Uric acid, heart failure survival, and the impact of xanthine oxidase inhibition

Increasing evidence suggests that serum uric acid (UA), a product of xanthine oxidase (XO), may be a useful marker for metabolic, hemodynamic, and functional staging in heart failure (HF) and a valid predictor of survival in HF patients. Recent data support an expanded role for UA and the XO pathway in the pathogenesis of HF, as studies have shown that an elevation in the enzymatic activity of XO can lead to increases in oxidative stress, endothelial dysfunction, and reduced myocardial function. Numerous population studies have previously reported that elevated UA levels are an independent predictor of cardiovascular mortality, and recent evidence suggests that lowering serum levels of UA may lead to improved outcomes in HF patients. The question of whether UA is only a marker rather than a causal factor in the pathogenesis of HF remains. Regardless of whether UA levels are ready for routine clinical use, either as a prognostic factor or novel therapeutic target, further prospective studies are necessary to demonstrate that routine measurement or reduction of UA levels improves outcomes in HF patients.     

Exercise and the coronary circulation-alterations and adaptations in coronary artery disease

Coronary vasorelaxation depends on nitric oxide (NO) bioavailability, which is a function of endothelial nitric oxide synthase-derived NO production and NO inactivation by reactive oxygen species. This fine-tuned balance is disrupted in coronary artery disease (CAD). The impairment of NO production in conjunction with excessive oxidative stress promotes the loss of endothelial cells by apoptosis, leads to a further aggravation of endothelial dysfunction and triggers myocardial ischemia in CAD. In healthy individuals, increased release of NO from the vasculature in response to exercise training results from changes in endothelial nitric oxide synthase expression, phosphorylation, and conformation. However, exercise training has assumed a role in cardiac rehabilitation of patients with CAD, as well, because it reduces mortality and increases myocardial perfusion. This has been largely attributed to exercise training-mediated correction of coronary endothelial dysfunction in CAD. Indeed, regular physical activity restores the balance between NO production and NO inactivation by reactive oxygen species in CAD, thereby enhancing the vasodilatory capacity in different vascular beds. Because endothelial dysfunction has been identified as a predictor of cardiovascular events, the partial reversal of endothelial dysfunction secondary to exercise training might be the most likely mechanism responsible for the exercise training-induced reduction in cardiovascular morbidity and mortality in patients with CAD.     

Diastolic dysfunction in exercise and its role for exercise capacity

Diastolic dysfunction is frequent in elderly subjects and in patients with left ventricular hypertrophy, vascular disease and diabetes mellitus. Patients with diastolic dysfunction demonstrate a reduced exercise capacity and might suffer from congestive heart failure (CHF). Presence of symptoms of CHF in the setting of a normal systolic function is referred to as heart failure with normal ejection fraction (HFNEF) or, if evidence of an impaired diastolic function is observed, as diastolic heart failure (DHF). Reduced exercise capacity in diastolic dysfunction results from a number of pathophysiological alterations such as slowed myocardial relaxation, reduced myocardial distensibility, elevated filling pressures, and reduced ventricular suction forces. These alterations limit the increase of ventricular diastolic filling and cardiac output during exercise and lead to pulmonary congestion. In healthy subjects, exercise training can enhance diastolic function and exercise capacity and prevent deterioration of diastolic function in the course of aging. In patients with diastolic dysfunction, exercise capacity can be enhanced by exercise training and pharmacological treatment, whereas improvement of diastolic function can only be observed in few patients.     

Physical training as an adjunct therapy in patients with congestive heart failure: Patient selection, training protocols, results, and future directions

Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF: reduced endothelium-dependent vasodilation and altered skeletal muscle metabolism. Physical exercise training has evolved as an important therapeutic approach to influence these noncardiac causes of exercise intolerance. It has been shown to enhance the oxidative capacity of the working skeletal muscle, to attenuate ergoreflex activity, to correct endothelial dysfunction, and to improve ventilation. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 mL/kg.min^-1. Uncertainty remains concerning optimal patient selection, training protocol, and long-term effects on cardiac function. For patients experiencing stable CHF while on optimal cardiac medication, a combination of inhospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potential as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.     

