Heart Failure Subjects Research Articles

Cardiovascular effects of I/D angiotensin-converting enzyme gene polymorphism in healthy subjects. Findings after follow-up of six years

Background — An increasing number of studies with conflicting results regarding the association between angiotensin-converting enzyme (ACE) gene deletion polymorphism and cardiovascular disease has recently been published. The present prospective long-term study was conducted to evaluate whether the DD genotype could also be associated with a higher prevalence of hypertension in healthy subjects over 6 years of follow-up.We also investigated the effects of the ACE-I/D genotypes on diastolic function by echocardiography in healthy subjects without any risk factors and any events after 6 years of follow-up.Methods — Population: 684 healthy volunteers (aged 25-55 years) normotensive and free of cardiovascular diseases, with acceptable echocardiographic window were enrolled. All subjects had to have a normal electrocardiogram (ECG) and echocardiogram (ECHO) at entry.All subjects have undergone a complete physical examination, 12-lead ECG and ECHO; DNA analysis and serum cholesterol have been performed on venous blood samples. All subjects underwent a clinical evaluation each year for the 6-year duration of the study. In addition, 275 subjects without any risk factors underwent an ECHO every year of the follow-up, to check the influence of genotypes on myocardial diastolic performances.Results — All 684 subjects completed 6 years of follow-up.We obtained 3 genetically distinct groups: 1) the ACE-DD group (n = 225, 80 F/145 M, mean age 43.4 ± 7.6 years) with 42 hypertensive subjects (18.3%), 5 heart failure (HF) subjects and 6 subjects with acute coronary syndromes (ACS). There was no association between family history, smoking habit, hypercholesterolaemia and events. 2) the ACE-ID group (n = 335, 116 F/219 M, mean age 43.6 ± 7 years) with16 hypertensive subjects (4.7%) and 3 subjects with ACS. 3) the ACE-II group (n = 124, 45 F/79 M, mean age 42.5 ± 6.9 years) with 2 hypertensive subjects (1.6%) and 1 HF subject.The incidence of hypertension and cardiovascular events, was significantly higher in the ACE-DD (53 cases, 23%) than in the ACE-ID and ACE-II groups (20 and 3 cases, 5.9% and 2.4%, respectively), p = 0.0001.The higher incidence of hypertension was observed in the older age groups (36-45 and 46-55 years) with ACE-DD and ACE-ID genotypes. Moreover, ACE-DD significantly and early affected myocardial diastolic properties in the total group examined, also when stratified for age. There was a reduction of E/A ratio and it was more evident in subjects aged 36-45 and 46-55 years, p = 0.0001.Conclusion — Our data suggest that ACE-DD polymorphism is associated with a higher incidence of hypertension in baseline healthy subjects, irrespective of other risk factors, and appears to affect the diastolic function. These effects were apparent predominantly in the older age groups.

Exercise Intolerance in Adult Congenital Heart Disease

Although some patients with adult congenital heart disease (ACHD) report limitations in exercise capacity, we hypothesized that depressed exercise capacity may be more widespread than superficially evident during clinical consultation and could be a means of assessing risk. Cardiopulmonary exercise testing was performed in 335 consecutive ACHD patients (age, 33+/-13 years), 40 non-congenital heart failure patients (age, 58+/-15 years), and 11 young (age, 29+/-5 years) and 12 older (age, 59+/-9 years) healthy subjects. Peak oxygen consumption (peak VO2) was reduced in ACHD patients compared with healthy subjects of similar age (21.7+/-8.5 versus 45.1+/-8.6; P<0.001). No significant difference in peak VO2 was found between ACHD and heart failure patients of corresponding NYHA class (P=NS for each NYHA class). Within ACHD subgroups, peak VO2 gradually declined from aortic coarctation (28.7+/-10.4) to Eisenmenger (11.5+/-3.6) patients (P<0.001). Multivariable correlates of peak VO2 were peak heart rate (r=0.33), forced expiratory volume (r=0.33), pulmonary hypertension (r=-0.26), gender (r=-0.23), and body mass index (r=-0.19). After a median follow-up of 10 months, 62 patients (18.5%) were hospitalized or had died. On multivariable Cox analysis, peak VO2 predicted hospitalization or death (hazard ratio, 0.937; P=0.01) and was related to the frequency and duration of hospitalization (P=0.01 for each). Exercise capacity is depressed in ACHD patients (even in allegedly asymptomatic patients) on a par with chronic heart failure subjects. Lack of heart rate response to exercise, pulmonary arterial hypertension, and impaired pulmonary function are important correlates of exercise capacity, as is underlying cardiac anatomy. Poor exercise capacity identifies ACHD patients at risk for hospitalization or death.

