The T.O.S.CA. Project: research, education and care.

Despite recent and exponential improvements in diagnostic-therapeutic pathways, an existing "GAP" has been revealed between the "real world care" and the "optimal care" of patients with chronic heart failure (CHF). We present the T.O.S.CA. Project (Trattamento Ormonale dello Scompenso CArdiaco), an Italian multicenter initiative involving different health care professionals and services aiming to explore the CHF "metabolic pathophysiological model" and to improve the quality of care of HF patients through research and continuing medical education.

Impaired endothelial- and nonendothelial-mediated vasodilation in patients with acute or chronic hypothyroidism.

OBJECTIVE: Vascular dysfunction and accelerated atherosclerosis are prominent features of hypothyroidism. The relative roles of thyroid hormone (TH) deficiency and the associated vascular risk conditions are still unclear. We studied the impact of acute and chronic hypothyroidism on vascular reactivity. PATIENTS: We studied 12 patients with chronic primary hypothyroidism (cHY; TSH: 52 +/- 14 mU/l), seven patients with acute hypothyroidism secondary to total thyroidectomy (aHY; TSH: 97 +/- 24) and 13 healthy subjects (TSH: 1.2 +/- 0.5). MEASUREMENTS: We measured forearm blood flow (FBF) using plethysmography during intra-brachial infusion of: acetylcholine (ACh), sodium nitroprusside (NP) and norepinephrine (NE). We also measured serum C-reactive protein (CRP), TNF-alpha, asymmetric dimethylarginine (ADMA) and the forearm balance of nitric oxide (NO) during ACh infusion. RESULTS: As compared with the controls, the vasodilatory response to ACh was reduced in cHY (P = 0.001) and aHY (P = 0.04), as was the forearm release of NO (P < 0.05). During NP infusion, FBF rose to 24 +/- 2 ml/dl/min in the controls and to significantly lower values in cHY (12 +/- 1; P = 0.001) and aHY (15 +/- 2; P = 0.004). NE-induced vasoconstriction was similar in the controls and aHY, but blunted in cHY. Serum CRP, TNF-alpha and ADMA were not different in the three groups. CONCLUSIONS: (i) Hypothyroidism associates with endothelial and nonendothelial mediated vascular dysfunction; (ii) these defects are evident even after short-term hypothyroidism, indicating that TH deficiency per se is sufficient to alter vascular homeostasis; and (iii) chronic, but not acute, hypothyroidism impairs the vasoconstrictory effect of NE in the resistance vessels.

[Anabolic/catabolic imbalance in chronic heart failure]. / Squilibrio anabolico/catabolico nello scompenso cardiaco cronico.

A metabolic imbalance between anabolic drive and catabolic forces is commonly observed in chronic heart failure (CHF) patients, with the latter prevailing over anabolic hormones. Moreover, anabolic deficiencies are independent markers of poor prognosis. This finding represents a solid background for the implementation of therapeutic trials based on replacement therapy. The somatotropic axis (GH/IGF-1) is the most powerful anabolic axis of the body and its decline is related with a poor outcome and a worse clinical status. Growth hormone (GH) administration may enter the therapeutic arena as adjunctive treatment in patients affected by CHF and GH/IGF-1 deficiency. The T.O.S.CA. project aims at investigating the relationship between CHF and hormonal deficiency.

Enhancement of vascular endothelial function by recombinant human thyrotropin.

