Pharmacotherapy of dilated cardiomyopathy: Current status and future directions

Summary The current status and future directions of the pharmacotherapy of dilated cardiomyopathy are reviewed. The Japanese multicenter study on the effect of β-blockers revealed significant improvement of NYHA functional classification, LV end-diastolic dimension, ejection fraction, and exercise tolerance time in patients with dilated cardiomyopathy. From our study using normal rabbits, metoprolol augmented adenylate cyclase activity without upregulation of the β-adrenergic receptor number. Carteolol, a β-adrenergic blocker with intrinsic sympathomimetic action, prevented the development of dilatation and hypertrophy of the heart in the chronic stage following murine encephalomyocarditis (EMC) viral myocarditis. Metoprolol exerted no such effect. Animal experiments indicated that immunosuppressive treatment for inflammatory myocarditis may aggravate the clinical course of the disease. However, immunosuppressive treatment in acute myocarditis should be reevaluated with the use of newly developed antiviral agents. A new synthetic immunoactive peptide FK 565, given before or simultaneously with viral inoculation, proved effective in inhibiting myocardial virus replication and myocardial damage in murine EMC viral myocarditis. Beneficial effects of captopril on survival rate and myocardial injury were demonstrated dose dependently in murine EMC viral myocarditis, even when the treatment was started around the peak of virus replication, namely, on day 4–14 after inoculation. Captopril may be promising for the treatment of acute myocarditis, and hopefully for prevention of the progression from myocarditis to dilated cardiomyopathy.     

Oral Administration of Candesartan Improves the Survival of Mice with Viral Myocarditis through Modification of Cardiac Adiponectin Expression

Purpose We examined the effects of the angiotensin II receptor type1 blocker candesartan on myocarditis injury in a murine model of acute myocarditis. We hypothesized that candesartan improves cardiac damage by inducing cardiac expression of adiponectin. Methods and results We examined changes in heart failure caused by myocarditis in mice by candesartan based on induction of cardiac adiponectin expression. We intraperitoneally injected encephalomyocarditis virus in C3H mice, then orally administered candesartan (10 mg/kg/day) or vehicle (control). The 7 day survival rate was 18% in the control group, but 60% in the candesartan group. The heart weight/body weight ratio in the candesartan group was significantly lower than in the control group. Circulating adiponectin concentrations on day 7 were significantly higher in the candesartan group compared with the control group (7.91 ± 0.61 vs. 6.04 ± 2.26 μg/ml, P < 0.05). Comparative expression of cardiac adiponectin mRNA in the candesartan group was significantly higher than in the control group on day 7 (55.4 ± 41.3 vs. 5.3 ± 7.7, P < 0.05). Immunohistochemical staining and in situ hybridization showed that cardiac expression of adiponectin protein and mRNA was present in the candesartan group on day 7. Conclusion Oral administration of candesartan improves survival and decreases myocardial damage in mice with viral myocarditits and induces expression of cardiac adiponectin. The induction of adiponectin might provide cardioprotective effects against acute heart failure due to viral myocarditis.     

Beta-blockade in heart failure: adding SENIORS to the mix.

In early 2005, results of the SENIORS trial, a Study of theEffects of Nebivolol Intervention on Outcomes and Rehospitalizationin Seniors with Heart Failure was published.^1,2 A total of 2128patients over the age of 70 were randomized to receive eithernebivolol or placebo for a mean follow-up time of 21 months.Nebivolol is a third generation highly selective ß₁-adrenergicreceptor inhibitor with vasodilator properties mediated throughnitric oxide release. Treatment with this agent decreased all-causemortality or cardiovascular hospitalization (P=0.04). Althoughprevious studies using ß-blockers (bisoprolol, carvedilol,or metroprolol) demonstrated a decreased relative risk of deathin heart failure,³ they enrolled     

Diagnosis and management of viral myocarditis

Opinion statement Myocarditis has been shown to be a common cause of cardiomyopathy; it is believed to account for 25% of all cases of heart failure in humans. Unfortunately, the disease is difficult to detect clinically before a myopathic process ensues. Treatment of myocarditis-induced heart failure includes the standard regimen of diuretics, digoxin, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and β-adrenergic blockers. Treatment of myocarditis itself is dependent on the etiology of the illness. Additional treatments under investigation for viral and autoimmune myocarditis include immunosuppressants, nonsteroidal anti-inflammatory agents, immunoglobulins, immunomodulators, and antivirals, with no specific therapy having a real advantage over standard treatment for heart failure. Despite advances in treatment, more work needs to be done in the early detection of myocarditis. In addition, better means need to be established for distinguishing between viral and noninfectious autoimmune forms of the disease so that appropriate treatment can be instituted.     

