Abstract: BACKGROUND: Left ventricular (LV) remodeling occurs in the remote normal region in the LVs after myocardial infarction (MI) and is closely involved in heart failure. METHODS: We assessed myocardial oxygen consumption using a clearance rate constant K (mono) for the time activity curves of (11)C-acetate in 15 patients with a prior anterior wall MI, 8 with a prior inferior wall MI, and 10 age-matched normal control subjects. LV end-systolic volume index (ESVI) was determined by echocardiography. RESULTS: The LVESVI was significantly greater in patients with an anterior and inferior MI than in control subjects. The heart rate systolic pressure product did not differ among the groups. K (mono) in the remote normal region in patients with an anterior MI was significantly less than that in the corresponding area in control subjects (0.055 +/- 0.005 vs 0.065 +/- 0.008 min(-1), P < .001). K (mono) in the remote normal region in those with an inferior MI was also significantly less compared with controls (0.054 +/- 0.007 vs 0.069 +/- 0.010 min(-1), P < .01). CONCLUSION: In patients with a prior MI and LV remodeling, myocardial oxidative metabolism is apparently impaired in the remote normal region where augmented myocardial energy production is needed against the increased end-systolic wall stress caused by LV dilatation.

Abstract: BACKGROUND: It is unknown whether the association of anemia with elevated plasma levels of B-type and atrial natriuretic peptides (BNP and ANP) is mediated by the hemodynamic effects of anemia. METHODS AND RESULTS: The study group comprised 237 consecutive patients (BNP, median [interquartile range], 28.3 [9.5-77.1] pg/ml; ANP, 17.8 [8.5-39.0] pg/ml) undergoing determination of hemoglobin (Hb) and natriuretic peptide levels and cardiac catheterization for evaluation of coronary artery disease (CAD). Hb correlated with BNP (r=-0.36, p<0.001) and ANP (r=-0.35, p<0.001). Patients with anemia (Hb <12 g/dl for females; <13 g/dl for males, n=63) were more likely to be older with reduced body mass index and renal function, greater severity of CAD and to have higher heart rate, mean pulmonary capillary wedge pressure, and cardiac output. Anemia was a significant predictor for elevated (>third quartile value) natriuretic peptide levels and the predictive value remained significant after adjustment for other predictors, including increased left ventricular end-diastolic pressure and differences in clinical and hemodynamic variables between patients with and without anemia (adjusted odds ratio [95% confidence interval] for elevated BNP and ANP levels, 7.39 [2.76-19.8] and 2.56 [1.08-6.07], respectively). CONCLUSION: Anemia is an independent predictor for elevated natriuretic peptide levels in patients with known or suspected CAD.

Abstract: OBJECTIVE: To assess the relationship between depression, reduced heart rate (HR) variability, and altered HR dynamics among patients with end-stage renal disease who are receiving hemodialysis (HD) therapy. METHODS: We analyzed the 24-hour electrocardiograms of 119 outpatients receiving chronic HD. HR variability was quantified with the standard deviation of normal-to-normal R-R intervals, the triangular index, and the powers of the high- (HF), low- (LF), very-low (VLF), and ultra-low frequency (ULF) components. Nonlinear HR dynamics was assessed with the short-term (alpha(1)) and long-term (alpha(2)) scaling exponents of the detrended fluctuation analysis and approximate entropy. The depression level was assessed using the Beck Depression Inventory, Second Edition (BDI-II). HR variability and dynamics measurements were compared by gender, diabetes, and depression with adjustment for age and serum albumin concentration. RESULTS: Most indices of HR variability and dynamics were negatively correlated with age, serum albumin concentration, depression score, and were lower in women and patients with diabetes. The alpha(2) was inversely associated with these variables. Depressed men had significantly lower HF, LF, VLF, and marginally lower ULF than nondepressed persons after adjustment for diabetes and other covariates; no difference in depression was observed in women. The alpha(2) showed marginally significant difference in depression independent from gender and diabetes. CONCLUSIONS: Among the patients who received HD, depression is associated with reduced HR variability and loss of fractal HR dynamics. However, the influence of depression on HR variability may vary by gender and physiological backgrounds. Further prospective studies are necessary to confirm their association with poor prognosis.