CONTEXT: The cardiovascular consequences of thyroid diseases are attributed to the altered secretion of thyroid hormones. The possibility that TSH also affects the cardiovascular system has been poorly explored. Endothelial cells and vascular smooth muscle cells possess TSH receptors. OBJECTIVE: The study was designed to determine whether TSH exerts any effect on vascular homeostasis. SUBJECTS AND METHODS: Two different double-blind, controlled studies were performed, one in eight healthy volunteers and the other in six thyroidectomized patients. Recombinant human (rh) TSH (or saline) was infused intrabrachially (1 mU/min) to raise TSH to severe hypothyroidism levels (approximately 100 microU/ml). Endothelium-dependent and -independent vasodilation was tested by intraarterial infusion of acetylcholine and sodium nitroprusside, respectively, and forearm blood flow was measured by plethysmography. RESULTS: Endothelium-dependent vasodilation was potentiated by rhTSH (P < 0.05 for the treatment effect; general linear model). The dynamics of the response was also profoundly affected by rhTSH because the dose-response curve was much steeper than in controls (P < 0.02 for the interaction between TSH and acetylcholine). rhTSH had no effect on endothelium-independent vasodilation (P = NS for both treatment and interaction). During rhTSH infusion, free T(3) levels increased slowly from 2.3 +/- 0.2 to 3.6 +/- 0.2 pg/ml. In thyroidectomized patients, rhTSH potentiated endothelium-mediated vasodilation to an extent similar to that of healthy subjects (P = 0.05 for the treatment effect and P = 0.01 for the interaction), without affecting the response to nitroprusside. In these patients, thyroid hormones remained unchanged during rhTSH infusion. CONCLUSIONS: rhTSH exerts marked effects on the resistance vessels by enhancing endothelial-mediated vasodilation, independent of changes in thyroid hormone concentration.

Long-term cardiovascular effects of levothyroxine therapy in young adults with congenital hypothyroidism.

CONTEXT: Congenital hypothyroidism (CH) is the most prevalent endocrine disorder in the newborn and is routinely treated with life-long levothyroxine replacement therapy. Although several studies have demonstrated that such therapy may impact on the cardiovascular system, little is known with regard to the effects of long-term levothyroxine administration in patients with CH. OBJECTIVE: The aim of the current study was to evaluate whether long-term levothyroxine replacement therapy in young adults with CH is associated with cardiovascular abnormalities. PATIENTS AND METHODS: Thirty young adults with CH aged 18.1 +/- 0.2 yr and 30 age- and sex-matched controls underwent cardiac and carotid Doppler ultrasound and symptom-limited cardiopulmonary exercise testing. Hypothyroidism was diagnosed by neonatal screening, and levothyroxine treatment was initiated within the first month of life and carefully adjusted to maintain TSH levels in the normal range and free T(4) in the high-normal range. RESULTS: Compared with controls, hypothyroid patients exhibited left ventricular diastolic dysfunction, impaired exercise capacity, and increased intima-media thickness. At multiple regression analysis, the number of episodes of plasma TSH levels less than 0.5 mU/liter and greater than 4.0 mU/liter from the age of 1 yr onward, and mean TSH plasma levels during puberty were independent predictors of diastolic filling and cardiopulmonary performance indexes (multiple r values: 0.61-0.75). CONCLUSIONS: Long-term levothyroxine treatment in young adults with congenital hypothyroidism is associated with impaired diastolic function and exercise capacity and increased intima-media thickness.

Effects of growth hormone on exercise capacity and cardiopulmonary performance in patients with chronic heart failure.