Effects of granulocyte colony-stimulating factor upon coxsackievirus B3 myocarditis in mice

Granulocyte colony-stimulating factor is a potent activatorof mature granulocytes, and subsequently enhances superoxiderelease. The purpose of this study was to investigate the effectsof granulocyte colony-stimulating factor upon murine coxsackievirusB3 myocarditis in relation to free radical-mediated cardiacdamage. Two-week-old, male, C₃H/He mice were inoculated intraperitoneallywith coxsackievirus B3. Gramulocyte colony-stimulating factor20 µg.kg^–1. day^–1, polyethylene glycol-conjugatedsuperoxide dismutase (an enzyme catalyzing the conversion ofO₂^- to H₂O₂) 1 x 10³ U.kg^–1 day^–1 and granulocytecolony-stimulating factor 20 µg. kg^–1 day^–1,plus polyethylene glycol-conjugated superoxide dismutase 1 x10³ U.kg^–1. day^–1, were injected subcutaneouslydaily on days 0 to 14. Treated groups were compared to the infected,untreated group. The survival rate in the polyethylene glycol-conjugatedsuperoxide dismutase group was higher than that of the untreatedgroup on day 14, but on day 7, cardiac pathology was not significantlydifferent among the four groups. On day 14, the scores of cellularinfiltration, myocardial necrosis and calc were lower in thepolyethylene glycol-conjugated superoxide disnuitase group andin the granulocyte colony-stimulating factor plus polyethyleneglycol-conjugated superoxide dismutase group than in the untreatedgroup. The myocardial virus titres on days 7 and 14 did notd sign y among the four groups. The number of total white bloodcell and neutrophil counts were signifIcantly greater in thegranulo cyte colony-stimulating factor group than in the untreatedgroup on day 7. Taken altogether with the previous reports andpresent evidence that the administration of granulocyte colony-stimulatingfactor did not exacerbate coxsackievirus B3 myocarditis, itmay be that oxygen-free radicals appeared to be derived notfrom leukocytes but from other components in this experimentalmodel of myocarditis, whereas the myocardium was inflamed withleukocytes.     

Effects of granulocyte colony-stimulating factor upon coxsackievirus B3 myocarditis in mice

Granulocyte colony-stimulating factor is a potent activatorof mature granulocytes, and subsequently enhances superoxiderelease. The purpose of this study was to investigate the effectsof granulocyte colony-stimulating factor upon murine coxsackievirusB3 myocarditis in relation to free radical-mediated cardiacdamage. Two-week-old, male, C₃H/He mice were inoculated intraperitoneallywith coxsackievirus B3. Gramulocyte colony-stimulating factor20 µg.kg^–1. day^–1, polyethylene glycol-conjugatedsuperoxide dismutase (an enzyme catalyzing the conversion ofO₂^- to H₂O₂) 1 x 10³ U.kg^–1 day^–1 and granulocytecolony-stimulating factor 20 µg. kg^–1 day^–1,plus polyethylene glycol-conjugated superoxide dismutase 1 x10³ U.kg^–1. day^–1, were injected subcutaneouslydaily on days 0 to 14. Treated groups were compared to the infected,untreated group. The survival rate in the polyethylene glycol-conjugatedsuperoxide dismutase group was higher than that of the untreatedgroup on day 14, but on day 7, cardiac pathology was not significantlydifferent among the four groups. On day 14, the scores of cellularinfiltration, myocardial necrosis and calc were lower in thepolyethylene glycol-conjugated superoxide disnuitase group andin the granulocyte colony-stimulating factor plus polyethyleneglycol-conjugated superoxide dismutase group than in the untreatedgroup. The myocardial virus titres on days 7 and 14 did notd sign y among the four groups. The number of total white bloodcell and neutrophil counts were signifIcantly greater in thegranulo cyte colony-stimulating factor group than in the untreatedgroup on day 7. Taken altogether with the previous reports andpresent evidence that the administration of granulocyte colony-stimulatingfactor did not exacerbate coxsackievirus B3 myocarditis, itmay be that oxygen-free radicals appeared to be derived notfrom leukocytes but from other components in this experimentalmodel of myocarditis, whereas the myocardium was inflamed withleukocytes.     

