Moderate CHF Research Articles

Intraspecific scaling laws are preserved in ventricular hypertrophy but not in heart failure.

It is scientifically and clinically important to understand the structure-function scaling of coronary arterial trees in compensatory (e.g., left and right ventricular hypertrophy, LVH and RVH) and decompensatory vascular remodeling (e.g., congestive heart failure, CHF). This study hypothesizes that intraspecific scaling power laws of vascular trees are preserved in hypertrophic hearts but not in CHF swine hearts. To test the hypothesis, we carried out the scaling analysis based on morphometry and hemodynamics of coronary arterial trees in moderate LVH, severe RVH, and CHF compared with age-matched respective control hearts. The scaling exponents of volume-diameter, length-volume, and flow-diameter power laws in control hearts were consistent with the theoretical predictions (i.e., 3, 7/9, and 7/3, respectively), which remained unchanged in LVH and RVH hearts. The scaling exponents were also preserved with an increase of body weight during normal growth of control animals. In contrast, CHF increased the exponents of volume-diameter and flow-diameter scaling laws to 4.25 ± 1.50 and 3.15 ± 1.49, respectively, in the epicardial arterial trees. This study validates the predictive utility of the scaling laws to diagnose vascular structure and function in CHF hearts to identify the borderline between compensatory and decompensatory remodeling.

Abstract 48: Differentiation of Moderate and Severe Ischemic Heart Failure by Invasive and Non-invasive Assessments of Diastolic Function in a Rat Model of Chronic Heart Failure

Background: This work is designed to determine if specific left ventricle (LV) pressure-volume relations, hemodynamic, and echo derived parameters of diastolic function are able to separate severe from moderate CHF in rats with left coronary artery occlusion. Hypothesis: Echocardiographic indices of diastolic function, end-diastolic pressure (EDP), dead volume, stiffness constants (k), and pressure volume relations predict the severity of CHF in infarcted rats. Methods: Male Sprague Dawley rats (N=14) were randomized to undergo left coronary artery ligation or sham operation. Echocardiography was performed at 3 and 6 weeks post coronary ligation. The rats were categorized into moderate or severe CHF according to their LVEDP at 6 weeks post ligation. Invasive hemodynamic measurements with solid state micro manometer pressure catheters as well as diastolic pressure-volume relation values were obtained at the 6 week end point. Results: Moderate and severe CHF rats had significantly (P<0.05) elevated left ventricular (LV) end-diastolic pressure (LV EDPs), prolonged time constants of LV relaxation (tau), and decreased peak development pressures. When moderate versus severe CHF rats were separated based on LV EDP, early diastolic anterior wall radial relaxation velocity as well as e’, and E/e’ had strong correlations with invasive hemodynamic measurements of diastolic functions. There was a trend towards decreased compliance as measured by stiffness constants in severe heart failure group. Differences (P<0.05) in dead volume, mean arterial pressure (MAP), tau, and ejection fraction (EF) were also displayed. End diastolic pressure-volume analyses illustrated significant differences in plot positioning and curvature. Conclusion: While it is possible to separate rats with moderate and severe CHF in the rat coronary artery ligation model, the separation is not simply based on a specific EF value. This work may be useful in deciding whether there is a differential effect of new treatments for severe versus moderate CHF.

Efficacy and safety of a 60-week treatment with candesartan in Japanese patients with mild to moderate chronic heart failure

BackgroundChronic heart failure (CHF) is an increasingly common cardiovascular disease despite recent advances in its diagnosis and management. Methods and resultsA multicenter, open-label study was designed to assess the efficacy and safety of 60-week treatment with candesartan in Japanese patients with mild to moderate CHF. Primary efficacy endpoints were changes from baseline in plasma brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), end-diastolic dimension, and New York Heart Association (NYHA) functional class. Two hundred and eighty-nine eligible patients were divided into 2 groups based on the daily dose at the end of treatment: high-dose (HD, 8mg, N=170) and low-dose (LD, 2 or 4mg, N=119). Neither plasma BNP levels nor LVEF changed from the baseline to the end of treatment in the LD group, whereas BNP significantly improved from 61.6 to 50.1pg/mL (p=0.0005) and LVEF from 57.2 to 60.1% (p=0.0005) in the HD group. The changes in NYHA functional class were comparable between groups: 21.2% improved and 76.3% unchanged in the LD group and 20.6% improved and 79.4% unchanged in the HD group. No safety concerns were observed in either group. ConclusionsHD candesartan was more effective in improving plasma BNP levels and cardiac function than LD in Japanese CHF patients. Both LD and HD candesartan were well tolerated in CHF patients.