Abstract: Heart failure is defined as the pathologic state in which the heart is unable to pump blood at a rate required by the metabolizing tissues or can do so only with an elevated filling pressure. Heart failure in adults most frequently results from the inability of the left ventricle to fill (diastolic performance) or eject (systolic performance) blood. The severity of heart failure and its prognosis are more closely related to the degree of diastolic filling abnormalities than the ejection fraction, which underscores the importance of understanding the mechanisms of diastolic abnormalities in heart failure.

Abstract: The difference between peak mitral annular velocity during early diastole (Ea) and the propagation velocity of left ventricular (LV) early diastolic filling flow (Vp) obtained using Doppler imaging as LV relaxation parameters was not fully elucidated. Thus, this issue was investigated in 117 patients with suspected coronary artery disease. During cardiac catheterization, LV volumes, the LV relaxation time constant Tp, and inertia force of late systolic aortic flow were obtained. Ea significantly and closely correlated with Tp (r = -0.70, p <0.0001) and significantly but weakly correlated with LV ejection fraction (r = 0.37, p <0.0001) and inertia force (r = 0.34, p = 0.0002). Conversely, Vp significantly and closely correlated with both LV ejection fraction (r = 0.66, p <0.0001) and inertia force (r = 0.72, p <0.0001) and significantly but weakly correlated with Tp (r = - 0.35, p = 0.0001). In conclusion, Ea and Vp reflect different aspects of LV behavior from end-systole to early diastole. Ea can be used to index LV relaxation, whereas Vp might not be a proper parameter of LV intrinsic relaxation because it is significantly dependent on LV systolic function and LV chamber size at end-systole. Both parameters are not interchangeable as those of LV early diastolic function. Vp may be a noninvasive parameter of LV elastic recoil.

Abstract: This article reviews the available evidence from observational studies concerning the effect of statin therapy in patients who have heart failure and a preserved ejection fraction (diastolic heart failure). Observational studies suggest that statin therapy is associated with lower mortality in patients who have diastolic heart failure. These results emphasize the need for a randomized study of the effect of statins in diastolic heart failure. Until the results of such studies are available, it is recommended to use statins in patients with diastolic heart failure who otherwise have an indication for statin therapy.

Abstract: We investigated the contribution of a dilated right-sided heart to roentgenographic cardiomegaly in patients with heart failure (HF) and a normal ejection fraction (EF; diastolic HF) and those with HF and a decreased EF (systolic HF). We compared the cardiothoracic ratio (CTR) on upright chest roentgenograms and major- and minor-axis dimensions of the 4 cardiac chambers on echocardiograms in patients with HF and a normal EF (> or =0.50, n = 35) and those with a decreased EF (<0.50, n = 37) and examined the correlation between the CTR and cardiac chamber dimensions. The CTR did not differ between patients with normal and decreased EF values (0.58 +/- 0.07 vs 0.60 +/- 0.06, p = 0.26). Left-side cardiac chamber dimensions were substantially smaller in patients with a normal EF than in those with a decreased EF (left ventricular minor-axis dimension, 4.4 +/- 0.7 vs 5.8 +/- 0.8 cm, p <0.001). In contrast, right-side cardiac chamber dimensions were generally similar between groups. The CTR correlated with major-axis dimensions of the right ventricle and right atrium (p <0.01 for the 2 comparisons), but not with the left-side cardiac chamber dimensions (all p values >0.05). In conclusion, the CTR predominantly reflects right- rather than left-sided heart size in patients with HF. Right-sided heart size is similar between patients with normal and decreased EF values. Thus, despite the substantial difference in left ventricular size and EF, there is substantial overlap in the CTR between patients with diastolic and systolic HFs and the CTR is unable to discriminate between groups.

