Beneficial Cardiac Effects Research Articles

Effects of Physical Exercise on Myocardial Telomere-Regulating Proteins, Survival Pathways, and Apoptosis

The purpose of this study was to study the underlying molecular mechanisms of the protective cardiac effects of physical exercise. Telomere-regulating proteins affect cellular senescence, survival, and regeneration. C57/Bl6 wild-type, endothelial nitric oxide synthase (eNOS)-deficient and telomerase reverse transcriptase (TERT)-deficient mice were randomized to voluntary running or no running wheel conditions (n = 8 to 12 per group). Short-term running (21 days) up-regulated cardiac telomerase activity to >2-fold of sedentary controls, increased protein expression of TERT and telomere repeat binding factor (TRF) 2, and reduced expression of the proapoptotic mediators cell-cycle-checkpoint kinase 2 (Chk2), p53, and p16. Myocardial and leukocyte telomere length did not differ between 3-week- and 6-month-old sedentary or running mice, but telomerase activity, TRF2 and TERT expression were persistently increased after 6 months and the expression of Chk2, p53, and p16 remained down-regulated. The exercise-induced changes were absent in both TERT(-/-) and eNOS(-/-) mice. Running increased cardiac expression of insulin-like growth factor (IGF)-1. Treatment with IGF-1 up-regulated myocardial telomerase activity >14-fold and increased the expression of phosphorylated Akt protein kinase and phosphorylated eNOS. To test the physiologic relevance of these exercise-mediated prosurvival pathways, apoptotic cardiomyopathy was induced by treatment with doxorubicin. Up-regulation of telomere-stabilizing proteins by physical exercise in mice reduced doxorubicin-induced p53 expression and potently prevented cardiomyocyte apoptosis in wild-type, but not in TERT(-/-) mice. Long- and short-term voluntary physical exercise up-regulates cardiac telomere-stabilizing proteins and thereby induces antisenescent and protective effects, for example, to prevent doxorubicin-induced cardiomyopathy. These beneficial cardiac effects are mediated by TERT, eNOS, and IGF-1.

Mineralocorticoid antagonism and cardiac hypertrophy

Aldosterone provides circulatory support by promoting reabsorption of sodium in exchange for potassium in the kidney. Mineralocorticoid receptors (MRs) are found in nonepithelial (vessel, heart, and brain) and epithelial tissues. Excess aldosterone may exert harmful effects by provoking hypertrophy and fibrosis in the cardiovascular system, thus contributing to reduced vascular compliance and increased ventricular stiffness. Primary aldosteronism is the most common cause of mineralocorticoid-induced hypertension, and MR antagonism offers the best prospect for achieving therapeutic goals. MR blockade also ameliorates pathological changes in the heart in the setting of low-aldosterone hypertension. The beneficial cardiac effects of MR antagonists are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by activation of MRs. MR antagonism thus may have wide therapeutic potential in various cardiovascular diseases, with its benefit not limited to those characterized by aldosterone or salt excess.

Intracoronary Infusion of Levosimendan to Treat Postpericardiotomy Heart Failure

Systemic hypotension limits the intravenous use of levosimendan, particularly in coronary disease. Published reports show that the intracoronary administration of levosimendan in animal models causes an increase of coronary blood flow without systemic hypotension. In this case report, the intracoronary administration of levosimendan bolus in a 74-year-old man with postpericardiotomy heart failure elicited beneficial cardiac effects, increasing both systolic and diastolic functions and blood flow in all of the grafts. No changes of heart rate and systemic arterial blood pressure were observed.

Bisoprolol Improves Echocardiographic Parameters of Left Ventricular Diastolic Function in Patients with Systemic Hypertension

Left ventricular (LV) diastolic dysfunction (LVD) is a common complication secondary to hypertension. It has been reported that bisoprolol is effective in reducing blood pressure and has beneficial cardiac effects in patients with hypertension. However, its effect on LV diastolic function has not been studied in detail. In this study, we sought to determine bisoprolol’s effect on left ventricle diastolic function. Data from 25 patients were statistically analyzed. Peaks E and A wave, E/A ratio, isovolumetric relaxation time and E wave deceleration time were measured echocardiographically. Doppler echocardiography measurements after bisoprolol treatment revealed an improvement in LV diastolic function. In conclusion, our results show that treatment with bisoprolol, improves echocardiographic parameters of LV diastolic function after 3 months of treatment.