Provider Recommendations for Colorectal Cancer Screening in Elderly Veterans

Decisions regarding colorectal cancer (CRC) screening in the elderly depend on providers' assessment of likelihood of benefit partly based on patient comorbidity and past screening history. We aimed to describe providers' experiences and practice patterns regarding screening for CRC in elderly patients in the VA system. A survey was sent to VA primary care providers who had previously participated in the CanCORS-sponsored Share Thoughts on Care study and at a VA medical center. The surveys consisted of clinical vignettes that varied by patient age (75, 80, or 85 years), comorbidity, and past CRC screening history. Completed questionnaires were received from 183 of 351 providers (52%). Ninety-five percent of providers would recommend screening for a healthy 75 year old compared to 66% and 39% for a healthy 80 and 85 year old, respectively (p-values < 0.0001). Providers were more likely to recommend screening for a 75 year old with moderate CHF versus severe CHF [61% versus 15%, OR 9.0 (95% CI 5.8-14.0), p < 0.0001] and more likely to recommend screening for an 80 year old with prior colonoscopy within the preceding 10 years, versus 5 years [42% versus 23%, OR 2.6 (95% CI 1.9-3.5), p < 0.0001]. A substantial minority of respondents (range 15-21%) reported they would screen a 75 year old with an active malignancy, severe CHF, or severe COPD. Provider demographic characteristics were not significantly associated with the probability of a screening recommendation. VA providers incorporate patient age, comorbidity, and past CRC screening history into CRC screening recommendations for elderly veterans; however, substantial proportions of these recommendations are inappropriate.

Adjuvant Chemotherapy for Stage III Colon Cancer: Do Physicians Agree About the Importance of Patient Age and Comorbidity?

We surveyed cancer physicians to understand how patients' age and comorbidity influence adjuvant chemotherapy recommendations and whether physician or practice characteristics also affect these recommendations. National survey of surgeons and medical oncologists caring for patients with colorectal cancer regarding whether they would recommend adjuvant chemotherapy for hypothetical patients with stage III colon cancer who varied by age (55 v 80 years) and comorbid illness (none, moderate, severe congestive heart failure [CHF]). Repeated measures logistic regression was used to assess the influence of patient, physician, and practice characteristics on chemotherapy recommendations. Of 1,096 physicians, nearly all recommended chemotherapy for patients who were 55 years old with no comorbidity (99.0%), 55-years old with moderate CHF (88.6%), or 80 years old with no comorbidity (92.6%); many fewer recommended chemotherapy for 55-year-old patients with severe CHF (24.9%) or 80-year-old patients with moderate (47.2%) or severe (9.0%) CHF (P < .001). Younger physicians (P < .001) were more likely than others to recommend adjuvant chemotherapy overall, although physician factors explained little of the variability in recommendations. Physicians agree with guidelines recommending adjuvant chemotherapy for young, healthy patients with stage III colon cancer but differ widely on recommendations for patients who are older and sicker. Few physician or practice characteristics were associated with recommendations. For older and sicker patients, the individual physicians seen may have a substantial impact on the likelihood of receiving chemotherapy. Understanding better the sources of variation not explained by patients' clinical characteristics may allow improved tailoring of therapy to patients most likely to benefit.