BACKGROUND: Because GH exerted beneficial effects in various experimental models of heart failure, we investigated the effects of GH on physical exercise capacity and cardiopulmonary performance in patients with dilated cardiomyopathy and chronic heart failure (CHF). METHODS: Twenty-two patients with CHF (New York Heart Association functional class II-III) underwent spirometry and a symptom-limited, cardiopulmonary exercise testing before and after 3 months of GH (n = 11; seven males; seven idiopathic; 57 +/- 11 yr; 4 IU sc every other day) or placebo (n = 11; eight males; six idiopathic; 54 +/- 10 yr) administration, in a randomized, double-blind trial. Background CHF therapy remained unchanged. RESULTS: GH, but not placebo, increased IGF-I serum concentration (from 144 +/- 35 to 293 +/- 58 ng/ml; P < 0.005) and improved New York Heart Association functional class (from 2.4 +/- 0.5 to 1.8 +/- 0.4; P < 0.005), exercise duration (from 831 +/- 273 to 925 +/- 266 sec; P < 0.005), peak power output (from 245 +/- 127 to 280 +/- 132 W; P < 0.05), peak minute ventilation (from 52.5 +/- 16.1 to 61.3 +/- 17.3 liters/min; P < 0.05), peak oxygen consumption (from 19.8 +/- 5.6 to 25.1 +/- 5.6 ml/kg.min; P < 0.005), and anaerobic threshold (from 14.9 +/- 4.8 to 20.0 +/- 4.5 ml/kg.min; P < 0.005) without affecting lung function parameters. Furthermore, the slope of the relationship between minute ventilation and pulmonary carbon dioxide production (ventilatory efficiency) decreased from 34.7 +/- 5.1 to 31.7 +/- 5.3 (P < 0.005), whereas the slope of the relation between percent predicted heart rate reserve used and percent observed metabolic reserve used (chronotropic index) rose from 0.57 +/- 0.20 to 0.69 +/- 0.18 (P < 0.005). CONCLUSION: Given the predictive value of physical exercise capacity and cardiopulmonary performance in CHF progression, these data provide additional insights into the mechanisms by which GH may potentially benefit CHF patients.

Acute effects of triiodothyronine on endothelial function in human subjects.

CONTEXT: Thyroid hormone regulates several cardiovascular functions, and low T(3) levels are frequently associated with cardiovascular diseases. Whether T(3) exerts any acute and direct effect on endothelial function in humans is unknown. OBJECTIVE: Our objective was to clarify whether acute changes in serum T3 concentration affect endothelial function. DESIGN, SETTING, AND SUBJECTS: Ten healthy subjects (age, 24 +/- 1 yr) participated in a double-blind, placebo-controlled trial at a university hospital. INTERVENTIONS: T3 (or placebo) was infused for 7 h into the brachial artery to raise local T3 to levels observed in moderate hyperthyroidism. Vascular reactivity was tested by intraarterial infusion of vasoactive agents. MAIN OUTCOME MEASURES: We assessed changes in forearm blood flow (FBF) measured by plethysmography. RESULTS: FBF response to the endothelium-dependent vasodilator acetylcholine was enhanced by T3 (P = 0.002 for the interaction between T3 and acetylcholine). The slopes of the dose-response curves were 0.41 +/- 0.06 and 0.23 +/- 0.04 ml/dl x min/microg in the T3 and placebo study, respectively (P = 0.03). T3 infusion had no effect on the FBF response to sodium nitroprusside. T3 potentiated the vasoconstrictor response to norepinephrine (P = 0.006 for the interaction). Also, the slopes of the dose-response curves were affected by T3 (1.95 +/- 0.77 and 3.83 +/- 0.35 ml/dl x min/mg in the placebo and T3 study, respectively; P < 0.05). The increase in basal FBF induced by T3 was inhibited by NG-monomethyl-L-arginine. CONCLUSIONS: T3 exerts direct and acute effects on the resistance vessels by enhancing endothelial function and norepinephrine-induced vasoconstriction. The data may help clarify the vascular impact of the low T3 syndrome and point to potential therapeutic strategies.

Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes.