Exercise Effects on LV Diastolic Function

Hypertension is associated with impaired LV diastolic function. Although exercise training is recommended for reducing resting BP, each workout acutely raises BP and hence, may have adverse cardiac effects. Increased fatness also has adverse cardiac effects. Conversely, exercise reduces fatness. For this reason, along with reductions in resting BP, exercise training may lead to beneficial cardiac effects. PURPOSE: To determine effects of exercise training on LV diastolic function in relation to changes in fitness, fatness, and BP. METHODS: A randomized trial of 6-months of aerobic and resistance exercise training performed 3 times per week was conducted in participants aged 55–75 years healthy except for untreated mild hypertension (SBP 130–159 or DBP 85–99 mm Hg) and a mean (SD) BMI of 29.5 (4.4). LV diastolic function was assessed as early (peak E) and late (peak A) diastolic filling by pulse-wave Doppler imaging, propagation rate (Vp) by Color Mode imaging, and early (peak Em) and late (peak Am) diastolic velocities by tissue Doppler imaging. Fitness was measured as peak VO2 and muscle strength, and fatness by anthropometry, DEXA, and MRI. RESULTS: 51 exercisers (25 men; 26 women) and 53 controls (26 men; 27 women) completed the trial. At 6 months, exercisers had significantly higher aerobic and strength fitness and lower DBP and fatness versus controls. No parameter of LV diastolic function differed between groups. Using stepwise regression analysis, among 6-month individual changes in fitness, fatness, BP, and LV parameters, the following independent associations (P<.05 or less) were found: increased peak E with reduced abdominal total fat (R2 = .06); decreased peak A with increased waist circumference (R2 = .10) and increased peak VO2 (additional R2 = .10); increased E/A with increased peak VO2 (R2 = .06) and reduced waist-hip ratio (additional R2 = .05); increased Vp with reduced waist-hip ratio (R2 = .06); increased E/Vp with reduced waist-hip ratio (R2 = .04); increased peak Em with reduced abdominal total fat (R2 = .10); increased Em/Am with reduced abdominal total fat (R2 = .09); and decreased E/Em with reduced SBP (R2 = .07). CONCLUSION: When analyzed by group assignment, exercise training had no effects on LV diastolic function. However, a pattern of modest improvements in LV diastolic function was seen among those participants achieving the greatest increases in fitness and reductions in abdominal obesity and resting BP. Reduced abdominal fatness was the most prevalent mediator of change in LV diastolic function and may be a mechanism by which exercise improves cardiac health.

Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Failure in Low-Aldosterone Hypertensive Rats

Chronic elevation of plasma aldosterone contributes to heart failure. Mineralocorticoid receptor (MR) antagonism is cardioprotective in such a setting, but whether such protection occurs in the presence of low-aldosterone concentrations remains unclear. We investigated whether MR blockade attenuates cardiac hypertrophy and failure in rats with salt-sensitive hypertension. Dahl salt-sensitive (DS) rats fed a high-salt diet from 7 weeks develop concentric left ventricular (LV) hypertrophy secondary to hypertension at 12 weeks followed by heart failure at 19 weeks (DS-CHF). DS rats on such a diet were treated with a non-antihypertensive dose of the selective MR antagonist eplerenone from 12 to 19 weeks. Renin activity and aldosterone concentration in plasma were decreased in DS-CHF rats compared with controls. LV hypertrophy and fibrosis, as well as macrophage infiltration around coronary vessels, were apparent in DS-CHF rats. The amounts of mRNAs for 11beta-hydroxysteroid dehydrogenase type 1, MR, monocyte chemoattractant protein 1, and osteopontin were increased in these hearts. Treatment of DS-CHF rats with eplerenone inhibited these changes in gene expression, as well as coronary vascular inflammation and heart failure. Eplerenone attenuated both the decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in DS-CHF rat hearts. MR blockade with eplerenone thus resulted in attenuation of LV hypertrophy and failure, without an antihypertensive effect, in rats with low-aldosterone hypertension. The beneficial cardiac effects of eplerenone are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs.