Transient reduction in myocardial free oxygen radical levels is involved in the improved cardiac function and structure after long-term allopurinol treatment initiated in established chronic heart failure.

AIMS: Oxidative stress, i.e. imbalance between reactive oxygen species (ROS) and antioxidant defences, contributes to the progression of chronic heart failure (CHF). Acute inhibition of xanthine oxidase (XO), which produces ROS, improves mechanical efficiency of the failing heart, but whether long-term XO inhibition exerts beneficial effects in CHF is unknown. METHODS AND RESULTS: In rats with established CHF induced by left coronary ligation, we assessed the effects of a 5-day and a 10-week treatment with the XO inhibitor allopurinol (50 mg kg(-1) day(-1)) on haemodynamics and left ventricular (LV) function and structure. Both acute and chronic allopurinol treatment increase cardiac output without modification of arterial pressure, but only chronic allopurinol treatment reduces LV end-diastolic pressure and LV relaxation constant. Chronic allopurinol treatment decreases both LV systolic and diastolic diameters, but acute allopurinol treatment only decreases LV systolic diameter. Moreover, chronic allopurinol decreases LV weight and collagen density. Despite XO inhibition after acute and chronic allopurinol treatment, as both treatments reduce uric acid plasma levels, only acute allopurinol treatment reduces LV ROS determined using electron spin resonance spectroscopy. However, the CHF-enhanced myocardial thiobarbituric acid reactive substances levels were never modified. CONCLUSION: In experimental CHF, long-term allopurinol treatment, initiated in a pathological state of overt CHF, improves LV haemodynamics and function and prevents LV remodelling. These long-term effects are, at least partially, caused by a transient reduction of myocardial ROS shortly after initiation of allopurinol treatment, but whether other mechanism(s), independent of myocardial redox 'status', such as reduced inflammation, are implicated remains to be confirmed.     

From Left Ventricular Dysfunction to Heart Failure in the Elderly Patient

The pathophysiology of the syndrome of congestive heart failure (CHF) is different in elderly patients compared to middle-aged subjects. When the syndrome of CHF predominantly results from left ventricular (LV) systolic dysfunction, peripheral mechanisms in elderly patients are less apt to compensate for the decline in LV performance due to deconditioning of the skeletal muscles, decreased vasodilatory response to exercise, and reduced capacity to excrete sodium. These all develop with age. LV diastolic dysfunction, i.e., LV filling impairment, appears to be a more frequent cause of CHF in elderly patients than in middle-aged subjects. Hypertrophy of the cardiac myocyte is associated with a prolongation of the calcium transient which, in turn, results from a decreased concentration of the enzyme responsible for reuptake of calcium in the sarcoplasmic reticulum. Cardiac myocyte hypertrophy results from a steady loss of myocytes and a progressive rise in arterial impedance which are both observed with aging. Notwithstanding subendocardial myocardial ischemia which is frequently associated with LV wall hypertrophy, prolongation of the calcium transient leads to impaired LV wall relaxation and the syndrome of LV diastolic dysfunction. The goals of therapy are also different in elderly patients compared to middle-aged patients. In elderly patients, one is less concerned about restoring a near normal exercise capacity, and aims at preventing acute episodes of decompensation which frequently accompany excessive sodium intake. Therefore, strict adherence to diet and careful titration of the dosages of medication to renal function are important considerations when treating CHF in elderly patients. In particular, cardiac glycosides, which should be avoided with CHF due to LV diastolic dysfunction, should be carefully titrated to creatinine clearance and body weight when treating elderly patients with LV systolic dysfunction in sinus rhythm. Similarly, the dosages of most angiotensin-converting enzyme inhibitors should be reduced in elderly patients.     