Abstract: Heart failure (HF) has traditionally been divided into HF with a reduced ejection fraction (EF; systolic HF) and HF with a normal EF (diastolic HF). Both groups have reductions in exercise tolerance, neurohumoral activation, and abnormal left ventricular (LV) filling dynamics and impaired relaxation. Although the normal EF indicates that pump performance is adequately compensated, some of the patients with HF and a normal EF have reduced longitudinal systolic velocity indicating cardiac muscular contractile dysfunction. Regardless of EF, the severity of HF and its prognosis and degree of exercise intolerance are closely related to the degree of diastolic filling abnormalities. Patients with HF and a reduced EF have ventricular dilatation and elongated myocytes, whereas patients with HF and a normal EF do not. Thus, patients with HF have diastolic abnormalities regardless of EF and many patients with HF and a normal EF have contractile abnormalities despite preserved systolic pump performance. Heart failure with a normal EF and a reduced EF differs in the systolic LV pump performance and the type of remodeling. The mechanism of the differing remodeling responses is not known, but aging, sex differences, and diabetes may contribute.

Abstract: Nearly half of patients with heart failure (HF) have a normal ejection fraction (EF) and have been labeled as having diastolic HF. Diastolic HF is characterized by a normal EF, a variable amount of concentric left ventricular hypertrophy, and abnormal diastolic function. Differentiating diastolic HF from HF with a reduced EF (systolic HF) is important because these two forms of HF have different pathophysiology and thus might require different therapeutic approaches. Nevertheless, patients with diastolic HF and those with systolic HF have similar clinical symptoms and signs. Thus, clinical history and physical examination do not differentiate between diastolic and systolic HF. There is accumulating evidence that diastolic dysfunction is related to the severity of HF and prognosis regardless of EF. Thus, it is important to evaluate both systolic and diastolic function not only to differentiate between diastolic and systolic HF but also to identify high-risk patients.

Abstract: Patients with an impaired relaxation pattern of Doppler left ventricular filling may have elevated or normal plasma B-type natriuretic peptide (BNP) levels. We hypothesized that elevated BNP levels occur in patients whose left atrial pressure increases after exercise. We examined the relationship between BNP levels and left ventricular filling pressure at rest and immediately after maximal exercise, estimated by Doppler tissue imaging, in 80 patients undergoing exercise echocardiography and showing impaired relaxation pattern. The ratio of early diastolic mitral inflow to annular velocities at rest did not correlate with BNP (r = 0.13, P = .23). In contrast, ratio of early diastolic mitral inflow to annular velocities after exercise correlated with BNP (r = 0.57, P < .001). Ratio of early diastolic mitral inflow to annular velocities after exercise greater than 9.9 discriminated patients with BNP greater than 100 pg/mL (n = 16) from those with BNP less than 100 pg/mL (n = 64) with a sensitivity of 75% and a specificity of 84%. In conclusion, elevated left ventricular filling pressure after maximal exercise predicts increased BNP levels in patients with impaired relaxation pattern.

Abstract: BACKGROUND: No therapy has been shown to improve survival in heart failure (HF) with a normal ejection fraction (EF). There are plausible reasons to hypothesize that statins may be of benefit in HF with a normal EF. METHODS AND RESULTS: We evaluated 137 patients with HF and an EF > or =0.50. The effect of treatment received at study entry on survival was determined. During a follow-up of 21+/-12 months, 20 deaths were observed. Treatment with an ACE inhibitor or receptor blocker, beta-blocker, or calcium blocker had no significant effect on survival. In contrast, treatment with a statin was associated with a substantial improvement in survival (relative risk of death [95% CI] 0.22 [0.07 to 0.64]; P=0.006). Patients receiving statins had higher baseline LDL cholesterol than those not receiving statins (153+/-45 versus 98+/-33 mg/dL, P<0.01). After statin therapy, LDL cholesterol levels fell to a similar level (101+/-32 mg/dL) as in patients not receiving statins (98+/-33 mg/dL). After adjustment for differences in baseline clinical variables between groups (hypertension, diabetes, coronary artery disease, and serum creatinine), statin therapy was associated with lower mortality (adjusted relative risk of death [95% CI] 0.20 [0.06 to 0.62]; P=0.005). Similarly, after propensity matching, statin therapy was associated with improved survival (log-rank 6.12; P=0.013) and a trend toward improved survival without cardiovascular hospitalization (log-rank 3.02; P=0.082). CONCLUSIONS: Statin therapy may be associated with improved survival in patients with HF and a normal EF.