Vascular dysfunction, low-grade inflammation, insulin resistance, and impaired fibrinolysis have each been reported to be present in type 2 diabetes, but their relationships, and the role of obesity, have not been investigated. We measured insulin sensitivity (euglycemic clamp), forearm blood flow responses to graded local acetylcholine (Ach) and sodium nitroprusside (SNP) infusions, plasma concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, von Willebrand factor (vWF), plasminogen activator inhibitor (PAI)-1, tissue plasminogen activator (tPA), and high-sensitivity C-reactive protein (hs-CRP) in 81 diabetic patients. When patients were stratified by insulin resistance, more severe insulin resistance was associated (P < 0.05) with overweight, central fat distribution, hypertension, and dyslipidemia (with similar sex distribution, age, fasting plasma glucose, and HbA1c). With regard to vascular function, both endothelium-dependent (Ach) (-22, -40, and -52%; P < 0.0001) and -independent (SNP) (-3, -7, and -27%; P < 0.02) vasodilatation were progressively reduced across insulin resistance tertiles. In multivariate analysis, inflammatory markers (IL-6, hs-CRP, and TNF-alpha) were independently associated with insulin resistance and fasting glycemia, fibrinolytic markers PAI-1 and tPA with insulin resistance and central fat distribution, and vascular indexes (vWF, Ach, and SNP vasodilation) with insulin resistance and obesity or cytokines (TNF-alpha or IL-6). In type 2 diabetes, insulin resistance is associated with vascular dysfunction/damage, impaired fibrinolysis, and low-grade inflammation independently of obesity and poor glycemic control.

Growth Hormone Deficiency Is Associated with Worse Cardiac Function, Physical Performance, and Outcome in Chronic Heart Failure: Insights from the T.O.S.CA. GHD Study.

BACKGROUND: Although mounting evidence supports the concept that growth hormone (GH) deficiency (GHD) affects cardiovascular function, no study has systematically investigated its prevalence and role in a large cohort of chronic heart failure (CHF) patients. Aim of this study is to assess the prevalence of GHD in mild-to-moderate CHF and to explore clinical and functional correlates of GHD. METHODS: One-hundred thirty CHF patients underwent GH provocative test with GHRH+arginine and accordingly categorized into GH-deficiency (GHD, n = 88, age = 61.6±1.1 years, 68% men) and GH-sufficiency (GHS, n = 42, age = 63.6±1.5 years, 81% men) cohorts. Both groups received comprehensive cardiovascular examination and underwent Doppler echocardiography, cardiopulmonary exercise testing, and biochemical and hormonal assay. RESULTS: GHD was detected in roughly 30% of CHF patients. Compared to GHD, GHS patients showed smaller end-diastolic and end-systolic LV volumes (-28%, p = .008 and -24%, p = .015, respectively), lower LV end-systolic wall stress (-21%, p = .03), higher RV performance (+18% in RV area change, p = .03), lower estimated systolic pulmonary artery pressure (-11%, p = .04), higher peak VO2 (+20%, p = .001) and increased ventilatory efficiency (-12% in VE/VCO2 slope, p = .002). After adjusting for clinical covariates (age, gender, and tertiles of LV ejection fraction, IGF-1, peak VO2, VE/VCO2 slope, and NT-proBNP), logistic multivariate analysis showed that peak VO2 (ß = -1.92, SE = 1.67, p = .03), VE/VCO2 slope (ß = 2.23, SE = 1.20, p = .02) and NT-proBNP (ß = 2.48, SE = 1.02, p = .016), were significantly associated with GHD status. Finally, compared to GHS, GHD cohort showed higher all-cause mortality at median follow-up of 3.5 years (40% vs. 25%, p < .001, respectively), independent of age, sex, NT-proBNP, peak VO2 and LVEF. CONCLUSIONS: GH deficiency identifies a subgroup of CHF patients characterized by impaired functional capacity, LV remodeling and elevated NT-proBNP levels. GHD is also associated with increased all-cause mortality.

Growth hormone- and pressure overload-induced cardiac hypertrophy evoke different responses to ischemia-reperfusion and mechanical stretch.