Trainingstherapie bei kardiologischen Patienten (Sportkardiologie)

Clinical application of physical exercise has developed into an evidence-based therapeutic option for cardiovascular diseases, especially coronary artery disease (CAD) and chronic heart failure (CHF). In CAD regular physical exercise training partially corrects endothelial dysfunction and leads to an economization of left ventricular function. Meta-analyses have shown a reduction of angina pectoris symptoms and a decrease of total and cardiovascular mortality by regular aerobic exercise training. Endurance training for CHF reduces cardiac afterload by correcting peripheral endothelial dysfunction und leads to a better left ventricular function. In addition exercise training reduces the adrenergic tone and the stimulation of the renin-angiotensin-aldosterone system in CHF. Exercise training provides positive effects on the metabolism and function of skeletal muscle (e.g. reduced inflammation and oxidative stress). Supervised regular physical exercise training in CHF is safe and has improved the morbidity in clinical studies. Thus aerobic exercise training is an important component of therapeutic management of stable CAD and CHF with a class 1a recommendation in the current guidelines.     

Antioxidant vitamins attenuate oxidative stress and cardiac dysfunction in tachycardia-induced cardiomyopathy.

OBJECTIVES: We administered antioxidant vitamins to rabbits with pacing-induced cardiomyopathy to assess whether antioxidant therapy retards the progression of congestive heart failure (CHF). BACKGROUND: Although oxidative stress is increased in CHF, whether progression of heart failure could be prevented or reduced by antioxidants is not known. METHODS: Rabbits with chronic cardiac pacing and sham operation were randomized to receive a combination of beta-carotene, ascorbic acid and alpha-tocopherol, alpha-tocopherol alone or placebo over eight weeks. Echocardiography was used to measure cardiac function weekly. Resting hemodynamics and in vivo myocardial beta-adrenergic responsiveness were studied at week 8. Animals were then sacrificed for measuring myocardial beta-receptor density, norepinephrine (NE) uptake-1 site density, sympathetic neuronal marker profiles, tissue-reduced glutathione/oxidized glutathione (GSH/GSSG) ratio and oxidative damage of mitochondrial DNA (mtDNA). RESULTS: Rapid cardiac pacing increased myocardial oxidative stress as evidenced by reduced myocardial GSH/GSSG ratio and increased oxidized mtDNA and produced cardiac dysfunction, beta-adrenergic subsensitivity, beta-receptor downregulation, diminished sympathetic neurotransmitter profiles and reduced NE uptake-1 carrier density. A combination of antioxidant vitamins reduced the myocardial oxidative stress, attenuated cardiac dysfunction and prevented myocardial beta-receptor downregulation and sympathetic nerve terminal dysfunction. Administration of alpha-tocopherol alone produced similar effects, but the effects were less marked than those produced by the three vitamins together. Vitamins produced no effects in sham-operated animals. CONCLUSIONS: Antioxidant vitamins reduced tissue oxidative stress in CHF and attenuated the associated cardiac dysfunction, beta-receptor downregulation and sympathetic nerve terminal abnormalities. The findings suggest that antioxidant therapy may be efficacious in human CHF.     

Molecular mechanisms of hypertension--reactive oxygen species and antioxidants: a basic science update for the clinician