Vasodilator Effect of Endothelin in Cutaneous Microcirculation of Heart Failure Patients

The heart failure syndrome is associated with a reduced vasodilatory capacity in cutaneous microvessels. The aim of this study was to investigate the hypothesis that an altered activity of the endothelin system contributes to this reduction. The skin blood flow was recorded by laser Doppler flowmetry in patients with congestive heart failure and in age- and gender-matched controls without clinical signs of heart failure. The vessels were stimulated by iontophoretic administration of endothelin-1. The involvement of the endothelin(A) receptor was studied by co-administration of a specific antagonist; the role of the endothelin(B) receptor was studied by the administration of the selective agonist sarafotoxin 6c. The plasma levels of endothelin-1, C-reactive peptide and N-terminal-pro-Brain Natriuretic Peptide were elevated in heart failure patients. Unexpected, endothelin-1 induced an endothelin(A) mediated vasodilation. In the heart failure group the dilation was reduced to less than half as compared to control. The response to local warming was reduced in parallel indicating that the attenuation of the response in the heart failure group can be explained by the general decline in vascular reactivity. The response to endothelin(B) receptor stimulation did not differ between the groups. The reduction in endothelin-1 responsiveness is paralleled by a general reduction in microvascular vasodilatory capacity, a phenomenon of increased vascular stiffness in the of heart failure subjects.

Cardiovascular effects of I/D angiotensin-converting enzyme gene polymorphism in healthy subjects. Findings after six years follow up

The present prospective long-term study was conducted to evaluate whether the DD genotype could also be associated with a higher prevalence of hypertension in healthy subjects over 6 years of follow-up. We also investigated the effects of the ACE-I/D genotypes on diastolic function by echocardiographic method in healthy subjects without any risk factors and without any events after 6 years of follow-up. 684 healthy volunteers (aged 25–55 years) with acceptable echocardio-graphic window were enrolled. Physical examination,12-lead ECG, echocardiograms and venous blood samples for DNA analysis were performed. All subjects had a clinical evaluation each year for the 6 year. In addition,275 subjects without any risk factors underwent an ECHO every year of the follow-up, to check the influence of genotypes on myocardial diastolic performances. All 684 subjects completed 6 years of follow up. We obtained 3 genetically distinct groups. ACE-DD group,(n=225,80F/145M,mean age 43.4±7.6 years),had 42 hypertensive subjects (18.3%), 5 heart failure (HF) subjects and 6 subjects with acute coronary syndromes (ACS).There was not association between family history,smoking habit,hypercholesterolemia and events.ACE-ID group: (n=335, 116F/219M, mean age 43.6±7 years),had 16 hypertensive subjects (4.7%),and 3 subjects with ACS. ACE-II group:(n=124,45/79 F/M, mean age 42.5±6.9 years),had 2 hypertensive subjects (1.6%), and 1 HF subject. The incidence of hypertension and cardiovascular events, were significantly higher in ACE-DD (53 cases, 23%) than ACE-ID and ACE-II groups (20 and 3 cases,5.9% and 2.4%, respectively), p=0.0001. The higher incidence of hypertension was observed in the older age groups (36–45 and 46–55 years) with ACE-DD and ACE-ID genotypes. Moreover, ACE-DD significantly and early affected myocardial diastolic properties in the whole examined group, also when stratified for the age. There was a reduction of E/A ratio and it was more evident in subjects aged 36–45 and 46–55 years, p=0.0001.Our data suggest that ACE-DD polymorphism is associated to a higher incidence of hypertension and appears to affect the diastolic function.

