Untreated Congestive Heart Failure Research Articles

Effects of Angiotensin 1-7 and Mas Receptor Agonist on Renal System in a Rat Model of Heart Failure.

Congestive heart failure (CHF) is often associated with impaired kidney function. Over- activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid salt/water retention and cardiac hypertrophy in CHF. While the deleterious effects of angiotensin II (Ang II) in CHF are well established, the biological actions of angiotensin 1-7 (Ang 1-7) are not fully characterized. In this study, we assessed the acute effects of Ang 1-7 (0.3, 3, 30 and 300 ng/kg/min, IV) on urinary flow (UF), urinary Na+ excretion (UNaV), glomerular filtration rate (GFR) and renal plasma flow )RPF) in rats with CHF induced by the placement of aortocaval fistula. Additionally, the chronic effects of Ang 1-7 (24 µg/kg/h, via intra-peritoneally implanted osmotic minipumps) on kidney function, cardiac hypertrophy and neurohormonal status were studied. Acute infusion of either Ang 1-7 or its agonist, AVE 0991, into sham controls, but not CHF rats, increased UF, UNaV, GFR, RPF and urinary cGMP. In the chronic protocols, untreated CHF rats displayed lower cumulative UF and UNaV than their sham controls. Chronic administration of Ang 1-7 and AVE 0991 exerted significant diuretic, natriuretic and kaliuretic effects in CHF rats, but not in sham controls. Serum creatinine and aldosterone levels were significantly higher in vehicle-treated CHF rats as compared with controls. Treatment with Ang 1-7 and AVE 0991 reduced these parameters to comparable levels observed in sham controls. Notably, chronic administration of Ang 1-7 to CHF rats reduced cardiac hypertrophy. In conclusion, Ang 1-7 exerts beneficial renal and cardiac effects in rats with CHF. Thus, we postulate that ACE2/Ang 1-7 axis represents a compensatory response to over-activity of ACE/AngII/AT1R system characterizing CHF and suggest that Ang 1-7 may be a potential therapeutic agent in this disease state.

Abstract 9961: Combination Therapy with Selective Endothelin Type A Receptor Blockade and Angiotensin-converting Enzyme Blockade Improves Survival of Congestive Heart Failure Similarly to Both Monotherapies: Study in Ren-2 Transgenic Hypertensive Rats with Aorto-Caval Fistula

Introduction: New therapeutic strategies for congestive heart failure (CHF) are needed, and the current knowledge, including our previous studies, suggests that targeting the endothelin (ET) system could be a promising approach. Hypothesis: Chronic selective blockade of ET type A (ETA) receptors combined with angiotensin-converting enzyme inhibitor (ACEi) would attenuate the course of CHF induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Methods: ACF was created in Ren-2 transgenic rats (TGR), a model of angiotensin II-dependent hypertension, at the animal age of 8 weeks. Two weeks later the animals were randomly divided into four groups and the therapy began: chronic selective blockade of ETA receptors with atrasentan (ETA block.) (5 mg.kg-1.day-1 in drinking water, n = 31), angiotensin-converting enzyme inhibitor (ACEi) (trandolapril, 2 mg.L-1 in drinking water, n = 32), a combination of atrasentan plus trandolapril (ETA block. + ACEi) ( 5 mg.kg-1.day-1 + 2 mg.L-1 in drinking water, n = 31) or placebo (n = 30). Sham-operated TGR represented a control group (n = 8). The follow-up period was 20 weeks. GraphPad Prism 7 was used for statistical analysis with a log-rank (Mantel-Cox) test to analyze survival data. Results: All sham-operated rats survived till the end of the study. Contrary, all untreated CHF rats died by week 12. The treatment with the ETA block. or with ACEi similarly improved the survival rate, and the final rate was 45 % in ETA block. group (p < 0,01) and 62 % in ACEi group (p < 0,01), the combinational therapy (ETA block. + ACEi) improved survival rate over placebo (52 %, p < 0,01) but not compared with both monotherapies. Conclusions: Our present results suggest that in ACF TGR, the combination treatment with ETA block. and ACEi did not markedly attenuate CHF-dependent mortality over both monotherapies. Thus, more preclinical research needs to be done to deeper understand the endothelin system in CHF.