OBJECTIVE: To compare the molecular, histological, and functional characteristics of growth hormone (GH)- and pressure overload-induced cardiac hypertrophy, and their responses to ischemia-reperfusion and mechanical stretch. DESIGN: Four groups of male Wistar rats were studied: aortic banding (n=24, AB) or sham (n=24, controls) for 10 weeks, and GH treatment (n=24; 3.5mg/kg/day, GH) or placebo (n=24, controls) for 4 weeks. At 13 weeks, the rats were randomly subjected to: (i) assessment of basal left ventricular mRNA expression of sarcoplasmic reticulum calcium-ATPase (SERCA-2), phospholamban (PLB), and Na(+)-Ca(2+) exchanger (NCX) and collagen volume fraction (CVF) (Protocol A, 8 rats in each group); (ii) left ventricular no-flow ischemia with simultaneous evaluation of intracellular Ca(2+) handling and ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) content (Protocol B, 12 rats in each group); or (iii) left ventricular mechanical stretch for 40 min with assessment of tumor necrosis-alpha (TNF-alpha) mRNA (Protocol C, 4 rats in each group). Protocol B and C were carried out in a Langendorff apparatus. RESULTS: In Protocol A, no difference was found as to myocardial mRNA content of Ca(2+) regulating proteins and CVF in GH animals vs controls. In contrast, in the AB group, myocardial mRNA expression of SERCA-2 and PLB was downregulated while that of NCX and CVF were increased vs. controls (p<0.05). In Protocol B, recovery of left ventricular function was significantly decreased in AB vs GH groups and controls and this was associated with 1.6-fold increase in intracellular Ca(2+) overload during reperfusion (p<0.05). Baseline ATP content was similar in the four study groups, whereas PCr and Pi was lower in AB vs GH rats and controls. However, the time courses of high-energy phosphate metabolic changes did not differ during ischemia and reperfusion in the four study groups. In Protocol C, no detectable TNF-alpha mRNA level was found in the left ventricular myocardium of GH treated rats and controls at baseline, while a modest expression was noted in AB animals. Mechanical stretch resulted in de novo myocardial TNF-alpha mRNA expression in GH group and controls, which was dramatically increased in AB animals ( approximately 5-fold above baseline, p<0.001). CONCLUSIONS: The data show that cardiac hypertrophy activated by short-term GH treatment confers cardioprotection compared with pressure overload with regard to molecular and histological characteristics, and responses to ischemia-reperfusion and mechanical stretch.

Hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21ras activation.

BACKGROUND: Patients with cardiac hypertrophy are at increased cardiovascular risk. It has been hypothesized that hydroxymethylglutaryl coenzyme A reductase inhibitors may exert beneficial effects other than their cholesterol-lowering actions. The aims of the study were to assess the in vivo effects of simvastatin (SIM) on cardiac hypertrophy and on Ras signaling in rats with ascending aorta banding. METHODS AND RESULTS: Wistar rats were randomized to receive either treatment with SIM or placebo, and then short-term (group I) and long-term (group II) left ventricular pressure overload was performed by placing a tantalum clip on ascending aorta. At the end of treatment period, left and right ventricular weight, body weight, and tibial length were measured and echocardiographic evaluations were performed. Ras signaling was investigated by analyzing Ras membrane localization and activation, ERK2 phosphorylation, and p27(kip1) and cdk4 levels. In SIM-treated rats, a significant reduction of left ventricular weight/body weight, echocardiographic left ventricular mass, and left ventricular end-diastolic diameter and end-diastolic pressure was found. In rats with pressure overload, SIM treatment significantly reduced Ras membrane targeting, Ras in vivo activation, ERK2 phosphorylation, and the ratio cdk4/p27(kip1). CONCLUSIONS: HMG CoA inhibitor SIM inhibits in vivo Ras signaling and prevents left ventricular hypertrophy development in aortic-banded animals.

Growth hormone corrects vascular dysfunction in patients with chronic heart failure.