?2-mediated glucose production during carvedilol and metoprolol titration in heart failure

Background Metoprolol and carvedilol are commonly used in heart failure (HF). Previous studies in hypertension indicate worsening of insulin sensitivity with metoprolol but not with carvedilol. However in HF, their relative effects on glucose production have not been directly compared. This study compares fasting glucose and β2-mediated glucose production during metoprolol and carvedilol titration in HF patients. Methods From a previous cohort of HF subjects whose metoprolol or carvedilol were titrated to maximally tolerated doses (up to metoprolol 200mg/d or carvedilol 25mg twice daily) over 5 visits, we analyzed (1) fasting glucose and (2) glucose AUC0–180min upon a β2-agonist (terbutaline) infusion in nondiabetic individuals. Results Fasting glucose (mg/dL) in the metoprolol group (n=9) decreased from 91.1±2.6 (baseline) to 86.9±2.0 (end of titration) while it increased from 91.8±3.1 to 95.7±2.6 with carvedilol (n=6) (p=0.0273, ANCOVA for the comparison between groups). AUC0–180 (mmol/L× 180 min) upon terbutaline infusion decreased from 5.6±0.3 to 4.8±0.1 with metoprolol versus from 5.8±0.3 to 5.0±0.1 with carvedilol (p=NS). AUC0–180 for both metoprolol and carvedilol decreases as drug dosages increase (p=0.0006, repeated measures ANOVA), with a trend toward bigger reduction with metoprolol. Conclusions Metoprolol and carvedilol at clinically relevant doses do not impair fasting glucose in HF. As beta blockade increases, β2-mediated glucose production is reduced. Clinical Pharmacology & Therapeutics (2005) 77, P54–P54; doi: 10.1016/j.clpt.2004.12.096

Heart failure with preserved systolic function

At least 30% of patients with congestive heart failure have preserved systolic function in the absence of significant valvular heart disease. These patients have diastolic dysfunction. Patients are frequently older and hypertensive. The rate of hospitalization in these patients is similar to that in patients with systolic dysfunction. Mortality is intermediate between that of patients with systolic dysfunction heart failure and normal subjects. Diagnosis requires a clear demonstration of the presence of the heart failure syndrome, normal systolic function, and the absence of valvular disease that could increase left atrial pressures. The diagnosis is supported by evidence of diastolic dysfunction that, from a practical point of view, will be provided most frequently by tissue Doppler imaging. Few randomized data are available on efficacy of therapeutic approaches. Acute treatment centers on reducing central blood volume with diuretics and nitrates and controlling heart rate, particularly in the setting of atrial fibrillation. Further treatment centers on reversing underlying pathophysiologic changes, particularly left ventricular hypertrophy. Control of hypertension and antagonism of the renin-angiotensin-aldosterone system appear to be promising therapeutic approaches.

Functional impact of rate irregularity in patients with heart failure and atrial fibrillation receiving cardiac resynchronization therapy

Atrial fibrillation (AFib) with a rapid ventricular response may adversely impact cardiac performance, especially in patients with heart failure. However, it remains uncertain whether rhythm irregularity per se has unfavourable effects apart from tachycardia, and whether rate regularization alone can improve heart function. Nine subjects with chronic AFib, atrioventricular nodal block, and symptomatic heart failure (ejection fraction 14-30%) were studied using a pressure-volume catheter. Ventricles were biventricularly paced (RV-apex, LV-lateral wall) at 80 or 120 min(-1) mean rate, using regular or irregular, Poisson-distributed stimulation. At 80 min(-1), ventricular function was similar between the two pacing modes. However, at 120 min(-1), irregular pacing impaired systolic (dP/dt(max): -8.2%, P<0.001) and diastolic function (dP/dt(min): +21%, P<0.001, LV end-diastolic pressure: +26%, P=0.007) compared with regular rate pacing. Contractile function during irregular pacing varied with the ratio of preceding/pre-preceding intercycle (RR) interval (dP/dt(max): 80 b.p.m.: r=0.69; 120 b.p.m.: r=0.74), whereas pre-load had little effect on instantaneous contractility. In heart failure subjects with AFib, RR-interval irregularity worsens cardiac function at elevated but not at normal range heart rate. Overall rate control is most important in these patients while rate regularization of rapid AFib may impart additional benefits.

Evidence against a major role for angiotensin converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation.