Bioenergetic and Antioxidant Properties of Coenzyme Q10: Recent Developments

For a number of years, coenzyme Q (CoQ10 in humans) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in plasma, and extensively investigated its antioxidant role. These two functions constitute the basis on which research supporting the clinical use of CoQ10 is founded. Also at the inner mitochondrial membrane level, coenzyme Q is recognized as an obligatory co-factor for the function of uncoupling proteins and a modulator of the transition pore. Furthermore, recent data reveal that CoQ10 affects expression of genes involved in human cell signalling, metabolism, and transport and some of the effects of exogenously administered CoQ10 may be due to this property. Coenzyme Q is the only lipid soluble antioxidant synthesized endogenously. In its reduced form, CoQH2, ubiquinol, inhibits protein and DNA oxidation but it is the effect on lipid peroxidation that has been most deeply studied. Ubiquinol inhibits the peroxidation of cell membrane lipids and also that of lipoprotein lipids present in the circulation. Dietary supplementation with CoQ10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoproteins to the initiation of lipid peroxidation. Moreover, CoQ10 has a direct anti-atherogenic effect, which has been demonstrated in apolipoprotein E-deficient mice fed with a high-fat diet. In this model, supplementation with CoQ10 at pharmacological doses was capable of decreasing the absolute concentration of lipid hydroperoxides in atherosclerotic lesions and of minimizing the size of atherosclerotic lesions in the whole aorta. Whether these protective effects are only due to the antioxidant properties of coenzyme Q remains to be established; recent data point out that CoQ10 could have a direct effect on endothelial function. In patients with stable moderate CHF, oral CoQ10 supplementation was shown to ameliorate cardiac contractility and endothelial dysfunction. Recent data from our laboratory showed a strong correlation between endothelium bound extra cellular SOD (ecSOD) and flow-dependent endothelial-mediated dilation, a functional parameter commonly used as a biomarker of vascular function. The study also highlighted that supplementation with CoQ10 that significantly affects endothelium-bound ecSOD activity. Furthermore, we showed a significant correlation between increase in endothelial bound ecSOD activity and improvement in FMD after CoQ10 supplementation. The effect was more pronounced in patients with low basal values of ecSOD. Finally, we summarize the findings, also from our laboratory, on the implications of CoQ10 in seminal fluid integrity and sperm cell motility.

Skeletal muscle myofibrillar protein oxidation in heart failure and the protective effect of Carvedilol

Heart failure is characterized by limited exercise tolerance and by a skeletal muscle myopathy with atrophy and shift toward fast fibres. An inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production, can worsen muscle damage. In a well established model of heart failure, the monocrotaline treated rat, we show that CHF is accompanied by oxidation of the skeletal muscle actin, tropomyosin and myosin, which further depresses muscle function and exercise capacity. We have also tested the efficacy of Carvedilol, a non-selective β 1–β 2-blocker, which has been widely used in clinical trials to improve exercise tolerance and reduce mortality in moderate and severe CHF, in preventing contractile protein oxidation in CHF rats. As comparison we used Bisoprolol a β 1 selective agent, without known anti-oxidative properties. Carvedilol at the dose of 2 mg/kg per day was able to prevent the myofibrillar protein oxidation, while Bisoprolol (0.1 mg/kg) did it only partially, as demonstrated by the oxyblot analysis. While Carvedilol improved force production on isolated muscles, Bisoprolol did not. After the COMET trial, the anti-oxidative capacity of Carvedilol has been invoked as one of the mechanism that makes this drug superior to other selective β-blockers in the treatment of CHF. One of the reason of Carvedilol superiority could be the effect on skeletal muscle with reduction of contractile protein peroxidation, amelioration of muscle function and improvement of exercise tolerance. Inhibition of reactive oxygen species (ROS) production, and of pro-inflammatory cytokines may also lead to a decreased muscle wastage, another factor contributing to worsening of exercise tolerance.

Cessation of pulmonary and coronary secretion of adrenomedullin peptides in the progression of human heart failure.