OBJECTIVES: The goal of this study was to test the hypothesis that growth hormone (GH) administration to patients with chronic heart failure (CHF) corrects their vascular dysfunction. BACKGROUND: Endothelial dysfunction is a prominent feature of CHF. Recent evidence indicates that GH plays a role in vascular reactivity. METHODS: We studied vascular reactivity in 16 patients with CHF (New York Heart Association class II to III) before and after three months of GH (4 IU subcutaneously every other day) or placebo administration in a randomized, double-blind trial. We measured forearm blood flow (FBF) by strain-gauge plethysmography during intrabrachial, graded infusion of acetylcholine (ACh) and sodium nitroprusside (NP). We also measured the forearm balance of nitrite and cyclic guanosine monophosphate (cGMP) before and during ACh infusion. Maximal oxygen uptake (VO2max) was measured by breath-to-breath respiratory gas analysis. RESULTS: Before treatment, the response of FBF to ACh was flat (p = NS). Growth hormone, but not placebo, greatly improved this response (p = 0.03) and, concomitantly, increased the forearm release of nitrite and cGMP (p < 0.05). Growth hormone also potentiated the FBF response to NP (p = 0.013). Growth hormone interacted with ACh response (p = 0.01) but not with the response to NP (p = NS). Accordingly, GH enhanced the slope of the dose-response curve to ACh (p < 0.05) but not to NP. The VO2max increased significantly after GH treatment (20 +/- 2 and 26 +/- 2 ml x Kg(-1) x min(-1) before and after GH treatment, respectively, p < 0.05) but not after placebo. CONCLUSIONS: A three-month treatment with GH corrected endothelial dysfunction and improved non-endothelium-dependent vasodilation in patients with CHF. The data highlight the potential role of GH in the progression of congestive heart failure.

Growth hormone prolongs survival in experimental postinfarction heart failure.

OBJECTIVES: We evaluated the effects of growth hormone (GH) on survival in experimental heart failure (HF). BACKGROUND: Growth hormone has been beneficial in various models of experimental HF. Whether GH also affects HF progression and survival is not known. METHODS: A total of 119 rats with moderate myocardial infarction were randomized to receive either GH (3.5 mg/kg every other day) or placebo for 28 days. Treatment was initiated one month after coronary ligation; the follow-up lasted 13 months. In the surviving animals, Doppler echocardiography and closed-chest Millar left ventricular (LV) catheterization were performed. Apoptosis, collagen volume fraction, and capillary density in the LV zone remote from infarction were measured. The early effects of GH on apoptosis were also assessed in a subgroup of eight infarcted rats, treated as specified earlier and euthanized at one month. RESULTS: Survival rate was 68% in GH-treated rats and 48% in the placebo group (p = 0.0377). Growth hormone had no effect on myocardial architecture, systolic function, and sarcoplasmatic reticulum calcium ATPase-2 messenger ribonucleic acid. Growth hormone improved LV relaxation; this was associated with a 50% reduction in collagen volume fraction and a 27% increase in capillary density. Growth hormone reduced the apoptotic index by 50% at one month and by 33% at 13 months. CONCLUSIONS: Growth hormone prolonged survival of rats with postinfarction HF. This effect was associated with marked attenuation of cardiomyocyte apoptosis and pathologic interstitial remodeling in the surviving myocardium and enhanced LV relaxation.

Red wine consumption improves insulin resistance but not endothelial function in type 2 diabetic patients.

Epidemiological studies have shown that red wine consumption is associated with less cardiovascular mortality in the general population and in the diabetic patients. To determine whether red wine improves insulin resistance in diabetic patients and to explore the relation between insulin sensitivity and endothelial function, we studied vascular reactivity and insulin-mediated glucose uptake in 9 type 2 diabetic patients before and after 2 weeks of red wine consumption (360 mL/d, wine-treated diabetics) and 8 type 2 diabetic patients who did not consume wine (control diabetics). Vascular reactivity was evaluated by plethysmography during intraarterial infusion of acetylcholine (Ach), sodium nitroprusside, and L-N-monomethylarginine. Forearm nitrite balance was measured during Ach infusion. Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp at 1 mU/kg per minute. The basal forearm blood flow and the response to Ach, to sodium nitroprusside, and to L-N -monomethylarginine were unchanged both in the wine-treated and in the control diabetics. In contrast, insulin-mediated whole body glucose disposal improved by 43% after red wine consumption (from 2.79 +/- 0.4 to 4.02 +/- 0.5 mg/kg of lean body mass per minute, P = .02), but did not change in the control group. In conclusion, red wine consumption for 2 weeks markedly attenuates insulin-resistance in type 2 diabetic patients, without affecting vascular reactivity and nitric oxide production.