To investigate the role of angiotensin-converting enzyme-related carboxypeptidase (ACE2) in angiotensin peptide metabolism in the human coronary circulation. Angiotensin I and angiotensin II, and their respective carboxypeptidase metabolites, angiotensin-(1-9) and angiotensin-(1-7), were measured in arterial and coronary sinus blood of heart failure subjects receiving angiotensin-converting enzyme (ACE) inhibitor therapy and in normal subjects not receiving ACE inhibitor therapy. In addition, angiotensin I, angiotensin II and angiotensin-(1-7) were measured in arterial and coronary sinus blood of subjects with coronary artery disease before, and at 2, 5 and 10 min after, intravenous administration of ACE inhibitor. In comparison with normal subjects, heart failure subjects receiving ACE inhibitor therapy had a greater than 40-fold increase in angiotensin I levels, but angiotensin-(1-9) levels were low (1-2 fmol/ml), and similar to those of normal subjects. Moreover, angiotensin-(1-7) levels increased in parallel with angiotensin I levels and the angiotensin-(1-7)/angiotensin II ratio increased by 7.5-fold in coronary sinus blood. Intravenous administration of ACE inhibitor to subjects with coronary artery disease rapidly decreased angiotensin II levels by 54-58% and increased angiotensin I levels by 2.4- to 2.8-fold, but did not alter angiotensin-(1-7) levels or net angiotensin-(1-7) production across the myocardial vascular bed. The failure of angiotensin-(1-9) levels to increase in response to increased angiotensin I levels indicated little role for ACE2 in angiotensin I metabolism. Additionally, the levels of angiotensin-(1-7) were more linked to those of angiotensin I than angiotensin II, consistent with its formation by endopeptidase-mediated metabolism of angiotensin I, rather than by ACE2-mediated metabolism of angiotensin II.

Role of beta1- and beta2-adrenoceptor polymorphisms in heart failure: a case-control study.

We hypothesised that the polymorphisms of the genes encoding for beta1- and the beta2-adrenoceptors may have a role in the pathogenesis of heart failure (HF). We therefore compared the polymorphisms of the beta1-adrenoceptor gene (Arg389Gly), the beta2-adrenoceptor gene (Arg16Gly, Gln27Glu) and their combinations in patients with HF and normal subjects living in the same area. A total of 256 cases with HF (left ventricular ejection fraction < or = 40%) and 230 normal subjects were enrolled. The beta1- and beta2-adrenoceptor gene polymorphisms were assessed by PCR, followed by restriction enzyme digestion. No differences were observed in the distribution of any of the three genotypes studied in patients with HF and normal subjects. An analysis of the genotype combinations showed a non-significant increase in the risk of HF associated with the Arg389Gly16Gln27 (odds ratio = 1.4; 95%CI 0.5-3.6) and Arg389Gly16 Glu27 (odds ratio = 1.2; 95%CI, 0.5-2.8) homozygous allele combinations. None of the three most common polymorphisms of beta-adrenoreceptors are associated with an increased risk of HF.

Disproportionate increase in prevalence of diabetes among patients with congestive heart failure due to systolic dysfunction

Background Despite new therapies, the prevalence of heart failure continues to escalate. The prevalence of diabetes, a risk factor for heart failure, also continues to rise. To further understand the increasing prevalence of heart failure, we compared trends in the prevalence of diabetes among individuals with diagnosed heart failure versus those in the general population. Methods Fourteen randomized trials between 1989 and 1999 including subjects with heart failure ( n=34,633) were reviewed. For each trial, the enrollment date was used to estimate the yearly prevalence of diabetes among study participants with heart failure. The prevalence of diabetes in the general population was estimated based on United State's Center for Disease Control statistics from 1989 to 1999. The prevalence of diabetes between heart failure subjects and the general population was compared using a two-sample t-test for independent samples with unequal variances. Results The prevalence of diabetes increased from 2.6% to 4.0% from 1989 to 1999 in the general U.S. population. Among patients with heart failure, the prevalence of diabetes increased from 13% to 47%. Diabetes prevalence estimates varied significantly ( p<0.001) between the general population and individuals with heart failure during the study period. Conclusions The rising prevalence of diabetes may partially explain the growing epidemic of heart failure. Increased efforts targeting diabetes and other cardiovascular risk factors are warranted in attenuating the rising prevalence of heart failure.