Effective Treatment of Secondary Hypogonadism with Clomiphene Citrate in a Male Patient with Secondary Polycythemia and History of Transient Ischemic Attack

Testosterone replacement therapy is the mainstay treatment for both primary and secondary hypogonadism. Clinical benefits of testosterone include improvement of the muscle mass, libido, and bone density. However, there are potential risks associated with it, including hypercoagulability, prostate cancer, worsening sleep apnea, cardiovascular disease etc. There are contraindications for treatment as per current guidelines of AACE/. Therefore, initiating testosterone should be done with caution and after excluding breast, prostatic cancers, PSA above 4ng/ml or above 3ng/ml in high risk patients-AfricanAmerican or having first degree relative with prostatic cancer, untreated Congestive heart failure, untreated severe sleep apnea, thrombophilia, Stroke, Transient ischemic attack (TIA) and myocardial Infarction (MI) within 6 months, Hematocrit (HCT) above 50% or if the patient seeks fertility. Given the high prevalence of cardiovascular disease worldwide testosterone replacement therapy may not be an option for every patient. We are describing a case regarding a patient successfully treated with the SERM- Clomiphene citrate a SERM with improvement of Testosterone to normal ranges, improvement of erectile dysfunction and morning erections and libido without the side effects of testosterone injections like polycythemia.

Is Two Better Than One? Anticipation of a Favorable Hemodynamic Profile by Combining the Hypnotic Drugs for Induction of Anesthesia.

Is Two Better Than One? Anticipation of a Favorable Hemodynamic Profile by Combining the Hypnotic Drugs for Induction of Anesthesia.

SECONDARY HYPERPARATHYROIDISM IN AFRICAN AMERICANS WITH HEART FAILURE AND MILD TO MODERATE RENAL INSUFFICIENCY.

Purpose Secondary hyperparathyroidism (SHPT) has been reported in African Americans (AAs) hospitalized with untreated congestive heart failure (CHF) that suggests that the elevation in serum parathyroid hormone (PTH) is not simply furosemide-related urinary wasting of Ca 2+ and Mg 2+ . SHPT has also been found in AAs hospitalized with CHF who had been treated medically. In patients with chronic renal failure, a marked decline in creatinine clearance of Methods and Results At the time of admission, serum PTH (pg/mL) and calculated creatinine clearance (CrCl; mL/min) by Cockcroft-Gault formula were determined in 68 AAs followed at the Regional Medical Center in Memphis: 18 were inpatients (11 M, 7 F; 53.7 ± 2.9 years) with CHF of protracted duration (D ≥ 4 weeks) and 19 were inpatients (13 M, 6 F; 50.7 ± 2.7 years) with CHF of shorter (1-2 weeks) duration (D 1-2 weeks) at the time of admission, each of whom had reduced ejection fraction (EF) ( Conclusions SHPT was found in all AAs with CHF of a protracted nature and 59% with CHF of a shorter duration but not in those with compensated failure or non-HF controls. Renal dysfunction was present in AAs with decompensated failure and in whom SHPT was present. However, based on calculated CrCl, renal dysfunction was considered to be of either mild or moderate severity. Thus, renal insufficiency is not likely a major covariant contributing to the appearance of SHPT in AAs with CHF.

SECONDARY HYPERPARATHYROIDISM, INTRACELLULAR CALCIUM OVERLOADING, AND OXIDATIVE STRESS IN RATS WITH ALDOSTERONISM.