In human heart failure (CHF), adrenomedullin (AM) counteracts vasoconstriction and sodium retention. We investigated circulating levels of proadrenomedullin N-20 peptide (PAMP) and AM, and left ventricular expression of preproAM and calcitonin receptor-like receptor (CRLR) mRNA. Peptide levels were determined from the left ventricle, pulmonary artery, coronary sinus, and antecubital vein in patients demonstrating severe CHF (n = 12; mean +/- SEM cardiac index, 1.9 +/- 0.2 l/min/m(2); pulmonary wedge pressure, 32 +/- 1 mmHg), moderate CHF (n = 11; cardiac index, 2.9 +/- 0.2; pulmonary wedge pressure, 14 +/- 2), and in controls (n = 11). Left ventricular mRNA was quantified using RT-PCR and Southern blot hybridization. Depending on sites of measurement, PAMP and AM in severe CHF were 1.3 - 2.0 and 1.2 - 1.9 times as high as in moderate CHF, and 3.8 - 4.6 and 2.3 - 2.8 times as high as in controls. Only patients with moderate CHF demonstrated pulmonary and coronary net release of both peptides, that is, significant step-ups in concentrations between the pulmonary artery, left ventricle, and coronary sinus. In failing ventricles, preproAM mRNA increased 2.9 times above control, but CRLR mRNA was unchanged. Altogether, the heart and the lungs release AM peptides in moderate CHF. This secretion breaks down in severe CHF: a process that may contribute to and indicate decompensation. Unlike AM, the CRLR is not transcriptionally upregulated in severe CHF.

Effect of short-term treatment with bumetanide, quinapril and low-sodium diet on dogs with moderate congestive heart failure.

To evaluate the effect of bumetanide, quinapril and a low-sodium diet on clinical response tolerance and side-effects on dogs with moderate congestive heart failure. A prospective clinical study, using 32 client-owned dogs with naturally occurring disease. Thirty-two dogs diagnosed with congestive heart failure (International Small Animal Cardiac Health Council stage II) due to mitral valve disease were included. During 4 weeks, patients received 0.5 mg/kg quinapril (Ectren, Menarini), 0.1 mg/kg bumetanide (Fordiuran, Boehringer Ingelheim) and a low sodium diet (CNM-CV, Purina) was fed. All dogs were examined weekly and results were treated statistically. The treatment was safe, effective and well-tolerated and no major side-effects were observed. There were no significant changes in measured haematological and biochemical variables, including serum electrolyte concentrations and urinary fractional excretion of electrolytes. This study suggests that the combined treatment with bumetanide, quinapril and low-sodium diet for controlling moderate CHF due to mitral insufficiency in dogs is simple, easy-to-administer and effective in controlling clinical signs and prompting improvement even after short-term treatment.

Changes of neurohumoral parameters and endothelin-1 in response to exercise in patients with mild to moderate congestive heart failure

Plasma endothelin levels are increased in patients with moderate and severe CHF. Conflicting data exist about the endothelin-1 (ET) level in patients with mild to moderate CHF and the effect of maximal exercise on plasma ET levels. Methods and results: We determined the plasma levels of ET and various neurohumoral parameters in 93 patients with CHF in functional class II and III of the NYHA classification at rest and after maximal bicycle exercise. Baseline ET level was increased compared to an age-matched healthy volunteer group (6.95±0.31 vs 3.29±0.17 pg/ml, mean±S.E.M., P<0.05), without significant differences between NYHA class II and III patients. Maximal exercise did not increase the ET level. In contrast, the neurohumoral parameters were significantly increased with maximal exercise. In conclusion, plasma levels of ET are increased in patients with mild to moderate CHF. However, no further increase in response to exercise was observed. Thus, it is highly unlikely that exercise capacity may be limited by ET-mediated peripheral vasoconstriction.

Determinants of the blood pressure response to the first dose of ACE inhibitor in mild to moderate congestive heart failure

To investigate the relationship in patients with heart failure between BP response to the first dose of ACE inhibitor and (1) plasma drug concentration and (2) baseline clinical and laboratory variables. We studied individual placebo-corrected BP responses to initiation of treatment with one of a number ACE inhibitor preparations in 132 patients with mild to moderate CHF. Various pharmacokinetic/pharmacodynamic models were compared. We assessed the strength of association between baseline physiological and laboratory variables and the BP response as assessed directly from the AUC(0,10 h) and indirectly from the slope of the PK/PD relationship. Predictive models for response variables were developing using regression analysis. BP response was primarily related to plasma drug concentration. The association between the fall in BP and baseline variables was weak. The strongest single predictor of BP response was baseline mean arterial pressure (r2 = 5.8%, P = 0.02). The best combinations of predictor variables contained mean arterial pressure, plasma renin activity, creatinine concentration and age (r2 = 14.4%, P = 0.37). When the choice of ACE inhibitor was added, the predictive power of the model increased (r = 23.6%, P < 0.01) but left the majority of the variability in response unexplained. The first-dose blood pressure response to ACE inhibition cannot be accurately predicted from baseline pathophysiological variables in patients with mild to moderate CHF. The choice of ACE inhibitor accounts for a small proportion of the variability in response but wide inter-individual variability exists in the response to each treatment.