Biomechanical efficiency is decreased in heart failure during low‐level steady state and maximal ramp exercise

Previous studies of biomechanical efficiency (external work/energy input--Watt/O(2) consumed) in heart failure (HF) using cardiopulmonary exercise testing (CPET) and magnetic resonance spectroscopy (MRS) have had discordant results with increased efficiency by CPET and decreased efficiency by MRS. Compare biomechanical efficiency of HF subjects and normal controls during steady state (SS=35 W for 6 min) and ramp cycle ergometer exercise. The hypothesis was that HF subjects would have impaired biomechanical efficiency that correlated with HF symptoms. Biomechanical efficiency used the actual Vo(2) during exercise and recovery. Gross (Vo(2) above zero), Net (Vo(2) above the resting Vo(2)) and Work (Vo(2) above the unloaded pedaling Vo(2)) efficiencies were calculated. HF subjects had an 18% higher Vo(2) during SS exercise (P=0.029). Biomechanical efficiency was reduced during SS exercise (gross -15%, P=0.019, net -15%, P=0.062, and work -35%, P=0.002). Gross Efficiency during SS exercise had the strongest correlation with HF symptoms (r=0.55). During ramp exercise gross (-26%), net (-10%) and work (-8%) biomechanical efficiency were all reduced (all P<0.05). The slope of the Vo(2)/Watt relationship during ramp exercise had the best correlation with HF symptoms (r=0.46). HF subjects have an increased O(2) cost/Watt during SS and ramp exercise that correlates with HF symptoms of fatigue and breathlessness. Methods to improve biomechanical efficiency in HF subjects by exercise training or medications may improve the symptoms and the impaired exercise capacity associated with HF.

A comparison of oxygen uptake efficiency slope in normal and implant cardiac resynchronization therapy subjects

Introduction: In this study we aimed to determine the validity and usefulness of the oxygen uptake efficiency slope (OUES) as a variable to compare normal and heart failure subjects implanted with cardiac resynchronization therapy defibrillator (CRT-D) devices. Methods: Exercise tests were performed on a treadmill (modified CAEP protocol) by 18 biventricular patients (post implant ∼ 4wks, NYHA II-III) and 25 normal volunteers. Expired gas was continuously analyzed. Peak Vo2 and Ve/VCO2 slopes were determined from the CPX ventilatory data. The OUES was calculated from the data using then entire exercise duration using the OUES equation VO2=a log Ve+b, where VO2 is oxygen uptake (ml/kg/min) and Ve is minute ventilation (L/min) and the constant “a” is OUES. A comparison of the OUES between the normal and BiV patients was performed. Results: Summary data are illustrated in the table. The mean OUES and peak VO2 for the normal volunteers was significantly higher compared to CRT-D baseline. VE/VCO2 slope was significantly lower in normal compared to CRT-D baseline. Conclusion: Our results suggest that OUES is an objective measure of cardiopulmonary reserve that can potentially discriminate between normal and heart failure subjects. This may be a useful tool for the detection of functional status changes.*ResultsNormalCRT-D BaselineOUES37.4+9.117.8+6.5*Peak VO236.5+7.715.2+4.4*VE/VCO2 slope31.3+.537.7+1.2*p<0.001 compared to normals

Left ventricular chamber stiffness at rest as a determinant of exercise capacity in heart failure subjects with decreased ejection fraction.

Impaired exercise tolerance, determined by peak oxygen consumption (VO2 peak), is predictive of mortality and the necessity for cardiac transplantation in patients with chronic heart failure (HF). However, the role of left ventricular (LV) diastolic function at rest, reflected by chamber stiffness assessed echocardiographically, as a determinant of exercise tolerance is unknown. Increased LV chamber stiffness and limitation of VO2 peak are known correlates of HF. Yet, the relationship between chamber stiffness and VO2 peak in subjects with HF has not been fully determined. Forty-one patients with HF New York Heart Association [(NYHA) class 2.4 +/- 0.8, mean +/- SD] had echocardiographic studies and VO2 peak measurements. Transmitral Doppler E waves were analyzed using a previously validated method to determine k, the LV chamber stiffness parameter. Multiple linear regression analysis of VO(2 peak) variance indicated that LV chamber stiffness k (r2 = 0.55) and NYHA classification (r2 = 0.43) were its best independent predictors and when taken together account for 59% of the variability in VO2 peak. We conclude that diastolic function at rest, as manifested by chamber stiffness, is a major determinant of maximal exercise capacity in HF.