Vasopeptidase inhibition has beneficial cardiac effects in spontaneously diabetic Goto–Kakizaki rats

In this study we examined diabetes- and hypertension-induced changes in cardiac structure and function in an animal model of type 2 diabetes, the Goto–Kakizaki (GK) rat. We hypothezised that treatment with omapatrilat, a vasopeptidase inhibitor, which causes simultaneous inhibition of angiotensin converting enzyme and neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high sodium intake, compared to treatment with enalapril, a selective inhibitor of angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-sodium (NaCl 0.8%) or high-sodium (NaCl 6%) diet and enalapril, omapatrilat or vehicle for 12 weeks. The GK rats developed hypertension, cardiac hypertrophy and overexpression of cardiac natriuretic peptides and profibrotic connective tissue growth factor compared to nondiabetic Wistar rats. The high dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction. Enalapril and omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high dietary sodium. Compared to enalapril, omapatrilat reduced the echocardiographically measured left ventricular mass during normal-sodium diet and improved the diastolic function during high-sodium diet in GK rats. Furthermore, omapatrilat reduced relative cardiac weight more effectively than enalapril during high sodium intake. Our results suggest that both the renin–angiotensin and the neutral endopeptidase system are involved in the pathogenesis of diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective angiotensin converting enzyme inhibition alone.

Regression of Left Ventricular Hypertrophy After Arteriovenous Fistula Closure in Renal Transplant Recipients: A Long-Term Follow-Up

The long-term effects of hemodialysis arteriovenous fistula (AVF) closure on left ventricular (LV) morphology are unknown. Using echocardiography, we prospectively studied 17 kidney transplant recipients before, 1, and, 21 months after AVF closure (mean fistula flow 1371 +/- 727 mL/min). Eight kidney transplant recipients with a patent AVF, matched for age, time after AVF creation, and time after transplantation, served as controls. LV mass index (LVMI) decreased from 139 +/- 44 g/m2 before AVF closure to 127 +/- 45 g/m2 and 117 +/- 40 g/m2 at 1 and 21 months post-closure, respectively (p < 0.001), but remained unchanged in controls. LV hypertrophy prevalence (LVMI > 125 g/m2) decreased from 65% before, to 41% early, and 18%, late, after surgery (p = 0.008), mostly from a decrease in LV end-diastolic diameter. Consequently, the prevalence of LV concentric remodeling (relative wall thickness > 0.45 without hypertrophy) increased from 12% before, to 35% early, and 65% late, after surgery (p = 0.003). Diastolic arterial blood pressure increased from 78 +/- 15 mmHg before, to 85 +/- 13 mmHg early, and 85 +/- 10 mmHg late, after surgery (p < 0.015). In conclusion, closure of large and/or symptomatic AVF induces long-term regression of LV hypertrophy. However, residual concentric remodeling geometry as well as diastolic blood pressure increase may blunt the expected beneficial cardiac effects of the procedure.