Many factors have been implicated in the pathophysiology of hypertension such as upregulation of the renin-angiotensin-aldosterone system, activation of the sympathetic nervous system, perturbed G protein-coupled receptor signalling, inflammation, and altered T-cell function. Common to these processes is increased bioavailability of reactive oxygen species (ROS) (termed oxidative stress) due to excess ROS generation, decreased nitric oxide (NO) levels, and reduced antioxidant capacity in the cardiovascular, renal, and nervous systems. Although oxidative stress may not be the sole etiology of hypertension, it amplifies blood pressure elevation in the presence of other prohypertensive factors. In the cardiovascular system ROS play a physiological role in controlling endothelial function, vascular tone, and cardiac function, and a pathophysiological role in inflammation, hypertrophy, proliferation, apoptosis, migration, fibrosis, angiogenesis, and rarefaction, all of which are important processes contributing to endothelial dysfunction and cardiovascular remodelling in hypertension. A major source for cardiovascular ROS is a family of nonphagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox1, Nox2, Nox4, and Nox5). Other sources include mitochondrial enzymes, xanthine oxidase, and uncoupled NO synthase (NOS). Although convincing data from animal studies support a causative role for oxidative stress in the pathogenesis of hypertension, there is still no solid evidence that oxidative stress causes hypertension in humans. However, biomarkers of excess ROS are increased in patients with hypertension and oxidative damage is important in the molecular mechanisms associated with cardiovascular and renal injury in hypertension. Although clinical trials failed to show beneficial antihypertensive effects of antioxidants, strategies that combat oxidative stress by targeting Noxs in an isoform-specific manner may have therapeutic potential.     

Exercise training and endothelial dysfunction in coronary artery disease and chronic heart failure. From molecular biology to clinical benefits

Endothelial dysfunction (ED) has been documented in patients with both coronary artery disease (CAD) and chronic heart failure (CHF)-being responsible for exercise-induced myocardial ischemia in the former and increased afterload in the latter. In the last two decades exercise training has assumed a major role in both cardiovascular disorders. In CAD exercise training has established positive effects on myocardial perfusion. Recently, exercise training has been shown to attenuate paradoxical vasoconstriction in CAD. The improved ED after training explains the improvement of myocardial perfusion in the absence of changes in baseline coronary artery diameter. Since ED has been identified as a predictor of coronary events exercise may contribute to long-term reductions of cardiovascular mortality. In CHF the increased peripheral vascular resistance - especially during exercise - is more important. ED contributes to the peripheral vasoconstriction. Training programs have shown to improve ED in CHF. A long-term study of hemodynamic effects of training in CHF revealed a significant reduction of total peripheral resistance (TPR) that after 6 months with a concomitant increase in stroke volume. In a subgroup analysis a significant correlation between changes in TPR and changes in peripheral ED was observed. Cell culture and animal experiments suggest that shear stress increases the endothelial L-arginine uptake, enhances NO synthase activity and expression, and upregulates the production of extracellular superoxide dismutase, which prevents premature NO breakdown. All these molecular effects converge on a reduction of myocardial ischemic events in CAD and a decrease of afterload in CHF.     

Oxidative stress and congestive heart failure

Oxygen free radicals, produced by the reduction of oxygen during many cellular reactions, have been implicated in the pathogenesis of a variety of cardiovascular diseases. Extremely reactive, free radicals damage many cellular structures and interfere with multiple cell functions. Clinically, free radicals have been associated with coronary atherosclerosis, ischemia, and reperfusion injury (“stunning”), and other processes related to chronic myocardial dysfunction. Several studies have reported elevated markers of free radical mediated injury in patients with congestive heart failure (CHF), and the link between oxidative stress and the genesis and progression of chronic CHF is being increasingly explored. This review briefly highlights free radical biology and examines the rationale and evidence for the role of oxidative stress in chronic heart failure. (c)1999 by CHF, Inc.     

Neutrophil superoxide anion--generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy

OBJECTIVES: First, we sought to study the effects of short- and long-term vitamin C therapy on oxidative stress and endothelial dysfunction in chronic heart failure (CHF), and second, we sought to investigate the role of neutrophils as a cause of oxidative stress in CHF. BACKGROUND: Oxidative stress may contribute to endothelial dysfunction in CHF. Vitamin C ameliorates endothelial dysfunction in CHF, presumably by reducing oxidative stress, but this is unproven. METHODS: We studied 55 patients with CHF (ischemic and nonischemic etiologies) and 15 control subjects. Flow-mediated dilation (FMD) in the brachial artery was measured by ultrasound wall-tracking, neutrophil superoxide anion (O2-) generation by lucigenin-enhanced chemiluminescence and oxidative stress by measurement of free radicals (FRs) in venous blood using electron paramagnetic resonance (EPR) spectroscopy and plasma thiobarbituric acid reactive substances (TBARS). Measurements were performed at baseline in all subjects. The effects of short-term (intravenous) and long-term (oral) vitamin C therapy versus placebo were tested in patients with nonischemic CHF. RESULTS: At baseline, FRs were higher in patients with CHF than in control subjects (p < 0.01), TBARS were greater (p < 0.005), neutrophil O2- -generating capacity was enhanced (p < 0.005) and FMD was lower (p < 0.0001). Compared with placebo, short-term vitamin C therapy reduced FR levels (p < 0.05), tended to reduce TBARS and increased FMD (p < 0.05), but did not affect neutrophil O2- -generating capacity. Long-term vitamin C therapy reduced FR levels (p < 0.05), reduced TBARS (p < 0.05) and improved FMD (p < 0.05), but also reduced neutrophil O2- -generating capacity (p < 0.05). Endothelial dysfunction was not related to oxidative stress, and improvements in FMD with vitamin C therapy did not relate to reductions in oxidative stress. CONCLUSIONS: Oxidative stress is increased in ischemic and nonischemic CHF, and neutrophils may be an important cause. Vitamin C reduces oxidative stress, increases FMD and, when given long term, decreases neutrophil O2- generation, but the lack of a correlation between changes in endothelial function and oxidative stress with vitamin C implies possible additional non-antioxidant benefits of vitamin C.     

Cardiac remodeling and physical training post myocardial infarction

After myocardial infarction(MI), the heart undergoes extensive myocardial remodeling through the accumulation of fibrous tissue in both the infarcted and noninfarcted myocardium, which distorts tissue structure, increases tissue stiffness, and accounts for ventricular dysfunction. There is growing clinical consensus that exercise training may beneficially alter the course of post-MI myocardial remodeling and improve cardiac function. This review summarizes the present state of knowledge regarding the effect of post-MI exercise training on infarcted hearts. Due to the degree of difficulty to study a viable human heart at both protein and molecular levels, most of the detailed studies have been performed by using animal models. Although there are some negative reports indicating that post-MI exercise may further cause deterioration of the wounded hearts, a growing body of research from both human and animal experiments demonstrates that post-MI exercise may beneficially alter the course of wound healing and improve cardiac function. Furthermore, the improved function is likely due to exercise training-induced mitigation of reninangiotensin-aldosterone system, improved balance between matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1, favorable myosin heavy chain isoform switch, diminished oxidative stress, enhanced antioxidant capacity, improved mitochondrial calcium handling, and boosted myocardial angiogenesis. Additionally, meta-analyses revealed that exercise-based cardiac rehabilitation has proven to be effective, and remains one of the least expensive therapies for both the prevention and treatment of cardiovascular disease, and prevents re-infarction.     

L-arginine supplementation prolongs exercise capacity in congestive heart failure

BACKGROUND: In congestive heart failure (CHF), endothelial dysfunction may contribute to impairment of exercise induced vasodilatation and decreased exercise capacity. We hypothesised that administration of L-arginine, a precursor of nitric oxide (NO) and postulated antioxidant, may improve endothelium-dependent vasodilatation and exercise capacity and also exert antioxidant activity. AIMS: To investigate the effect of oral supplementation with L-arginine on exercise capacity and markers of oxidative stress in patients with mild to moderate CHF. METHODS: The study had a randomised double-blind cross-over design. Twenty one patients with stable NYHA II-III CHF underwent three exercise tests: initially, after oral administration of L-arginine (9 g/day for 7 days) or placebo. Blood was sampled prior to each test for plasma lipid peroxides, reduced sulphydryl groups and leukocyte oxygen free radical production. RESULTS: We found a higher prolongation of exercise duration time after L-arginine than after placebo (99+/-106 vs 70+/-99 s, p<0.05). There were no significant differences in markers of free radical activity. CONCLUSIONS: In patients with chronic stable CHF, oral supplementation with L-arginine prolongs exercise duration which may be due to NO-induced peripheral vasodilatation. The antioxidant properties of L-arginine have not been confirmed in this ex vivo study.     