Purpose Secondary hyperparathyroidism (SHPT) has been reported in patients hospitalized with untreated congestive heart failure (CHF) as well as those treated medically (Am J Med Sci 2006;331:30). Mechanisms responsible for Ca2+ dyshomeostasis include Ca2+ and Mg2+ wasting in urine and feces associated with aldosteronism and loop diuretic treatment and hypovitaminosis D in housebound individuals because of their effort intolerance. SHPT appears in rats receiving aldosterone (ALDO; 0.75 μg/h) and 1% NaCl in their drinking water (ALDOST), and where elevations in plasma parathyroid hormone (PTH) lead to intracellular Ca2+ overloading in diverse tissues, including peripheral blood mononuclear cells (PBMC). We hypothesized that the SHPT seen in rats receiving ALDOST could be prevented by cotreatment with 1,25(OH)2D3 (calcitriol; 6 ng/d SC) and a diet supplemented with Ca2+ (2.5%) and Mg2+ (0.5%) (CCM). Methods and Results Eight-week-old male Sprague-Dawley rats received ALDOST alone for 4 weeks or together with CCM. We monitored plasma PTH and ionized [Ca2+]o, cytosolic-free [Ca2+]i, and H2O2 production in PBMC. Compared with age-/gender-matched, untreated controls, we found that ALDOST (mean ± SEM) was accompanied by a reduction (p Conclusions The ionized hypocalcemia that accompanies aldosteronism in rats and that contributes to the appearance of SHPT can be prevented by calcitriol and dietary Ca2+ and Mg2+ supplements. In so doing, this regimen prevents PTH-mediated intracellular [Ca2+]i overloading and induction of oxidative stress. These findings raise the prospect that the SHPT found in CHF could be managed with macro- and micronutrients.

Pirfenidone Prevents the Development of a Vulnerable Substrate for Atrial Fibrillation in a Canine Model of Heart Failure

Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. In a canine model, congestive heart failure (CHF) produces significant atrial fibrosis and the substrate for sustained AF. This atrial remodeling is a potential therapeutic target. The objective of the present study is to evaluate the effects of the antifibrotic drug pirfenidone (PFD) on arrhythmogenic atrial remodeling in a canine CHF model. We studied 15 canines, divided equally into 3 groups: control, CHF canines not treated with PFD, and CHF canines treated with PFD. CHF was induced by ventricular tachypacing (220 bpm for 3 weeks), and oral PFD was administered for the 3-week pacing period. We performed electrophysiology and AF vulnerability studies, atrial fibrosis measurements, and atrial cytokine expression studies. Only canines in the untreated CHF group developed sustained AF (>30 minutes, 4 of 5 canines; P<0.05). Treatment of CHF canines with PFD resulted in an attenuation of arrhythmogenic left atrial remodeling, with a significant reduction in left atrial conduction heterogeneity index (median [25% to 75% interquartile range] 4.96 [3.53 to 5.64] versus 2.52 [2.11 to 2.82], P<0.01; pacing cycle length 300 ms), left atrial fibrosis (16.0% [13.0% to 17.5%] versus 8.7% [5.7% to 10.6%], P<0.01), and AF duration (1800 [1020 to 1800] seconds versus 6 [5 to 22] seconds, P<0.01). Immunoblotting studies demonstrated the drug's effects on multiple cytokines, including a reduction in transforming growth factor-beta1 expression. Treatment of CHF canines with PFD results in significantly reduced arrhythmogenic atrial remodeling and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.

Propargylamine derivatives provide therapeutic efficacy in in vitro and in vivo experimental models of heart diseases

Based on the premise that neurons and cardiac myocytes share similar mechanisms of cell death, we tested the hypothesis that the neuroprotective propargylamine derivatives (of which rasagiline was recently approved for Parkinsonian patients), TVP1022 (N-propargyl-1-S-aminoindan) and propargylamine, can provide protection against myocardial damage and death caused by several provocative stimuli, including volume-overload and those mimicking myocardial ischemia. The hypothesis was tested in H9c2 cardiac cell line, neonatal rat ventricular myocytes (NRVM), naive rats and rats with volume overload-induced congestive heart failure (CHF) created by aorto-caval fistula. Our main findings were: (1) In embryonic rat heart cell line H9c2, Fas-mediated apoptosis was prevented by TVP1022 and propargylamine. (2) In NRVM, Fas-mediated hypertrophy was blocked by TVP1022 and propargylamine. (3) In naive rats, 3 weeks of treatment with propargylamine increased the Bcl-2/Bax ratio by 200% and mitochondrial PKCε by 125%. (4) In CHF rats, after 3 weeks of treatment (1 week before surgery and 2 weeks after surgery) with TVP1022, mitochondrial PKCε was increased by 50%, cytosolic cytochrome C was reduced by 70% and mitochondrial Bax was reduced by 35%, compared to untreated CHF rats. (5) Importantly, TVP1022 completely prevented the hypertrophy as well as the reduction in fractional shortening (determined by echocardiography) in CHF rats. In conclusion, the molecular mechanisms underlying the cardioprotective efficacy of the propargylamine derivatives tested are very similar to those described for neuroprotection. Based on these findings, we propose that propargylamine derivatives should be considered as potential therapeutic agents for preventing and treating cardiovascular disorders.