Sympatho-modulatory therapies in perioperative medicine

With increasing life expectancy and improved surgical technology an ever-larger number of elderly patients with cardiovascular disease, or significant cardiovascular risk factors will undergo major surgery. More than 5% of an unselected surgical population undergoing non-cardiac surgery will suffer from perioperative cardiovascular complications including myocardial infarction and cardiac death. The incidence of adverse cardiac events may even reach 30% in high-risk patients undergoing vascular surgery causing a substantial financial burden of perioperative health care costs. 59 Thus, all therapeutic measures should be undertaken to reach the challenging goal of a lower incidence of perioperative cardiovascular complications. Gaining control over sympathetic nervous system activity, that is blunting the adrenergic response to the surgical trauma, traditionally represents an important aspect of anaesthetic practice. 21 Anaesthesiology has been regarded as the ‘practice of autonomic nervous system medicine’. While variable and moderate changes in sympathetic nervous system activity function as a servo-control mechanism and are even required to maintain and optimize cardiac performance, undue liberation of excitotoxic substances such as catecholamines and inflammatory cytokines, particularly during emergence from anaesthesia and the painful postoperative period, facilitates the occurrence of cardiovascular complications. 83 84 At this point, the life-supporting adrenergic drive (‘fight-or-flight-response’) turns into a potentially hazardous life-threatening maladaptation. In support of this concept, the beneficial effects of antiadrenergic treatment regimens in perioperative medicine have been confirmed, in observational studies, metaanalyses 55 1 66 and randomized controlled clinical trials. 43 54 59 63 80 84 However, the seemingly established concept of ‘sympatholysis’ as an effective cardioprotective treatment modality needs considerable refinement in the light of the many new experimental and clinical findings. The parlance of ‘sympatholytic’ protection erroneously equates annihilation of any type of adrenergic stimulation with cardioprotection and should be replaced by ‘sympathomodulatory’protection. The present review summarizes findings from large-scale heart failure trials and discusses basic and clinical aspects of individual sympatho-modulatory therapies, as currently used in perioperative medicine, including b-adrenergic antagonism, a2-agonism, and regional anaesthetic techniques. For limitation of space, reviews will often be cited where further references to the primary literature may be found.

Effects of long-term intake of edible oils on hypertension and myocardial and aortic remodelling in spontaneously hypertensive rats

The nature of dietary lipid intake contributes to blood pressure control. To test whether different edible lipid compounds are either beneficial or harmful to blood pressure and cardiac and aortic structure. Six groups of 3-month-old male spontaneously hypertensive rats (n = 5) received different edible oils (fish, canola, palm, olive and soybean oils, 1.5 g/kg per day + 1 IU/ml vitamin E) or a placebo (water) by gavage for 13 weeks. Stereology was used to analyse left ventricular cardiomyocytes, intramyocardial vessels, connective tissue, aortic lamellae and tunica media smooth muscle cells. Fish oil decreased blood pressure, and increases in blood pressure were prevented by both canola and palm oils. The cardiomyocyte and intramyocardial vessel indices were greater in the fish-, canola- and palm-oil groups and smaller in the soybean-oil, olive-oil and control groups; the opposite effects were found in interstitial connective tissue. The number of lamellae was smaller in the fish-oil group but greater in the soybean-oil, canola-oil, and olive-oil groups. Canola oil reduced aortic wall thickness, but palm oil did not. The number of smooth muscle cells was smaller in the groups given fish, canola and olive oils. The most beneficial cardiac and aortic structural effects occurred in the fish-oil group. Both canola oil and palm oil were also effective in reducing blood pressure, favouring myocardial remodelling, although they produced contrasting effects with regard to aorta wall structure. Soybean oil and olive oil had mild effects on myocardial and aortic structure.

924. Gene Therapy with IGF-1 Growth Factor for Heart Failure

Congestive heart failure (CHF) remains a significant therapeutic challenge. Efficacious therapies are few, and the incidence of CHF and associated death rates continue to rise. Interest in gene therapy for CHF can be directed towards preserving cardiomyocyte structure and improving its function. Beneficial cardiac effects of growth hormone and insulin-like growth factor-1 (IGF-1) have been shown in heart failure in several settings, but studies are lacking on such forms of treatment in the cardiomyopathic heart.