The Relationship Between Functional Capacity, Cardiac Function, and Quality of Life in Heart Failure Patients

1093 Some consensus exists in that physiological domains, symptoms, functional status, and health perceptions contribute to quality of life in a wide range of populations. Specific to heart failure, Green et al. (JACC 35:1245–55, 2000.) determined a significant correlation (r2 = 0.48, p < 0.001) between quality of life and a six-minute physical function walk test. PURPOSE: The intent of this investigation was to examine the relationship between functional capacity, cardiac function, and quality of life in male and female NYHA class II and III heart failure patients. METHODS: A total of 20 male (n = 11) and female (n = 9) subjects (age = 57 ± 2.5 yrs; height = 171.6 ± 2.0 cm; weight = 84.3 ± 3.0 kg) underwent a peak oxygen consumption (VO2peak) test on a treadmill to assess functional capacity (VO2peak = 16.6 ± 1.2 ml/kg/min; anaerobic threshold = 913.6 ± 51.9 ml). In the same visit, each subject completed the Kansas City Cardiomyopathy Questionnaire to assess the individual's quality of life. A twodimensional echocardiogram was performed on each subject to obtain an ejection fraction (EF) measurement (EF = 28.4 ± 1.8%). RESULTS: A regression analysis revealed a non-significant correlation between VO2peak and ejection fraction (r 2 = 0.07, p = 0.14). Additionally, there was a non-significant correlation between the quality of life and VO2peak (r2 = 0.11, p = 0.08), and between quality of life and ejection fraction (r2 = 0.02, p = 0.27). Anaerobic threshold demonstrated a non-significant correlation with both the quality of life (r2 = 0.16, p = 0.10) and the ejection fraction (r2 = 0.05, p = 0.39). Furthermore, there were no significant correlations detected between gender and either the VO2peak, ejection fraction, anaerobic threshold, or quality of life. CONCLUSION: This study exhibits that the VO2peak, anaerobic threshold, and EF% are all unrelated to quality of life in NYHA class II and III heart failure subjects. Our findings are in disagreement with those of Green et al. who utilized a 6-minute walk test. Perhaps this difference is specific to the direct assessment that we obtained for physiological metabolic capacity (VO2peak and anaerobic threshold) compared to the field testing that was performed by Green et al.

The Relationship Between Functional Capacity, Cardiac Function, and Quality of Life in Heart Failure Patients

1093 Some consensus exists in that physiological domains, symptoms, functional status, and health perceptions contribute to quality of life in a wide range of populations. Specific to heart failure, Green et al. (JACC 35:1245–55, 2000.) determined a significant correlation (r2 = 0.48, p < 0.001) between quality of life and a six-minute physical function walk test. PURPOSE: The intent of this investigation was to examine the relationship between functional capacity, cardiac function, and quality of life in male and female NYHA class II and III heart failure patients. METHODS: A total of 20 male (n = 11) and female (n = 9) subjects (age = 57 ± 2.5 yrs; height = 171.6 ± 2.0 cm; weight = 84.3 ± 3.0 kg) underwent a peak oxygen consumption (VO2peak) test on a treadmill to assess functional capacity (VO2peak = 16.6 ± 1.2 ml/kg/min; anaerobic threshold = 913.6 ± 51.9 ml). In the same visit, each subject completed the Kansas City Cardiomyopathy Questionnaire to assess the individual's quality of life. A twodimensional echocardiogram was performed on each subject to obtain an ejection fraction (EF) measurement (EF = 28.4 ± 1.8%). RESULTS: A regression analysis revealed a non-significant correlation between VO2peak and ejection fraction (r 2 = 0.07, p = 0.14). Additionally, there was a non-significant correlation between the quality of life and VO2peak (r2 = 0.11, p = 0.08), and between quality of life and ejection fraction (r2 = 0.02, p = 0.27). Anaerobic threshold demonstrated a non-significant correlation with both the quality of life (r2 = 0.16, p = 0.10) and the ejection fraction (r2 = 0.05, p = 0.39). Furthermore, there were no significant correlations detected between gender and either the VO2peak, ejection fraction, anaerobic threshold, or quality of life. CONCLUSION: This study exhibits that the VO2peak, anaerobic threshold, and EF% are all unrelated to quality of life in NYHA class II and III heart failure subjects. Our findings are in disagreement with those of Green et al. who utilized a 6-minute walk test. Perhaps this difference is specific to the direct assessment that we obtained for physiological metabolic capacity (VO2peak and anaerobic threshold) compared to the field testing that was performed by Green et al.