Normalization of renal aquaporin-2 water channel expression by fosinopril, valsartan, and combination therapy in congestive heart failure: a new mechanism of action

This study investigated the effect of fosinopril (Fos), valsartan (Val), and combination of both drugs (Fos + Val) on the cardiac and renal expression of aquaporin-1 (AQP1) and aquaporin-2 (AQP2) in congestive heart failure (CHF). A rat model of CHF was created by ligating the left anterior descending coronary artery to induce acute myocardial infarction (AMI). Rats were treated by Fos, Val, or Fos + Val for 4 weeks. In renal medulla and cortex, AMI was associated with 2.2- and 1.8-fold increase in AQP2 mRNA expression when compared with Sham-operated rats (medulla: 23.6 ± 2.8 vs. 52.3 ± 8.7%; P < 0.001; cortex: 19.4 ± 3.9 vs. 35.5 ± 7.1%; P < 0.05). All the treatment regimens were able to normalize AQP2 transcription in the renal medulla (Fos, 19.9 ± 4.9%; Val, 22.8 ± 4.9%; Fos + Val, 20.1 ± 5.1%; P = NS vs. Sham) and in the cortex (Fos, 21.2 ± 6.7%; Val, 20.4 ± 6.0%; Fos + Val, 18.9 ± 7.5%; P = NS vs. Sham). Similarly, the AQP2 protein expression increased by 2.1-fold after CHF ( P < 0.05), and was normalized by the treatment regimens (Sham, 0.57 ± 0.19%; CHF, 1.22 ± 0.45%; Fos, 0.39 ± 0.36%; Val, 0.46 ± 0.34%; Fos + Val, 0.36 ± 0.15%; all P < 0.05 vs. CHF). These treatment regimens also prevented the increase in body weight as found in untreated CHF rats (analysis of variance P < 0.05). The renal and cardiac AQP1 gene and protein expressions were unaltered in CHF or by medical therapy. There was no observed cardiac AQP2 expression in all the study groups. Treatment with Fos, Val, or combination therapy was effective in preventing the upregulation of renal AQP2 gene and protein expressions in CHF rats caused by AMI.

Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention.

While both the endothelin-1 (ET-1) and renin-angiotensin systems (RAS) are activated in congestive heart failure (CHF), the temporal sequence of this activation remains unclear. Understanding this pattern of neurohumoral activation may aid in understanding the significance of ET-1 in CHF and provide strategies for ET-1 antagonism. Although acute endothelin (ET) receptor antagonism improves systemic hemodynamics in CHF, clinical trials with chronic ET receptor antagonism report worsening CHF symptoms. In a canine model of progressive left ventricular dysfunction, we demonstrated activation of myocardial and plasma ET-1 without activation of the RAS during transition to overt CHF, suggesting that ET-1 contributes to this transition. We next evaluated the effects of chronic oral ET-A receptor antagonism on neurohumoral function, renal hemodynamics, and sodium excretion in pacing-induced CHF. After 7 days of treatment (n=7) with ET-A receptor antagonism (with LU135252), sodium excretion did not improve in treated versus untreated CHF (n=6). Furthermore, both plasma renin activity and plasma ET-1 increased with ET-A receptor blockade. Activation of the myocardial and plasma ET-1 systems precedes activation of the myocardial and plasma RAS in CHF. ET-A receptor antagonism in experimental CHF further activates the RAS without improving sodium excretion. These findings suggest an important role for ET-1 in the progression of CHF and a potential mechanism for the exacerbation of CHF symptoms observed in clinical trials with chronic ET receptor antagonism. Further studies with combined modulation of the ET and other neurohumoral systems in CHF are required.