[The role of aldosterone in the development of postinfarction fibrosis]. / II ruolo dell'aldosterone nello sviluppo della fibrosi postinfartuale.

Aldosterone was discovered in 1953, and until the beginning of the 1960s, when spironolactone was developed, it was the focus of considerable interest among the scientific community. The following 30 years represented a sort of Dark Age, interrupted by the Weber's classic studies. He first demonstrated the pivotal role of aldosterone in the promotion of cardiac hypertrophy and fibrosis and such an observation represented a solid background for the implementation of large survival trials, the RALES and the EPHESUS. These landmark studies showed that aldosterone receptor blockade prolongs survival in advanced and postinfarction heart failure, respectively. After a myocardial infarction, there is a significant upregulation of the local steroidogenic system in the area remote from the scar, that leads to a remarkable fibroblast activation, collagen deposition, and reactive fibrosis. Fibrosis in turn further impairs systolic and diastolic function, and induces electrical heterogeneity with attendant ominous arrhythmias. The following review will dwell upon the importance of fibrosis in postinfarction heart failure, the role of aldosterone, and the novel therapeutic approach based on mineralocorticoid receptor blockade.

Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure.

OBJECTIVES: To investigate the effects of aldosterone receptor blockade in postinfarction heart failure. METHODS: Eighty-seven rats with moderate myocardial infarction were randomized to receive either no drug or canrenone, the active metabolite of spironolactone, 20 mg/kg/day, or ramipril, 1 mg/kg/day, or a combination of the two drugs. Treatment was initiated 1 month after coronary ligation and lasted 4 weeks. Echocardiography was performed at baseline and after 4 weeks. LV catheterization, isolated heart studies, morphometric histology, myocardial norepinephrine and SERCA-2 mRNA were assessed at the end of the treatment period. RESULTS: Infarct sizes were 33+/-3, 32+/-3, 34+/-3, and 34+/-4% in the placebo, canrenone, ramipril, and combination groups, respectively. Canrenone attenuated LV remodeling, improved LV systolic and diastolic function, and markedly reduced interstitial and perivascular fibrosis. These effects were increased by concomitant ramipril therapy. Moreover, myocardial norepinephrine content was decreased while ventricular fibrillation threshold significantly augmented by canrenone. SERCA-2 levels remained unchanged. CONCLUSIONS: Canrenone attenuated LV dilation and interstitial remodeling, and improved LV filling dynamics and systolic function in the rat model of postinfarction heart failure. Addition of ramipril conferred further cardioprotection. Canrenone also reduced myocardial norepinephrine content and increased ventricular fibrillation threshold. The data provide a potential explanation for the decreased sudden death observed in the RALES study. The mechanisms of action of aldosterone inhibition are still poorly understood, despite its proven efficacy in heart failure. Rats with postinfarction heart failure were randomized to receive for 1 month either no drug or canrenone, or ramipril, or a combination of canrenone and ramipril. Canrenone treatment was associated with a significant attenuation of LV dilation, better LV diastolic and systolic dynamics, and a marked reduction of reactive fibrosis. These effects were enhanced by concomitant ramipril therapy. Moreover, canrenone increased ventricular fibrillation threshold and reduced myocardial norepinephrine content. The data may explain the reduced mortality demonstrated by the RALES.

Mesoglycan improves vascular reactivity and insulin sensitivity in patients with metabolic syndrome.