789-6 The 9-Minute Self-Powered Treadmill: Is It an Index of Submaximal Exercise Capacity in CHF?

The 9-minute self-powered treadmill (SPT) test has been employed to evaluate submaximal exercise tolerance in CHF, but its relationship to maximum exercise capacity is not well defined. Therefore, we examined the relationship of the distance walked during 9 minutes on a SPT to indices of respiratory gas exchange on the SPT and on a maximal treadmill test (modified Naughton protocol). 10 patients (PTS) with NYHA class II–III CHF (EF 20 ± 2%), and 6 age-matched sedentary controls (CON) were studied. CHF PTS walked less far (386 ± 38 vs 643 ± 21 m, p &lt; 0.001) and stopped more often (27 stops in 9 PTS vs no stops in CON, p &lt; 0.05). The highest VO 2 achieved on the SPT (SPT-VO 2 ) and the peak VO 2 on the maximal treadmill (peak VO 2 ) were both lower in CHF PTS (15.9 ± 1.4 vs 251 ± 0.9 and 16.5 ± 1.5 vs 309 ± 3.1 ml/kg/min respectively, both p &lt; 0.001). SPT distance correlated poorly with EF (r = 0.331 and insignificantly with NYHA class (r = -0.47, P = 0.13), but very closely with both SPT-VO 2 and peak-VO 2 (r = 0.8 = and r = 0.89, respectively, both p &lt; 0.005). SPT-VO 2 correlated closely with peak-VO 2 (r = 0.79, P = 0.006) in CHF PTS but not significantly in CON. Of note is that all CHF PTS achieved anaerobic threshold on the SPT vs only 1/6 CON (p &lt; 0.05). and SPT-VO 2 was 97.3% of the treadmill peak-VO 2 vs 83.8% in the CON. These findings demonstrate that in motivated subjects with moderate CHF, in distinction to control subjects, the 9-minute SPT test is more an index of maximal than submaximal exercise capacity. Although it may be useful in assessing exercise tolerance, this may explain why SPT, like other measurements of maximal exercise capacity, does not correlate well with symptom status in these patients.

707-1 Short-term ACE-Inhibition and Onset and Progression of Congestive Heart Failure in Patients with Acute Myocardial Infarction

Anterior acute myocardial infarction (AMI) is often complicated by clinical signs of CHI. We report the data of 1146 patients with anterior A.M.I. without previous history or clinical signs of CHF on admission and enrolled under the SMILE study. Patients were randomly allocated to a 6-week double blind treatment with placebo (P) or zofenopril (Z) and then followed-up for 1 year. Baseline demographic characteristics were similar in Z and P group who were comparable for blood pressure, ECG pattern, peak CPK, and concomitant drug treatment. After 6 weeks the cumulative occurrence of CHF was not different in Z and P groups (13.3% vs 13.9%; P = 0.234). Clinical signs of mild to moderate CHF were present in 11.7% ofthe Z population and 10.2% of the P group (P = 0.178) whereas severe refractory CHF occurred significantly less in Z (1.6%) compared to P (3.6%) patients (RR = 2.3: C.I. 95% 1–3.3: p = 0.0328). After 1 year the overall occurrence of CHF was 14.8% in P and 15.4% in Z treated patients. NYHA class I was more common among Z treated patients (8.2% vs 1.5%; P = 0.021) whereas the percentage of patients in NYHA class IV was higher in P treated patients (24.3% vs 11.0%; p = 0.001). In conclusion the early and long-term development and progression of CHF can be prevented by short-term administration of zofenopril in patients with acute myocardial infarction.

