorphism with left ventricular (LV) mass and function is not well defined at the population level. We investigated whether 2 tightly linked polymorphisms of angiotensinogen gene, M235T and G-6A, are associated with LV mass and function in a large population-based sample, composed mostly of patients with hypertension. Methods Two-dimensional guided M-mode and pulsed Doppler scan echocardiograms were performed in 605 participants. The angiotensinogen M235T was analyzed with a standard polymerase chain reaction test, and the G-6A variant was measured with mass spectrophotometry. Results The association of angiotensinogen gene to LV mass and LV mass indexed to body surface area (LVMI) differed significantly between subjects with normotensive and hypertensive conditions with respect to the direction of association (P < .005). The methionine-threonine/threonine-threonine genotype was negatively associated with LV mass and LVMI in patients with hypertension after adjustment for blood pressure, antihypertensive medication use, weight, and other covariates (P < .001), and patients with normotensive conditions with the methionine-threonine/threonine-threonine genotype had higher LV mass and LVMI (P = .04, for LV mass; P = .14, for LVMI). The association in patients with normotensive conditions was not influenced by blood pressure but was partly confounded by weight. Conclusion Variation in the angiotensinogen gene was modestly associated with LV mass independently of covariates in patients with hypertensive conditions. The direction of the association was opposite to that observed in patients with normotensive conditions, probably because of the influence of other risk factors or antihypertensive medication use or both. (Am Heart J 2002;143:854-60.)     

Peripheral endothelium-dependent flow-mediated vasodilatation is associated with left ventricular mass in older persons with hypertension

Background Increased left ventricular (LV) mass is associated with greater cardiovascular disease risk. Recent studies have also shown an association of increased LV mass with attenuated endothelium-dependent coronary flow reserve. Less is known about the association between LV mass and endothelium-dependent flow-mediated dilatation (FMD) in peripheral arteries, a noninvasive measure of endothelial function. Methods Sixty-two subjects with untreated mild hypertension, aged 55 to 75 years and otherwise healthy, were examined. Resting blood pressure was obtained by the average of 4 to 5 visits, each at least 1 week apart. LV mass was determined from magnetic resonance imaging and was indexed by body surface area, height and height^2.7. Body composition was assessed with dual energy x-ray absorptiometry. FMD was measured as the percent change of brachial artery diameter during reactive hyperemia by use of high-resolution ultrasound. Results Median LV mass index was 63 g/m² (interquartile range, 58-73). In bivariate analysis, LV mass was correlated to lean body mass (r = 0.63, P < .001), diastolic blood pressure (r = 0.35, P < .01), and FMD (r = −0.27, P < .05). In multivariate analysis, 44% of the variance in log-LV mass was explained by lean body mass. An additional 6% of the variance was explained by FMD (P < .05). For each 1% point decrease in FMD, LV mass increased by 1.1%. Conclusions In addition to the expected influences of body size, impairment of brachial artery FMD was independently related to LV mass in elderly subjects with mild hypertension who did not yet have LV hypertrophy. Whether mild hypertension is the common mechanism linking LV mass and endothelial function has yet to be determined. (Am Heart J 2002;144:39-44.)     

Improvements in blood rheology after cardiac rehabilitation and exercise training in patients with coronary heart disease