NT-proBNP and the diagnosis of heart failure: a pooled analysis of three European epidemiological studies.

Many studies have shown that the B-type natriuretic peptides (BNP and NT-proBNP) are proven diagnostic markers for heart failure due to left ventricular systolic dysfunction. The manner in which they are to be used is still being unravelled; most single centre studies have chosen the best concentration of the peptide on ROC analysis as their cut-point resulting in numerous different values for both BNP and NT-proBNP appearing in the literature. We report a different approach of defining an age and sex corrected abnormal concentration for NT-proBNP, derived from normal individuals within a large sample of 3051 subjects pooled from three European epidemiology studies and applying that to the entire population to detect HF and LVD. Three thousand and fifty one subjects were studied. Of these 10% (305) had significant LVD and 3.1% (94) had HF. The median concentrations of NT-proBNP (IQR) in normals, those with LVD and in heart failure subjects were 20 pg/ml (10.30), 117.3 pg/ml (28.145) and 269.6 pg/ml (54.323), P<0.001, respectively. The area under the ROC curve for NT-proBNP for the detection of 'heart failure' was 0.85 and 0.69 for LVD. NT-proBNP was an independent predictor of the presence of HF on multivariate analysis. An abnormal NT-proBNP was defined as being >95th centile for normals, age and sex corrected, and diagnosed HF with a sensitivity of 75% and a negative predictive value of 99%. In an additional analysis in a breathless subgroup of our population, in 30% a raised NT-proBNP concentration could be explained by HF due to LVD, in another 64% the high BNP level was associated with some other structural of functional cardiac abnormality or renal impairment. We were unable to assign a possible cause to the high NT-proBNP values in 5.9% of this breathless subgroup of the population. An abnormal NT-proBNP concentration is an accurate diagnostic test both for the exclusion of HF in the population and in ruling out LVD in breathless subjects. An elevated NT-proBNP merely indicates the presence of 'cardio-renal distress' and should prompt referral for further investigation.

Descriptors of dyspnea by patients with chronic obstructive pulmonary disease versus congestive heart failure

Objectives The purpose of this study was to determine whether differences existed between reports of dyspnea in stable chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF) subjects. Methods Sixty stable COPD ( n = 30) and CHF ( n = 30) male, outpatient subjects were studied. Subjects were asked to both endorse (from a pre-designed list of descriptors) and volunteer terms that best described their breathing discomfort. Subjects also reported the frequency and the intensity of breathlessness (0-10 scale) using the Pulmonary Functional Status and Dyspnea Questionnaire. Results From the endorsed list of descriptors, my breath does not go out all the way, was significantly different (COPD = 11, CHF = 4, P < .05) between groups. The most common terms volunteered by COPD subjects were scary ( n = 5, P < .02), hard to breathe ( n = 5), shortness of breath ( n = 4), and cannot get enough air ( n = 4), whereas CHF subjects volunteered the terms, shortness of breath ( n = 9), gasping ( n = 6), and cannot get enough air ( n = 4). There was no difference in the frequency with which both groups experienced dyspnea or times per month they reported severe to very severe dyspnea. Subjects with COPD experienced a higher intensity of breathlessness on different occasions P < .05. Conclusions Stable COPD and CHF patients use and recognize a variety of terms that describe their breathing distress. There was, however, only 1 unique term among the endorsed and volunteered terms, and that was among the COPD subjects. COPD and CHF subjects shared many common terms and also experienced dyspnea with similar frequency. The uniqueness of terms among the COPD group was less clear. The study highlights the variability of the dyspnea experience among COPD and CHF patients and the potential difficulty identifying unique dyspnea terms in these subjects.

Head-to-head comparison of the diagnostic utility of BNP and NT-proBNP in symptomatic and asymptomatic structural heart disease