Pimobendan, a novel Ca2+-sensitizer/PDE-inhibitor, improves cardiac function without tolerance to its vasodilating effects during long-term therapy in moderate CHF

Pimobendan, a novel Ca2+-sensitizer/PDE-inhibitor, improves cardiac function without tolerance to its vasodilating effects during long-term therapy in moderate CHF

Use of Pulmonary Artery Catheters in Patients with Acute Myocardial Infarction: Analysis of Experience in 5,841 Patients in the SPRINT Registry

This study analyzes the use of PAC in a registry comprising 5,841 hospitalized patients with AMI. A total of 371 patients received PAC. In-hospital mortality was higher in patients with CHF who received PAC, while there was no difference in patients with cardiogenic shock or persistent hypotension. Mortality in patients receiving PAC was higher irrespective of the presence or absence of "pump failure." A separate analysis of discharge summaries of 364 patients with CHF showed that PAC was used more frequently in sicker patients and that when severity of CHF was assessed, no difference in mortality was found in patients with mild or moderate CHF. We conclude that while a higher in-hospital mortality is found in patients receiving PAC, this excess is likely related to difference in severity of CHF, which had not been assessed in every individual. It is unlikely that PAC increases mortality.

Increasing the Dose of Furosemide Improves Symptoms in Moderate CHF

Increasing the Dose of Furosemide Improves Symptoms in Moderate CHF

4′-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data

4'-epi-doxorubicin (4'-epi-DX) is a new anthracycline antibiotic. It differs from doxorubicin (DX) by the epimerization of the OH group in position 4' of the aminosugar moiety, and was synthesized in an effort to find agents with a superior therapeutic index to the parent compound doxorubicin (DX). 4'-epi-doxorubicin binds to DNA and inhibits nucleic acid synthesis and function. The antitumor activity of 4'-epi-DX in several experimental tumors (Leukemias L 1210, P 388, Gross Leukemia, Sarcoma 180 ascitic and solid, C3H/HE mammary carcinoma) is similar to that of DX. However, 4'-epi-doxorubicin has greater antitumor activity than doxorubicin in Lewis lung carcinoma, MS-2 sarcoma lung metastasis, and human melanoma in athymic mice. In chronic toxicity studies there were no qualitative differences between 4'-epi-DX and DX; quantitatively, however, 4'-epi-DX was less toxic. In different experimental models 4'-epi-DX has been shown to be less cardiotoxic than its parent compound. In chronic toxicity studies in the rabbit, histopathologic findings revealed the same pattern of cardiotoxicity for both drugs but less marked with 4'-epi-DX. Distribution studies in mice with tumors showed a lower concentration of 4'-epi-DX in the heart, spleen and kidneys; the hepatobiliary metabolism and excretion of 4'-epi-DX investigated in the rat, indicated that the new analogue was more extensively metabolized than the parent compound. Pharmacokinetics of 4'-epi-DX in humans showed a multiexponential decrease of plasma levels; the same pattern was observed for the metabolite 13-OH epidoxorubicinol but with lower concentrations than the unchanged drug. A high plasma clearance (0.9-1.41/min), a terminal half-life of about 30-40 hr and a large volume of distribution were the main pharmacokinetic characteristics of 4'-epi-DX. A reduction of the dose appears to be appropriate in patients with liver function impairment. Phase II studies with 4'-epi-DX have indicated that the drug produces a pattern of acute toxicity, including acute cardiac toxicity, qualitatively similar to that of DX at identical doses but quantitatively lower, with particular regard to leukopenia and gastrointestinal toxicity. The range of single active doses is between 60 and 90 mg/m2, the most frequently employed doses schedules being 75 or 90 mg/m2 i.v. every 3 weeks. 4'-epi-DX has shown activity in a variety of tumors such as breast carcinoma, soft tissues sarcomas, NH lymphomas, leukemias, ovarian cancer and gastric cancer. Preliminary evidence of activity has been found in melanoma, rectal cancer and pancreatic cancer suggesting a broad spectrum of activity. As to chronic cardiac toxicity up to now only 2 mild to moderate and reversible CHF have been observed at doses of 1120 and 1235 mg/m2 in about 700 treated patients. Specific and comparative studies are in progress: preliminary findings from a randomized comparison of 4'-epi-DX vs DX in breast cancer indicated that 4'-epi-DX may have a lower cumulative cardiotoxicity.