Sympathetic Response to Ventricular Extrasystolic Beats in Hypertension and Heart Failure

Provoked premature ventricular contractions (PVCs) evoke, in concomitance with an early and late blood pressure fall and overshoot, an early sympathoexcitation and a later period of sympathoinhibition, respectively. The present study was designed to examine whether in healthy subjects this is the case for spontaneous PVCs. Because of their pathophysiological relevance for arrhythmogenesis, it was also designed to determine whether the sympathetic responses are different from those seen in essential hypertension and congestive heart failure. In 14 untreated mild essential hypertensives (EH; age, 53.8+/-2.6 years; mean+/-SEM), 20 untreated congestive heart failure patients (CHF; age, 56.7+/-2.5 years; New York Heart Association class, II or III), and 16 age-matched healthy subjects (control) in Lown class <II, we evaluated the blood pressure (Finapres), heart rate (ECG), and muscle sympathetic nerve traffic (MSNA; by microneurography) responses to isolated monofocal PVCs. MSNA, quantified as bursts/100 heart beats, was significantly increased in EH (57.8+/-3.8, P<0.05) and CHF patients (77.7+/-4.0, P<0.01) compared with controls (44.6+/-4.4). In controls, the PVC-induced blood pressure fall and overshoot were accompanied by a sympathoexcitation (144.2+/-14%), followed by a period of sympathoinhibition (average duration, 12043+/-985 ms). The responses were similar in EH but not in CHF, in whom the magnitude of the sympathoexcitation and particularly the duration of the subsequent sympathoinhibition were strikingly reduced (average reduction, -46.1 and -72.8%, respectively). The most important factor accounting for this reduction appeared to be an altered baroreflex response to the PVC-induced BP changes. These data demonstrate that the MSNA responses to spontaneous PVCs are similar in controls and EH but markedly impaired in CHF, presumably because of the baroreflex alteration. This may represent an important factor for the genesis of the life-threatening ventricular arrhythmias that characterize CHF.

Long-term angiotensin-converting enzyme and angiotensin I–receptor inhibition in pacing-induced heart failure: Effects on myocardial interstitial bradykinin levels

Background: We examined whether and to what degree long-term angiotensin-converting enzyme (ACE) inhibition, angiotensin type 1 (AT1)-receptor blockade, or combined inhibition in developing congestive heart failure (CHF) alter myocardial interstitial bradykinin (BF) levels. Methods and Results: Pigs (27–30 kg) underwent rapid pacing–induced CHF (240 bpm, 3 weeks; n = 10); pacing CHF with concomitant ACE inhibition (benezaprilat, 3.75 mg/day; n = 10); pacing CHF and concomitant AT1-receptor blockade (valsartan, 60 mg/day; n = 10); pacing CHF and combined inhibition (benezaprilat/valsartan, 1.87/60 mg/day, respectively; n = 10); or served as controls (no pacing, no treatment; n = 10). Steady-state myocardial interstitial BK levels were quantitated by microdialysis. Cardiac output decreased to 1.95 ± 0.18 L/min in pacing CHF compared with control (3.78 ± 0.38; P <.05). Cardiac output increased from untreated CHF values with concomitant ACE inhibition (3.91 ± 0.27 L/min), AT1-receptor blockade (3.30 ± 0.41 L/min), or combined ACE/AT1-receptor inhibition (4.13 ± 0.32 L/min; all P <.05 v CHF). With pacing CHF, myocardial interstitial BK levels were reduced by approximately 50% from control values and were normalized in the ACE inhibition and combined inhibition groups. Conclusions: Long-term ACE inhibition increases myocardial interstitial BK levels with CHF; addition of AT1-receptor blockade does not seem to abrogate these effects.

Treatment with a growth hormone secretagogue in a model of developing heart failure: effects on ventricular and myocyte function.