Background: B-type natriuretic peptide (BNP) and the amino-terminal fragment of the BNP prohormone (NT-proBNP) are markers for functional cardiac impairment and are elevated in heart failure (HF). Aim of the present study was to perform a head-to-head comparison of the diagnostic utility of BNP and NT-proBNP in symptomatic and asymptomatic structural heart disease. Methods: We prospectively classified 180 consecutive subjects according to ACC/AHA guidelines. Blood concentrations of BNP and NT-proBNP were determined by two fully automated chemiluminescent assays (Bayer and Roche method). Diagnostic utilities were tested by ROC analyses and logistic regression. Results: ROC curves of BNP and NT-proBNP in patients with symptomatic HF ( n=43) and asymptomatic subjects ( n=137) did not differ significantly (AUC 0.930 vs. 0.918, p=0.650), but comparison of patients with asymptomatic structural heart disease ( n=56) and subjects without structural disorder of the heart ( n=81) revealed different AUCs for the respective assays (0.735 vs. 0.839, p=0.009). In the population studied, age, sex and renal function had no impact on the diagnostic performance of both tests when compared by logistic regression models. Conclusions: Both assays facilitate diagnosis of symptomatic and asymptomatic structural heart disease. BNP and NT-proBNP may be equally useful as an aid in the differential diagnosis of probable signs or symptoms of HF. In contrast, NT-proBNP might be a more discerning marker of early cardiac dysfunction than BNP.

Does angiotensin-converting enzyme gene polymorphism affect blood pressure? Findings after 6 years of follow-up in healthy subjects.

There has been an increase in research into the association between angiotensin-converting enzyme (ACE) gene deletion polymorphism and cardiovascular disease, with conflicting results. The present prospective long-term study was conducted to evaluate whether the DD genotype could also be associated with a higher prevalence of hypertension in healthy subjects, over 6 years of follow-up. 684 healthy volunteers (aged, 25-55 years): normotensive and free of cardiovascular diseases, with acceptable echocardiographic window. All subjects had to have a normal electrocardiogram (ECG) and echocardiogram (ECHO) at entry. All subjects underwent a complete physical examination, 12-lead ECG and ECHO, and venous blood samples were drawn for DNA analysis and cholesterol. All subjects had a clinical evaluation each year for the 6 year duration of the study. All 684 subjects completed 6 years of follow-up. We identified three genetically distinct groups. The ACE-DD group (n=225, 80F/145M, mean age 43.4+/-7.6 years) had 42 hypertensive subjects (18.3%), 5 heart failure (HF) subjects and 6 subjects with acute coronary syndromes (ACS). There was no association between family history, smoking habit, hypercholesterolemia and events. The ACE-ID group (n=335, 116F/219M, mean age 43.6+/-7 years) had 16 hypertensive subjects (4.7%) and 3 subjects with ACS. The ACE-II group (n=124, 45F/79M, mean age 42.5+/-6.9 years) had 2 hypertensive subjects (1.6%) and 1 HF subject. The incidence of hypertension and cardiovascular events was significantly higher in the ACE-DD group (53 cases, 23%) than in the ACE-ID and ACE-II groups (20 and 3 cases, 5.9 and 2.4%, respectively), P=0.0001. The higher incidence of hypertension was observed in the older age groups (36-45 and 46-55 years) with ACE-DD and ACE-ID genotypes. Our data suggest that ACE-DD polymorphism is associated with a higher incidence of hypertension in baseline healthy subjects, irrespective of other risk factors. The higher incidence of hypertension was apparent predominantly in the older age groups.

Multiscale entropy analysis: a new measure of complexity loss in heart failure

Heart failure may lead to loss of complexity in physiologic dynamics. However, conventional entropy measures yield contradictory results. We applied a recently developed method, multiscale entropy (MSE) that quantifies the regularity of physiologic signals over multiple time scales. We tested the hypothesis that the rate at which entropy varies with time scale can discriminate between healthy and different classes of con- gestive heart failure (CHF) subjects. Material and Methods: We analyzed long-term Holter re- cordings from two group of subjects: 72 records from healthy subjects aged 5512 years and 43 from patients with CHF aged 5416. The CHF group included 12 subjects in NYHA classes I-II, and 31 subjects in classes III-IV. We calculated an entropy measure (SampEn) that applies to physiologic time series plotted as a function of time scale. Next, we computed the rate of change of entropy for scales smaller and larger than approximately 5 seconds and developed clustering criteria for the different groups. Results and Conclusions: Healthy and CHF subjects have different MSE curve profiles. Further, heart rate dynamics with CHF have significantly lower multiscale entropy values com- pared with healthy subjects. A 2-dimensional scatter plot based on the rate of variation of entropy with time scale showed robust separation of healthy and all CHF classes. These findings are consistent with the basic concept of information loss in cardio- vascular regulatory mechanisms in CHF and may be useful in clinical assessment.