Abstract: Patients with aortic stenosis (AS) may remain asymptomatic with good prognoses for many years but have poor prognoses once they develop symptoms. Because the presence of symptoms is subjective, B-type natriuretic peptide (BNP) may provide a more objective indication of the prognoses of patients with AS. We evaluated 124 patients with AS (valve area <1.2 cm(2)) with clinical evaluation, Doppler echocardiography, and BNP assessment and obtained up to 2 years of follow-up without valve replacement. Patients with syncope, angina, and/or heart failure were considered to have symptoms. The 24 patients without symptoms had lower BNP levels (187 +/- 193 pg/ml) than the 100 patients with symptoms (930 +/- 928 pg/ml, p <0.001). BNP indicated symptom status, with an area under the receiver-operating characteristic curve of 0.87 (p <0.001). The optimal discrimination of symptoms occurred with BNP >190 pg/ml. Survival was significantly influenced by the presence of symptoms (relative risk [RR] 7.5, p <0.01) and BNP tertile (RR 2.9, p <0.001). The 1-year mortality rate without surgery was 6% for BNP <296 pg/ml, 34% for BNP 296 to 819 pg/ml, and 60% for BNP >819 pg/ml. No patients with BNP <100 pg/ml died. The combination of BNP and symptoms provided a better prediction of survival than symptoms alone (chi-square 13.6, p <0.001). BNP significantly (RR 2.8, p <0.01) influenced survival after correction for other univariate predictors (coronary artery disease, symptoms, functional class, ejection fraction, and aortic valve area). In conclusion, elevated BNP indicates progressively worse survival in patients with AS treated medically. Thus, the measurement of BNP supplements the evaluation of symptoms in determining the prognoses of patients with AS.

Abstract: BACKGROUND: Although decreased heart rate variability (HRV) is an independent predictor of death in various populations, its prognostic value in patients with end-stage renal disease on chronic haemodialysis is unknown. METHODS: We prospectively studied 120 chronic haemodialysis patients (age 61+/-11 years; males 51%; diabetics 38%; duration of haemodialysis therapy 50+/-114 months) who underwent 24 h electrocardiography at baseline for analysis of time- and frequency-domain HRV. RESULTS: All HRV measures in the patients were significantly reduced compared with those obtained from 62 age-matched healthy subjects. During a follow-up period of 26+/-10 months, 21 patients died (17.5%); 10 from cardiac causes and 11 from non-cardiac causes (seven fatal strokes and four other causes). A Cox proportional hazards model revealed that, of the HRV measures, decreases in the triangular index (TI), very-low-frequency (0.0033-0.04 Hz) power, ultra-low-frequency (<0.0033 Hz) power (ULF) and the ratio of low-frequency (0.04-0.15 Hz) power to high-frequency (0.15-0.4 Hz) power had significant predictive value for cardiac death. None of the HRV measures, however, had predictive value for non-cardiac death, including stroke death. Even after adjustment for other univariate predictors including age, diabetes, serum albumin and coronary artery disease, the predictive value of decreased TI and ULF remained significant-adjusted relative risk (95% confidence interval) per 1 SD decrement of TI and ULF, 3.28 (1.08-9.95) and 1.92 (1.01-3.67), respectively. CONCLUSIONS: Decreases in some HRV measures, particularly those reflecting long-term variability, are independent predictors of cardiac death in chronic haemodialysis patients.