Exogenous administration of growth hormone (GH) and subsequently increased production of insulin-like growth factor-1 can influence left ventricular (LV) myocardial growth and geometry in the setting of congestive heart failure (CHF). This study determined the effects of an orally active GH secretagogue (GHS) treatment that causes a release of endogenous GH on LV function and myocyte contractility in a model of developing CHF. Pigs were randomly assigned to the following treatment groups: (1) chronic rapid pacing at 240 bpm for 3 weeks (n=11); (2) chronic rapid pacing and GHS (CP-424,391 at 10 mg x kg(-1) x d(-1), n=9); and (3) sham controls (n=8). In the untreated pacing CHF group, LV fractional shortening was reduced (21+/-2% versus 47+/-2%) and peak wall stress increased (364+/-21 versus 141+/-5 g/cm(2)) from normal control values (P:<0.05). In the GHS group, LV fractional shortening was higher (29+/-2%) and LV peak wall stress lower (187+/-126 g/cm(2)) than untreated CHF values (P:<0.05). With GHS treatment, the ratio of LV mass to body weight increased by 44% from untreated values. Steady-state myocyte velocity of shortening was reduced with pacing CHF compared with controls (38+/-1 versus 78+/-1 microm/s, P:<0.05) and was increased from pacing CHF values with GHS treatment (55+/-7 microm/s, P:<0.05). The improved LV pump function that occurred with GHS treatment in this model of CHF was most likely a result of favorable effects on LV myocardial remodeling and contractile processes. On the basis of these results, further studies are warranted to determine the potential role of GH secretagogues in the treatment of CHF.

Functional role of endogenous endothelin-1 in congestive heart failure treated with angiotensin II receptor antagonist.

Interactions between angiotensin (ANG) II and endothelin (ET)-1 receptor transduction pathways have been unclear in congestive heart failure (CHF). Therefore the objects of this study are, in CHF, whether production of ET-1 is modulated by ANG II and/or whether hemodynamic effects of endogenous ET-1 are modulated by ANG II. Twelve dogs were randomly assigned to two groups: untreated (n = 6) and treated with ANG II type 1 (AT1) receptor antagonist (TCV116, 1.5 mg/kg/d) (n = 6). After rapid ventricular pacing (240 bpm) for 4 weeks, plasma and cardiac ET-1 levels were compared between the two groups. Acute hemodynamic effects of a nonspecific ET(A&B) receptor antagonist, TAK044 (3 mg/kg plus 3 mg/kg/h i.v.) were examined in both groups by a conductance catheter and a micromanometer. After 4 weeks of pacing, plasma and cardiac tissue ET-1 levels were elevated in both groups to a similar degree. In the group treated with TCV116, TAK044 produced an increase in stroke volume and a decrease in total systemic resistance; heart rate was unchanged. The time constant of left ventricular (LV) relaxation was significantly decreased. The slope of LV end-systolic pressure-volume relation (E(ES)) was increased (p < 0.05), indicating an increased LV contractility. Thus endogenous ET-1 produces an arterial vasoconstriction and impairs LV contractility and relaxation in CHF with AT1 receptor antagonism. These hemodynamic responses to TAK044 in CHF treated with TCV116 were similar in untreated CHF. These results suggest that the production of ET-1 and the cardiac effects of endogenous ET-1 in CHF may be unaffected by ANG II acting through AT1 receptors.

ACE Inhibitors and Anemia in Congestive Heart Failure

The use of angiotensin-converting enzyme inhibitors can be accompanied by a number of adverse events, including cough, angioedema, and hyperkalemia, as well as a peculiar form of functional renal insufficiency. Other, less obvious side effects accompany ACE inhibitor use, such as a reduction in red blood cell production. This feature of ACE inhibitor use may be employed to good effect, as in the management of post-transplant erythrocytosis. Alternatively, the suppressive effect of ACE inhibitors on red blood cell production may intensify the anemia of chronic renal failure and/or congestive heart failure. The untreated congestive heart failure patient typically has an increased red blood cell mass as a consequence of increased erythropoietin levels, with the latter governed by congestive heart failure-related renal hypoxia. This is not expressed as an increase in hemoglobin concentration because of the increase in plasma volume that marks advanced congestive heart failure. ACE inhibitor therapy can be expected to both reduce plasma volume and decrease red blood cell production. As a result, the hemoglobin concentration changes very little in the ACE inhibitor-treated congestive heart failure patient and usually falls in the low normal range. Recently, erythropoietin has been employed to good effect in congestive heart failure patients with borderline anemia. (c)2000 by CHF, Inc.

Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure.

Release of growth hormone (GH), putatively through alterations in insulin growth factor-1 (IGF-1) levels, has been implicated to influence left ventricular (LV) myocardial structure and function. The objective of this study was to determine contributory mechanisms by which GH supplementation may influence LV function with the development of congestive heart failure (CHF). Pigs were assigned to the following groups: (1) chronic pacing at 240 bpm for 3 weeks (n = 10), (2) chronic pacing and GH supplementation (200 microg x kg(-1) x d(-1), n = 10), and (3) controls (n = 8). GH treatment increased IGF-1 plasma levels by nearly 2.5-fold throughout the pacing protocol. In the untreated pacing CHF group, LV fractional shortening was reduced and peak wall stress increased. In the pacing CHF and GH groups, LV fractional shortening was higher and LV wall stress lower than untreated CHF values. Steady-state myocyte velocity of shortening was reduced with pacing CHF and was unchanged from CHF values with GH treatment. In the presence of 25 nmol/L isoproterenol, the change in myocyte shortening velocity was reduced in the untreated CHF group and increased in the GH-treated group. LV sarcoplasmic reticulum Ca(2+)-ATPase abundance was reduced with pacing CHF but was normalized with GH treatment. Short-term GH supplementation improved LV pump function in pacing CHF as a result of favorable effects on LV remodeling and contractile processes. Thus, GH supplementation may serve as a novel therapeutic modality in developing CHF.

Amlodipine therapy in congestive heart failure: hemodynamic and neurohormonal effects at rest and after treadmill exercise

This study examined the acute effects of amlodipine treatment on left ventricular pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF), both at rest and with treadmill exercise. A total of 14 pigs were studied under control conditions and after the development of pacing-induced CHF (240 beats per minute, 3 weeks, n = 7) or with CHF and acute amlodipine treatment for the last 3 days of pacing (1.5 mg/kg per day, n = 7). Under resting conditions, left ventricular stroke volume (mL) was reduced with CHF compared with the normal state (15 ± 2 vs 31 ± 1, p <0.05) and increased with amlodipine treatment (23 ± 4, p <0.05). At rest, systemic vascular resistance increased with CHF compared with the normal state (3,078 ± 295 vs 2,131 ± 120 dyne · s cm −5, p <0.05) and was reduced after amlodipine treatment (2,472 ± 355 dyne · s cm −5, p <0.05). With exercise, left ventricular stroke volume remained lower and systemic vascular resistance higher in the CHF group, but was normalized with amlodipine treatment. With exercise, left ventricular myocardial blood flow increased from resting values, but was reduced from the normal state with CHF (normal: 1.69 ± 0.12 to 7.62 ± 0.74 mL/min per gram vs CHF: 1.26 ± 0.12 to 4.77 ± 0.45 mL/min per gram, both p <0.05) and was normalized with acute amlodipine treatment (1.99 ± 0.35 to 6.29 ± 1.23 mL/min per gram). Resting plasma norepinephrine was increased by >5-fold in the CHF group at rest and was not affected by amlodipine treatment. However, with exercise, amlodipine treatment blunted the increase in plasma norepinephrine by >50% when compared with untreated CHF values. Resting plasma endothelin levels increased with CHF compared with the normal state (10.9 ± 0.9 vs 2.8 ± 0.4 fmol/mL, p <0.05) and was reduced with amlodipine treatment (7.5 ± 1.5 fmol/mL, p <0.5). In other vascular beds, acute amlodipine treatment with CHF improved pulmonary and renal blood flow both at rest and with exercise; however, there were no effects observed on skeletal muscle blood flow. With the development of CHF, acute amlodipine treatment does not negatively influence left ventricular pump function, but rather may provide favorable hemodynamic and neurohormonal effects.