Oxidative stress and myocardial remodeling in chronic mitral regurgitation

Mechanisms of left ventricular (LV) dysfunction in isolated mitral regurgitation (MR) are not well understood. Vasodilator therapy in other forms of LV dysfunction reduces LV wall stress and improves LV function; however, studies in isolated MR show no beneficial effect on LV remodeling using vasodilator drugs or renin-angiotensin system blockade. Therefore, the search for new therapies that improve LV remodeling and function in isolated MR is clinically significant. Recent work in the authors' laboratory has demonstrated increased oxidants from a number of sources including the enzyme xanthine oxidase (XO) in the LV of patients with isolated MR. In addition to being a major source of reactive oxygen species, XO is linked to bioenergetic dysfunction because its substrates derive from adenosine triphosphate catabolism. Correspondingly, there was also evidence of aggregates of small mitochondria in cardiomyocytes, which is generally considered a response to bioenergetic deficit in cells. Future studies are required to determine whether XO and persistent oxidative stress are causative in maladaptive LV remodeling and offer potential therapeutic targets in ameliorating LV damage in patients with isolated MR.     

Uric acid and risk of myocardial infarction,stroke and congestive heart failure in 417 734 men and women in the Apolipoprotein MOrtality RISk study (AMORIS)

Objectives. Few studies have simultaneously analysed the influence of elevated serum uric acid (UA) on acute myocardial infarction (AMI), ischaemic and haemorrhagic stroke (IS, HS) and congestive heart failure (CHF) in large healthy populations. We, here, examine UA as a risk factor for AMI, stroke and CHF by age and gender in the Apolipoprotein MOrtality RISk (AMORIS) Study. Design. Prospective study (11.8 years, range 7–17) of fatal and nonfatal acute myocardial infarction, stroke and CHF through linkage with Swedish hospital discharge and mortality registers. Settings. Measurements of uric acid in 417 734 men and women from health check‐ups in Stockholm area. Results. There was a gradual increase in risk of AMI, stroke and CHF by increasing UA levels. Women had a stronger relationship between UA and both AMI and IS than men. Predictions of AMI were at least as powerful in the elderly as in the young, but not so for IS. Associations were markedly attenuated when adjusted for total cholesterol, triglycerides, hospital hypertension and diabetes status. The association between UA and HS was U‐shaped in both genders. CHF was more strongly related to UA than AMI and stroke and less affected by the adjustment factors. Conclusions. Already moderate levels of UA appear to be associated with an increased incidence of AMI, stroke and CHF in middle‐aged subjects without prior cardiovascular disease. These associations seem to increase gradually from lower to higher levels of UA. UA may be an important complementary indicator of cardiovascular risk in the general population.     

Role of oxidative stress in cardiovascular diseases

OBJECTIVES: In view of the critical role of intracellular Ca2 overload in the genesis of myocyte dysfunction and the ability of reactive oxygen species (ROS) to induce the intracellular Ca2+-overload, this article is concerned with analysis of the existing literature with respect to the role of oxidative stress in different types of cardiovascular diseases. OBSERVATIONS: Oxidative stress in cardiac and vascular myocytes describes the injury caused to cells resulting from increased formation of ROS and/or decreased antioxidant reserve. The increase in the generation of ROS seems to be due to impaired mitochondrial reduction of molecular oxygen, secretion of ROS by white blood cells, endothelial dysfunction, auto-oxidation of catecholamines, as well as exposure to radiation or air pollution. On the other hand, depression in the antioxidant reserve, which serves as a defense mechanism in cardiac and vascular myocytes, appears to be due to the exhaustion and/or changes in gene expression. The deleterious effects of ROS are mainly due to abilities of ROS to produce changes in subcellular organelles, and induce intracellular Ca2+-overload. Although the cause-effect relationship of oxidative stress with any of the cardiovascular diseases still remains to be established, increased formation of ROS indicating the presence of oxidative stress has been observed in a wide variety of experimental and clinical conditions. Furthermore, antioxidant therapy has been shown to exert beneficial effects in hypertension, atherosclerosis, ischemic heart disease, cardiomyopathies and congestive heart failure. CONCLUSIONS: The existing evidence support the view that oxidative stress may play a crucial role in cardiac and vascular abnormalities in different types of cardiovascular diseases and that the antioxidant therapy may prove beneficial in combating these problems.     

Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency

Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II-induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II-induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II-induced oxidative stress, cardiac TGFbeta-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II-induced cardiac remodeling and diastolic dysfunction in eNOS-/- mice as in wild-type mice. In eNOS-/- mice, the Ang II-induced cardiac oxidative stress and TGF-beta-Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II-treated eNOS-/- mice, with suppression of glomerular oxidative stress and TGF-beta-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II-induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-beta-Smad 2/3 signaling pathway by suppression of oxidative stress.     

The GH-IGF-I axis and the cardiovascular system: clinical implications

Background GH and IGF‐I affect cardiac structure and performance. In the general population, low IGF‐I has been associated with higher prevalence of ischaemic heart disease and mortality. Both in GH deficiency (GHD) and excess life expectancy has been reported to be reduced because of cardiovascular disease. Objective To review the role of the GH–IGF‐I system on the cardiovascular system. Results Recent epidemiological evidence suggests that serum IGF‐I levels in the low‐normal range are associated with increased risk of acute myocardial infarction, ischaemic heart disease, coronary and carotid artery atherosclerosis and stroke. This confirms previous findings in patients with acromegaly or with GH‐deficiency showing cardiovascular impairment. Patients with either childhood‐ or adulthood‐onset GHD have cardiovascular abnormalities such as reduced cardiac mass, diastolic filling and left ventricular response at peak exercise, increased intima‐media thickness and endothelial dysfunction. These abnormalities can be reversed, at least partially, after GH replacement therapy. In contrast, in acromegaly chronic GH and IGF‐I excess causes a specific cardiomyopathy: concentric cardiac hypertrophy (in more than two‐thirds of the patients at diagnosis) associated to diastolic dysfunction is the most common finding. In later stages, impaired systolic function ending in heart failure can occur, if GH/IGF‐I excess is not controlled. Abnormalities of cardiac rhythm and of cardiac valves can also occur. Successful control of acromegaly is accompanied by decrease of the left ventricular mass and improvement of cardiac function. Conclusion The cardiovascular system is a target organ for GH and IGF‐I. Subtle dysfunction in the GH–IGF‐I axis are correlated with increased prevalence of ischaemic heart disease. Acromegaly and GHD are associated with several abnormalities of the cardiovascular system and control of GH/IGF‐I secretion reverses (or at least stops) cardiovascular abnormalities.     

Diastolic function in valvular heart disease.

Diastolic dysfunction in patients with valvular heart disease is characterized by an impaired isovolumic relaxation, a normal or even enhanced early diastolic filling rate and an increased myocardial stiffness. These abnormalities do not depend on coexisting systolic dysfunction but are often combined. Several mechanisms are responsible for the occurrence of diastolic dysfunction, such as increased wall stress, altered myocardial structure, subendocardial hypoperfusion and/or diastolic calcium overload. Postoperative regression of myocardial hypertrophy is beneficial in regard to wall stress, subendocardial hypoperfusion and calcium overload but diastolic dysfunction might become worse after valve replacement due to a relative increase in interstitial fibrosis consequent to the decrease in myocyte mass (= myocardial remodeling). Persisting diastolic dysfunction with a substantial rise in left ventricular filling pressure can be observed during dynamic exercise in postoperative patients with preoperative severe pressure overload hypertrophy. Thus, diastolic dysfunction can be present as a primary derangement of cardiac function and can be unmasked as an abnormal response of diastolic filling pressure during exercise.