Abstract: BACKGROUND: Although altered nonlinear heart rate dynamics predicts death in patients with coronary artery disease (CAD), its prognostic value in chronic hemodialysis patients with CAD is unknown. METHODS: We analyzed 24-hour electrocardiogram for nonlinear heart rate dynamics and heart rate variability in a retrospective cohort of 81 chronic hemodialysis patients with CAD. RESULTS: During a follow-up period of 31 +/- 20 months, 19 cardiac and 8 noncardiac deaths were observed. Cox hazards model, including diabetes, left ventricular ejection fraction, and the number of diseased coronary arteries, revealed that abnormal alpha2 (defined as both increase and decrease in alpha2 because of its J curve relationship with cardiac mortality), decreased approximate entropy and decreased heart rate variability (triangular index and ultra-low frequency power) were significant and independent predictors of cardiac death. No significant and independent predictive power for noncardiac death was observed in either the heart rate dynamics or the heart rate variability measures. The predictive power of alpha2 and approximate entropy was independent of that of triangular index and ultra-low frequency power. Combinations of two categories of measures improved the predictive accuracy; overall accuracy of approximate entropy + ultra-low frequency power for cardiac death was 87%. CONCLUSION: Altered nonlinear heart rate dynamics are independent predictors of cardiac death in chronic hemodialysis patients with CAD and their combinations with decreased heart rate variability provide clinically useful markers for risk stratification.

Abstract: The R-R interval of the electrocardiogram during atrial fibrillation (AF) appears absolutely irregular. However, the Poincaré plot of the R-R interval reveals a sector shape of distribution that is unique to AF. Furthermore, the height of lower envelope (LE1.0) of the distribution and the degree of scatter above the envelope (scattering index) may reflect the refractoriness and concealment of atrioventricular (AV) conduction, respectively. We previously observed that both the LE1.0 and scattering index show clear circadian rhythms in patients with chronic AF and that the rhythms are blunted in those with congestive heart failure and chronic AF. In the present study, we examined if the blunted circadian rhythm of the AV conduction has prognostic value in patients with chronic AF. We studied a retrospective cohort of 120 patients who underwent 24h Holter monitoring at baseline. During an observation period of 33 +/- 16 mon, there were 25 deaths (21%) including 13 cardiac and 8 stroke deaths. All patients showed significant circadian rhythms in both LE1.0 and scattering index with acrophases occurring at night; however, patients dying subsequently from cardiac causes, but not those from fatal stroke were blunted in the circadian rhythms (the amplitudes were < 55% of those in surviving patients). Furthermore, the reduced circadian amplitude of scattering index was an increased risk for cardiac death even after adjustment of coexisting cardiovascular risks [adjusted relative risk (95% confidence interval) per 1-SD decrement, 4.24 (1.54-11.6)]. When patients were divided by the circadian amplitude of the scattering index of 36.5 msec (mean minus 1-SD), the 5yr cardiac mortality below and above the cutoff was 57 and 6%, respectively (log-rank test, p < 0.001). We conclude that the blunted circadian rhythm of AV conduction is an independent risk for cardiac death in patients with chronic AF.

Abstract: STUDY OBJECTIVES: We examined whether autonomic functions assessed by heart rate variability (HRV) during standardized head-up tilt testing (HUTT) predict risk for death in stable patients with coronary artery disease (CAD). DESIGN AND SETTING: Retrospective cohort study in medium-sized university general hospital. MEASUREMENTS AND RESULTS: In a cohort of 250 patients with CAD who were undergoing elective coronary angiography, we analyzed HRV during standardized HUTT under paced breathing with discontinuation of treatment with all medications. During a subsequent mean follow-up period of 99 months, there were 13 cardiac deaths and 12 noncardiac deaths. Cox regression analysis adjusted for cardiovascular risks revealed that increased postural change (supine to upright) in the power of low-frequency component (LF) power predicted an increased risk for cardiac death (relative risk [per 1-ln ms(2) increment], 4.36; 95% confidence interval, 1.64 to 11.6), while neither the high-frequency component nor its response to HUTT predicted any form of death. When the patients were trichotomized by the level of postural LF change (large drop, < or = - 0.6 ln[ms(2)]; small drop and rise, > 0 ln[ms(2)]), the three groups did not differ in terms of clinical features or CAD severity at baseline or coronary interventions during the follow-up period; however, the 8-year cardiac mortality rates were 0%, 6%, and 12%, respectively (p = 0.008 [log rank test]). Additionally, the difference was enhanced when analyzed excluding 64 patients who had been treated with a beta-blocker during the follow-up period (0%, 7%, and 15%, respectively; p = 0.006 [log rank test]). CONCLUSIONS: The postural response of HRV predicts the risk for death in patients with CAD. Postural LF increase (LF rise), in particular, is an independent risk factor for cardiac death.