Angiotension AT1Receptor Inhibition in Pacing Induced Heart Failure: Effects on Left Ventricular Myocardial Collagen Content and Composition

The progression of left ventricular (LV) dilation with congestive heart failure (CHF) is associated with an increased incidence of morbidity and mortality. The LV myocardial extracellular matrix has been implicated to play an important role in maintaining chamber shape and myocyte alignment. While angiotensin II AT1receptor (Ang AT1) receptor activation has been demonstrated to contribute to increased vascular resistance with the CHF, whether activation of the myocardial Ang AT1receptor system contributes to LV dilation and myocardial collagen remodelling with CHF remains unclear. The goal of this study was to examine the effects of Ang AT1receptor inhibition on LV geometry and myocardial collagen content and structure with the development of pacing CHF. Pigs (25 kg) were instrumented in order to measure LV function in the conscious state and were assigned to one of three groups: (1) Pacing CHF: rapid atrial pacing (240 bpm) for 3 weeks (n=7); (2) Pacing CHF and Ang AT1Block: concomitant Ang AT1receptor blockade (valsartan, Novartis, Basel 60 mg/day) and rapid pacing (n=7); (3) sham controls (n=7). The Ang AT1receptor antagonist was delivered by osmotic minipump and this dose has been demonstrated previously to significantly blunt the Ang-II pressor response. LV pump function and geometry was assessed by echocardiography and LV myocardial collagen content by computer assisted histomorphometry and biochemistry. In the pacing CHF group, LV fractional shortening was reduced (17±2v45±1%) and LV end-diastolic dimension increased (5.91±0.09v3.75±0.07 cm) compared to controls (P<0.05). In the pacing CHF and Ang AT1blockade group, LV pump function and dimensions were similar to untreated pacing CHF values. The relative content of LV myocardial fibrillar collagen was reduced with pacing CHF (7.6±0.4v11.3±0.6%) compared to controls (P<0.05), and was similarly reduced in the pacing CHF and Ang AT1receptor blockade group (8.3±0.4%,P<0.05). LV myocardial hydroxyproline was reduced with pacing CHF compared to controls (2.35±0.21v2.89±0.42 mg/gdwt,P<0.05). While reduced with pacing CHF and Ang AT1receptor blockade (2.54±0.25 mg/gdwt), this was not significantly different from controls (P=0.23). Ang AT1receptor inhibition in this model of CHF did not appear to favorably affect the degree of LV dilation and myocardial collagen structure. These results suggest that activation of the myocardial Ang AT1receptor may not significantly contribute to LV remodelling with pacing CHF.

Chronic oral endothelin type A receptor antagonism in experimental heart failure.

Endothelin-1 (ET-1) is a cardiovascular peptide that binds to two distinct receptors, ET(A) and ET(B), resulting in systemic and regional vasoconstriction, alteration in sodium excretion, mitogenesis, and release of other vasoactive peptides such as atrial natriuretic peptide (ANP). A role for ET-1 has been proposed in congestive heart failure (CHF) based on the increase in circulating ET-1 in this cardiovascular disease state. The present study determined the cardiorenal and endocrine responses to chronic selective oral ETA antagonism in experimental CHF. Two groups of conscious dogs underwent 21 days of pacing-induced CHF. These groups included a control untreated group (n = 6) and a group that received an orally active ET(A) receptor antagonist (A-127722, Abbott Pharmaceuticals, 5 mg/kg PO bid, n = 6). Each group was studied at baseline before the onset of CHF and after 14 and 21 days of CHF. Compared with the CHF control group, the ET(A) receptor antagonism group at 14 days of CHF showed lower mean arterial pressure and systemic vascular resistance. Similarly, ET(A) receptor antagonism markedly attenuated the increase in circulating ANP despite similar atrial pressures. At 21 days of CHF, ET(A) receptor antagonism lowered pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance in association with a higher cardiac output. Plasma ANP remained suppressed. Despite the lower mean arterial pressure and circulating ANP in the ET(A) receptor antagonist group, the absolute decrease in sodium excretion from baseline was less compared with the untreated CHF control group. The present investigation supports the conclusion that endogenous ET-1 participates in the systemic and pulmonary vasoconstriction, the elevation of ANP, and the sodium retention that characterize this model of experimental CHF, suggesting a potential therapeutic role for ET(A) receptor antagonism in CHF.

Aldosterone in syndromes of untreated congestive heart failure

Aldosterone in syndromes of untreated congestive heart failure