Dual inhibition of ACE and NEP provides greater cardioprotection in mice with heart failure*1

Background Vasopeptidase inhibitors (VPi) may provide a new means of treating hypertension and congestive heart failure, because they simultaneously block angiotensin-converting enzyme (ACE) and neutral endopeptidase-24.11 (NEP-24.11), thereby inhibiting the renin-angiotensin system and enhancing vasodilator and natriuretic substances such as kinins and natriuretic peptides. Methods Using B2 kinin receptor gene knockout mice (B2−/−), we tested the hypotheses that (1) VPi may provide better cardioprotection than ACE or NEP inhibitors alone (ACEi and NEPi) and (2) the effects of these inhibitors are partially mediated by kinins. Four weeks after myocardial infarction, B2−/− mice and B2+/+ mice were started on vehicle, ACEi (ramipril, 2.5 mg/kg/d), NEPi (candoxatril, 20 mg/kg/d) or VPi (omapatrilat, 50 mg/kg/d), which was continued for 20 weeks. Systolic blood pressure was measured weekly and cardiac function evaluated monthly by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were measured histopathologically. Results We found that ACEi or NEPi improved cardiac function and remodeling and that these effects were more obvious in mice receiving VPi. Furthermore, the beneficial cardiac effects of ACEi, NEPi, and VPi were significantly attenuated in B2−/− mice. We concluded that dual inhibition of ACE and NEP with VPi provides better cardioprotection than ACEi or NEPi alone in mice with congestive heart failure induced by myocardial infarction, and these effects are mediated at least in part via kinins.

Dual inhibition of ACE and NEP provides greater cardioprotection in mice with heart failure

Background Vasopeptidase inhibitors (VPi) may provide a new means of treating hypertension and congestive heart failure, because they simultaneously block angiotensin-converting enzyme (ACE) and neutral endopeptidase-24.11 (NEP-24.11), thereby inhibiting the renin-angiotensin system and enhancing vasodilator and natriuretic substances such as kinins and natriuretic peptides. Methods Using B 2 kinin receptor gene knockout mice (B 2−/−), we tested the hypotheses that (1) VPi may provide better cardioprotection than ACE or NEP inhibitors alone (ACEi and NEPi) and (2) the effects of these inhibitors are partially mediated by kinins. Four weeks after myocardial infarction, B 2−/− mice and B 2+/+ mice were started on vehicle, ACEi (ramipril, 2.5 mg/kg/d), NEPi (candoxatril, 20 mg/kg/d) or VPi (omapatrilat, 50 mg/kg/d), which was continued for 20 weeks. Systolic blood pressure was measured weekly and cardiac function evaluated monthly by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were measured histopathologically. Results We found that ACEi or NEPi improved cardiac function and remodeling and that these effects were more obvious in mice receiving VPi. Furthermore, the beneficial cardiac effects of ACEi, NEPi, and VPi were significantly attenuated in B 2−/− mice. We concluded that dual inhibition of ACE and NEP with VPi provides better cardioprotection than ACEi or NEPi alone in mice with congestive heart failure induced by myocardial infarction, and these effects are mediated at least in part via kinins.

Long-term effects of selective and nonselective endothelin receptor antagonists in mice with heart failure

Background: The ETA and ETB receptors mediate vasoconstriction, aldosterone release, and fibrosis. However, the role of ETB receptors is still controversial because those expressed on endothelial cells also stimulate vasodilatation and may oppose the actions of the ETA receptor. Plasma levels of endothelin-1 (ET-1) are increased in heart failure (HF) and are associated with myocardial dysfunction. The relative efficacy of selective and nonselective ET antagonists in the treatment of HF is unclear. We hypothesized that blockade of ETA receptors may improve cardiac function and prevent left ventricular remodeling in mice with HF, and these effects may be mediated in part by activation of ETB. Methods and Results: A mouse model of chronic HF induced by myocardial infarction (MI) was used. Seven days after MI, mice were divided into vehicle, ETA-ant, or ETA/B-ant groups and treated for 23 weeks. Cardiac function, LV dimensions, and hemodynamics were evaluated in conscious mice before MI and during treatment. Histologic analysis of the heart and liver was performed at the end of the study. HF significantly decreased EF and increased LV dimensions, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA). Both ETA-ant and ETA/B-ant slightly increased EF but had no significant effect on LV dimensions, hypertrophy, or ICF. Both treatments decreased MCSA; however, this was only significant in the ETA/B-ant group. Conclusions: Both selective and nonselective ET-ant have similar slight effects on cardiac function and remodeling. This suggests that (1) ETB receptors do not mediate the beneficial cardiac effects of ETA-ant and (2) blockade of the ET system alone may not provide significant cardioprotection, at least in mice with HF induced by MI.