Objectives Our purpose was to examine the effect of cardiac rehabilitation and exercise training on blood rheology in patients with coronary heart disease (CHD). Although increased blood and plasma viscosity have been associated with an increased risk of CHD, the effects of cardiac rehabilitation and exercise training on blood rheology in patients with CHD are uncertain. Methods We assessed whole blood effective viscosity (μ), hematocrit standardized blood viscosity (μ₄₅), red blood cell transport efficiency (τ_rbc), and plasma viscosity (PV) in 23 nonsmoking patients with CHD before and after a phase II cardiac rehabilitation and exercise training program. In addition, we compared the group data with the data of a healthy reference group of 10 subjects. Results Patients with CHD had significantly elevated μ (3.35 ± 0.35 cp vs 3.06 ± 0.19 cp, P < .05) and μ₄₅ (3.51 ± 0.29 cp vs 3.12 ± 0.06 cp, P < .001) and reduced τ_rbc (12.7% ± 1.0% · cp^-1 vs 14.2% ± 0.7% · cp^-1, P < .001) compared with healthy subjects. After rehabilitation, patients with CHD had reductions in PV (1.85 ± 0.18 cp vs 1.77 ± 0.11 cp, P < .01) and μ₄₅ (3.58 ± 0.22 cp vs 3.39 ± 0.22 cp, P < .0001) and an increase in τ_rbc (12.4% ± 0.8% · cp^-1 vs 13.2% ± 0.9% · cp^-1, P < .0001). Conclusions Cardiac rehabilitation improves blood rheology in patients with CHD by reducing μ₄₅ and PV and elevating τ_rbc. These improvements may contribute to the increased functional capacity and reduced morbidity and mortality that is associated with participation in cardiac rehabilitation and exercise programs. (Am Heart J 2002;143:349-55.)     

Elevated soluble P-selectin levels are associated with an increased risk of early adverse events in patients with presumed myocardial ischemia

Background Cell adhesion molecules (CAMs) play a pivotal role in the interactions between leukocytes, platelets, and vascular endothelium. Soluble CAMs (sCAMs) are shed from cell surfaces and reflect cellular activation. Elevated levels of sCAMs have been reported in the acute coronary syndromes. We hypothesized, therefore, that sCAMs might prove of prognostic value in patients with acute chest pain presumed to be the result of myocardial ischemia. Methods One hundred twenty-six consecutive patients with chest pain, thought clinically to represent myocardial ischemia, were studied prospectively. Soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin) and P-selectin (sP-selectin) levels were assayed at presentation, as were cardiac troponin I (cTnI) and creatine kinase-MB_mass (CK-MB_mass). The primary study end point was the occurrence of a serious cardiac event (SCE) during the index admission or the subsequent 3 months. Results sP-selectin and cTnI levels were significantly higher among patients who had an early SCE (P = .006 and P < .001, respectively). Both remained independently predictive (P < .001) in a multivariate regression equation. The other independent predictor was a history of vascular disease (P < .05). No other markers were significant predictors of early outcome. Conclusion Elevated sP-selectin levels, but not those of other sCAMs, are predictors of early adverse events in patients with chest pain presumed caused by myocardial ischemia. Their utility in predicting the outcome of individual patients is, however, limited. (Am Heart J 2002;143:235-41.)     

Evaluation of platelets in heart failure: is platelet activity related to etiology,functional class,or clinical outcomes?

Objectives We sought to determine whether platelet activity in patients with heart failure is related to an ischemic versus nonischemic etiologic condition, clinical disease severity, or adverse clinical outcomes. Background Platelet activity may affect outcome in patients with heart failure. A prospective evaluation of the relation of baseline platelet function to etiologic condition, New York Heart Association (NYHA) class, and clinical outcomes has not been previously reported. Methods Ninety-six consecutive outpatients with ambulatory heart failure with an ejection fraction <0.40 and NYHA Class II to IV symptoms who presented to the Duke Heart Failure Clinic and 14 healthy control subjects formed the study groups. Baseline characteristics and blood analyzed for thromboxane (Tx) B₂, 6-keto PGF_1α, platelet contractile force, adenosine diphosphate/collagen shear-induced closure time, whole blood aggregation and CD41, CD31, CD62p, and CD51/CD61 by flow cytometry were determined. Survival status and hospitalizations were determined in the heart failure patient cohort. Results The median age of patients was 65 years (22% female, 64% white). An ischemic etiologic condition was present in 61% of patients. The population had mild to moderate heart failure: NYHA class I (1%), II (41%), III (46%), and IV (12.5%) and severe ventricular dysfunction (median ejection fraction = 0.20). There were 39 clinical events (7 deaths, 3 cardiac transplants, 29 other first hospitalizations) in 305 median days of observation. Platelet activity, indicated by whole blood aggregation with 5 μmol adenosine diphosphate (P = .04) and Tx B₂ (P = .01), was higher in patients with heart failure. Whole blood aggregation was greater than the 90th percentile in 22% of patients with heart failure versus 7% of control subjects. Platelet function did not differ for any of the markers between the ischemic and nonischemic groups and was not affected by antecedent aspirin. There was no relation of NYHA class or the occurrence of events to platelet activity. Conclusion Platelet activity is heightened in 22% of outpatients with stable heart failure symptoms and is not affected by antecedent aspirin therapy. The degree of platelet activation is similar in ischemic and nonischemic patients with heart failure and is not related to clinical disease severity. Current methods to assess platelet activation do not appear to predict outcome. (Am Heart J 2002;143:1068-75.)     