OBJECTIVES: The aim of this study was to evaluate the acute and chronic effects of mesoglycan on the endothelial function and arterial elastic properties in patients with metabolic syndrome (MetS). BACKGROUND: MetS is defined by a clustering of vascular risk factors that demand both pharmacologic and non-pharmacologic interventions, including body weight reductions and physical activity. The correction of endothelial dysfunction and arterial wall distensibility associated with MetS have lately received increasing interest. METHODS: Thirty consecutive ambulatory patients affected by MetS were 2:1 randomized in a double-blind fashion to receive mesoglycan or placebo, respectively. In the first phase of the study, we evaluated the acute effects of a single i.m. administration of mesoglycan (60 mg) or placebo on vascular reactivity, as assessed by brachial flow-mediated dilation (FMD). Then, patients were chronically treated with mesoglycan per os (50 mg twice a day) or placebo for 90 days. At the end of this period, vascular reactivity and the arterial wall elastic properties were evaluated. RESULTS: In the mesoglycan group, FMD increased above baseline after acute administration, with a maximum increment of 52% after 2 h. FMD was also significantly greater than baseline after 90 days of chronic treatment. In the placebo group, FMD was unaffected by both acute and chronic mesoglycan administration. Moreover, after 90 days of mesoglycan treatment, a marked improvement in arterial distensibility and compliance was detected and arterial stiffness reduced significantly. CONCLUSIONS: This small, preliminary study shows that mesoglycan exerts relevant effects on vascular physiology, both in an acute setting as well as after prolonged, three-month treatment, in patients affected by metabolic syndrome.

Acute effects of growth hormone on vascular function in human subjects.

GH is involved in the long-term regulation of peripheral vascular resistance and vascular reactivity. We determined whether GH plays a role in the acute regulation of vascular function in humans. The acute vascular effects of GH were studied in eight healthy subjects according to a double-blind, placebo-controlled design. Forearm blood flow (FBF), vascular resistance, and nitric oxide (NO) production were monitored during a 4-h infusion of GH into the brachial artery at a rate chosen to raise local GH to stress levels (approximately 40 ng/ml). During GH infusion, FBF rose 75% (P < 0.05), whereas forearm vascular resistance decreased comparably (P < 0.05). These changes were paralleled by augmented forearm release of NO (P < 0.02). GH heightened the response of FBF to the endothelium-dependent vasodilator acetylcholine (Ach; P < 0.02). With the highest Ach dose, FBF reached 30.4 +/- 4.2 and 16.9 +/- 3.1 ml/dl x min in the GH and placebo studies, respectively (P < 0.005). The slopes of the dose-response curves also differed markedly (0.45 +/- 0.07 and 0.25 +/- 0.05 ml/dl x min/ microg in the GH and placebo studies, respectively; P < 0.01). GH caused an upward shift of the FBF response to the endothelium-independent vasodilator sodium nitroprusside (P < 0.01), but did not affect the slope of the dose-response curve. GH infusion did not cause any appreciable increment in the venous IGF-I concentration in the test arm. In conclusion, GH acutely lowers peripheral vascular resistance and stimulates endothelial function. These effects are mediated by activation of the NO pathway and appear to be independent of IGF-I.

Supraphysiological doses of GH induce rapid changes in cardiac morphology and function.

GH is an agent widely used in sport to improve physical performance and has been proposed as adjunctive therapy in several clinical conditions. However, its short-term effects on the normal human heart are poorly understood. Sixty young normal volunteers (30 males and 30 females) were enrolled in a multicenter, double-blind, placebo-controlled study. All subjects were randomized to receive GH (0.03 or 0.06 mg/kg.d) or placebo. A complete Doppler-echocardiographic examination was performed at baseline and after 4 wk of treatment. Low-dose GH did not significantly affect echocardiographic parameters. In contrast, high-dose GH increased left ventricular mass index by 12% (P < 0.05). The type of growth response was concentric, because left ventricular wall thickness but not diameter increased, leading to a 10% increase of relative wall thickness. These structural changes were associated with functional changes, including a significant increase in cardiac index and a decrease in peripheral vascular resistance; diastolic function was not altered. Fractional shortening and systemic blood pressure were unchanged in the two treatment groups. In conclusion, administration of GH for 4 wk at doses that simulate GH abuse in sport caused a high cardiac output state associated with concentric left ventricular remodeling.