Long-term effects of selective and nonselective endothelin receptor antagonists in mice with heart failure

Background: The ETA and ETB receptors mediate vasoconstriction, aldosterone release, and fibrosis. However, the role of ETB receptors is still controversial because those expressed on endothelial cells also stimulate vasodilatation and may oppose the actions of the ETA receptor. Plasma levels of endothelin-1 (ET-1) are increased in heart failure (HF) and are associated with myocardial dysfunction. The relative efficacy of selective and nonselective ET antagonists in the treatment of HF is unclear. We hypothesized that blockade of ETA receptors may improve cardiac function and prevent left ventricular remodeling in mice with HF, and these effects may be mediated in part by activation of ETB. Methods and Results: A mouse model of chronic HF induced by myocardial infarction (MI) was used. Seven days after MI, mice were divided into vehicle, ETA-ant, or ETA/B-ant groups and treated for 23 weeks. Cardiac function, LV dimensions, and hemodynamics were evaluated in conscious mice before MI and during treatment. Histologic analysis of the heart and liver was performed at the end of the study. HF significantly decreased EF and increased LV dimensions, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA). Both ETA-ant and ETA/B-ant slightly increased EF but had no significant effect on LV dimensions, hypertrophy, or ICF. Both treatments decreased MCSA; however, this was only significant in the ETA/B-ant group. Conclusions: Both selective and nonselective ET-ant have similar slight effects on cardiac function and remodeling. This suggests that (1) ETB receptors do not mediate the beneficial cardiac effects of ETA-ant and (2) blockade of the ET system alone may not provide significant cardioprotection, at least in mice with HF induced by MI.

Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B(2) kinin receptor gene knockout mice.

Using B(2) kinin receptor gene knockout mice (B(2)(-/-)), we tested the hypothesis that (l) lack of B(2) receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT(1)-ant), whereas lack of B(2) receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B(2)(-/-) and 129/SvEvTac mice (wild-type control, B(2)(+/+)). An ACEi (ramipril, 2.5 mg/kg/d) or AT(1)-ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B(2)(+/+) and B(2)(-/-) mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 64+/-10% versus 21+/-5% [P<0.01]; increase in CO, 69+/-17% versus 23+/-9% [P<0.01]; overall decrease in LVDd, -24+/-3% versus -7+/-4% [P<0.01]; and decrease in LV mass, -38+/-3% versus -6+/-6% [P<0.01]). AT(1)-ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 46+/-10% versus 25+/-9% [P<0.01]; increase in CO, 44+/-14% versus 15+/-5% [P<0.01]; overall decrease in LVDd, -14+/-4% versus -6+/-3% [P<0.01]; and decrease in LV mass, -33+/-4 versus -16+/-7% [P<0.01]). The effect of ACEi or AT(1)-ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B(2)(-/-) mice. We concluded that (1) lack of B(2) kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B(2) receptor play an important role in the cardioprotective effect of ACEi and AT(1)-ant.

Effects of growth hormone on cardiac dysfunction and gene expression in genetic murine dilated cardiomyopathy.

Beneficial cardiac effects of growth hormone (GH) have been shown in heart failure in several settings, but studies are lacking on this and other forms of treatment in the cardiomyopathic (CM) mouse heart. In mice with dilated cardiomyopathy due to disruption of the muscle LIM protein (MLP) gene [MLP null mice (MLP-/-)], natural history was first assessed by an initial echocardiogram at 8 weeks and a later follow-up study (n = 31). In most mice, left ventricular (LV) dilation increased and/or function decreased by 5 months, and 3 of 12 mice followed for 9 months died. At the end of follow-up, 22 MLP-/- mice (average age 10.2 months) had both LV dilation and reduced LV function and were selected for studies of GH effects on cardiac function and gene expression; mice were randomized to vehicle (controls) or recombinant human (rh) GH and restudied after 2 weeks. In the GH-treated group compared to the control group, LV % fractional shortening and LV wall thickness (echocardiography) were increased, the LV dP/dtmax (catheter-tip micromanometry) was enhanced, and LV relaxation (tau) improved; however, the LV weight was not significantly increased. The LV expression of many genes was altered in MLP-/- mice, and several were influenced by GH. Thus, short-term RhGH treatment improved LV function in a setting of chronic cardiac deterioration and significantly reduced elevated LV mRNA expression of some (ANP, BNP) but not other members of the embryonic gene program. The MLP null cardiomyopathic mouse can be useful for exploring altered signaling and therapeutic interventions in heart failure.

Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats.

Using Brown Norway Katholiek (BNK) rats, which are deficient in kininogen (kinin precursor) due to a mutation in the kininogen gene, we examined the role of endogenous kinins in 1) normal cardiac function; 2) myocardial infarction (MI) caused by coronary artery ligation; 3) cardiac remodeling in the development of heart failure (HF) after MI; and 4) the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEI) on HF after MI. Two months after MI, rats were randomly treated with vehicle or the ACEI ramipril for 2 mo. Brown Norway rats (BN), which have normal kininogen, were used as controls. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and ejection fraction (EF) as well as myocardial infarct size (IS), interstitial collagen fraction (ICF), cardiomyocyte cross-sectional area (MCA), and oxygen diffusion distance (ODD) were measured. We found that 1) cardiac hemodynamics, function, and histology were the same in sham-ligated BN and BNK rats; 2) IS was similar in BN and BNK; 3) in rats with HF treated with vehicle, the decrease in LVEF and the increase in LVEDV, LVESV, LVEDP, ICF, MCA, and ODD did not differ between BNK and BN; and 4) ACEI increased EF, decreased LVEDV and LVESV, and improved cardiac remodeling in BN-HF rats, and these effects were partially blocked by the bradykinin B(2) receptor antagonist icatibant (HOE-140). In BNK-HF rats, ACEI failed to produce these beneficial cardiac effects. We concluded that in rats, lack of kinins does not influence regulation of normal cardiac function, myocardial infarct size, or development of HF; however, kinins appear to play an important role in the cardioprotective effect of ACEI, since 1) this effect was significantly diminished in kininogen-deficient rats and 2) it was blocked by a B(2) kinin receptor antagonist in BN rats.

Renal Effects of L-DOPA in Heart Failure

We examined whether low-dose L-DOPA treatment induces natriuresis and diuresis in patients with congestive heart failure who have cardiac decompensation despite treatment with digoxin, a diuretic, and an angiotensin-converting enzyme inhibitor and who respond acutely to intravenously infused dopamine. In a randomized, double-blind, placebo-controlled crossover study, 11 patients with severe congestive heart failure received L-DOPA (0.10 g, p.o., t.i.d., for 1 day and then 0.25 g, p.o., t.i.d., for 2 days after a washout period of > or = 1 day), with assessments of plasma and urinary levels of catechols, urinary volume, and sodium content, and clinical and laboratory measures of improvement of congestive heart failure. L-DOPA elicited short-term, dose-related increases in urinary volume and sodium excretion. At the 0.10-g dose, L-DOPA increased plasma L-DOPA levels and urinary L-DOPA excretion by about fivefold, whereas at the 0.25-g dose, L-DOPA increased plasma and urinary L-DOPA by >50-fold. Twenty-four-hour urinary dopamine excretion increased by about fivefold after the low dose of L-DOPA and approximately 50-fold after the high dose. The results demonstrate that oral L-DOPA treatment can produce beneficial natriuretic and diuretic effects in selected patients with congestive heart failure. The bioavailability of oral L-DOPA appears to vary with the dose. These results support findings from previous studies about beneficial cardiac functional effects of L-DOPA in patients with refractory heart failure.

Efficacy of nasal continuous positive airway pressure therapy in chronic heart failure: importance of underlying cardiac rhythm

BACKGROUNDSome previous reports have indicated beneficial cardiac effects of nasal continuous positive airway pressure (NCPAP) in patients with severe congestive heart failure (CHF), but others have reported deleterious cardiac effects,...