Prognostic value of a negative stress echocardiographic study in diabetic patients

Background Diabetic patients have increased cardiovascular morbidity and mortality. We compared the long-term prognostic value of a negative, nonischemic stress echocardiogram in patients with and without diabetes. Methods Two hundred thirty-six consecutive subjects who had stress echocardiography and who were negative for inducible ischemia were included in the study. Baseline cardiac risk factors and cardiac events (cardiac death, nonfatal myocardial infarction, and coronary revascularization) were identified. Results Follow-up was obtained in 233 subjects for a mean duration of 25 months. There were 144 nondiabetic and 89 diabetic patients. At baseline, the diabetic group had a significantly higher incidence of hypertension, hyperlipidemia, and history of coronary artery disease but had a lower incidence of smoking (P < .05). Diabetic patients had a significantly higher incidence of cardiac events (19% vs 9.7%, P = .03) and worse event-free survival (P = .03). There were more nonfatal myocardial infarctions in the diabetic group (6.7% vs 1.4%, P < .05) and a trend toward a higher proportion of hard events (myocardial infarction and cardiac death) in diabetic patients (12.4% vs 5.6%, P = .11). The hard event rate per year of follow-up was 2.7% in nondiabetic and 6.0% in diabetic patients. In diabetic patients, a history of coronary artery disease was the only predictor of cardiac events (R = 0.18, P < .05). Conclusion Compared with nondiabetic patients, diabetic patients with negative stress echocardiograms are at greater risk for cardiac events. This appears to be due to a higher prevalence of established coronary disease in diabetic patients. (Am Heart J 2002;143:163-8.)     

The cardiac component of cardiac cachexia

Background Recent evidence suggests the importance of noncardiac mechanisms in the genesis of the syndrome of cardiac cachexia. This raises the question of the relative role of the heart itself in this syndrome. This study sought to assess the cardiac dimensions, mass, and function and changes in these parameters over time in patients with chronic heart failure with and without cachexia. Methods Doppler echocardiography was performed in 28 patients with nonedematous weight loss (>7.5% over a period of >6 months) compared with 56 matched patients without weight loss in a ratio of 1:2 (age 71 ± 13 vs 67 ± 8 years, P = .07; New York Heart Association class 2.9 ± 0.7 vs 2.6 ± 0.6, P = .08). In 18 cachectic and 35 noncachectic patients with previous echocardiographic recordings, we analyzed the changes in left ventricular (LV) dimensions and mass over time. Results Cardiac dimensions including LV diastolic (69 ± 9 mm vs 67 ± 13 mm) and systolic cavity diameter (58 ± 11 mm vs 55 ± 15 mm), LV mass (480 ± 180 g vs 495 ± 190 g), and LV systolic and diastolic function including fractional shortening (16% ± 10% vs 18% ± 10%), isovolumic relaxation time (29 ± 22 ms vs 36 ± 27 ms), and E/A ratio (2.7 ± 1.6 vs 3.3 ± 2.9) did not differ between cachectic and noncachectic patients (all P > .1). By analyzing changes in LV mass over time, we found an increase (>20%) in 2 (11%) cachectic and 14 (40%) noncachectic patients and a decrease in LV mass (>20%) in 9 (50%) cachectic and 8 (23%) noncachectic patients (χ² test, P < .05). Conclusions Although no specific cardiac abnormality could be detected echocardiographically in cachectic patients compared with patients with noncachectic chronic heart failure in a cross-sectional study, over time a significant loss of LV mass (>20%) occurs more frequently in patients with cardiac cachexia. (Am Heart J 2002;144:45-50.)