Prevention and reversal of LV remodeling with neurohormonal inhibitors

Opinion statement Left ventricular (LV) remodeling refers to alterations in ventricular mass, chamber size, and shape that result from myocardial injury, pressure, or volume overload. Numerous studies have demonstrated that LV remodeling correlates with the incidence of heart failure and death, supporting a causative role for remodeling in heart failure progression. Heart failure trials have shown that neurohormonal antagonists, including angiotensin-converting enzyme (ACE) inhibitors and β-adrenergic receptor blockers (β blockers), reduce remodeling in parallel with improved clinical outcomes. Existing data favor using angiotensin II type 1 (AT1) receptor antagonists (or “ARBs”), although their anti-remodeling effects are less well established. Recently, mineralocorticoid receptor antagonists have gained substantial interest based on favorable clinical trial results, although data regarding their effects on remodeling are limited. Thus, an optimal medical regimen to prevent or limit LV remodeling in patients with LV dysfunction should include both an ACE inhibitor and β-adrenergic receptor antagonist, irrespective of the degree of LV dysfunction and symptom status. For patients intolerant to ACE inhibitors, an AT1 receptor antagonist should be substituted. An aldosterone antagonist should be administered to patients with severe, New York Heart Association class III to IV heart failure who have normal or only mildly impaired renal function, or to those patients with depressed LV function following an acute myocardial infarction. Through the aggressive pharmacologic inhibition of both the renin-angiotensin-aldosterone and sympathetic nervous systems, progressive LV remodeling can be prevented or hindered, thereby favorably altering the natural history of the heart failure syndrome.     

Lessons learned from experimental myocarditis

We have developed murine models of viral myocarditis induced by encephalomyocarditis (EMC) virus in which severe myocarditis, congestive heart failure and dilated cardiomyopathy occur in high incidence. From these models, we have learned the natural history and pathogenesis and assessed not only new diagnostic methods but also therapeutic and preventive interventions. Autoantibodies against cardiac troponin I appeared in spontaneously developing autoimmune myocarditis in PD-1 deficient mice, who lack the T-cell receptor costimulatory molecule PD-1. The passive transfer of this antibody induced myocardial dysfunction. Later, this autoantibody was found in patients with myocarditis. Mast cell deficiency had beneficial effects in the viral myocarditis model, and anti-allergic agents prevented viral myocarditis. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blocker and an aldosterone receptor antagonist improved viral myocarditis, suggesting that the renin?Cangiotension?Caldosterone system may play an important role in the pathogenesis of viral myocarditis. Differential modulation of cytokine production was seen with various calcium channel blockers, and some calcium channel blocker improved viral myocarditis. Viral infection could lead to increased synthesis of immunoglobulin light chains (FLC). Serum levels of FLC were increased in myocarditis, and exogenously given FLC inhibited viral replication and improved myocarditis. We suggest that a strategy of drug development specifically addressing inflammation in myocarditis may provide increased benefit in terms of target organ damage.     

Anticardiolipin antibodies and antibodies to beta(2)-glycoprotein I in patients with Wegener's granulomatosis

SIR, In primary systemic vasculitides such as Wegener's granulomatosis(WG), vasculitis involving veins has been implicated as a contributoryfactor for thrombosis, although systematic studies of this problemare still lacking [1]. Other determinants for thrombosis havenot been evaluated in WG so far. Conventional anticardiolipin antibody (ACLA) assays detect bothß₂-glycoprotein I (ß₂GPI)-dependent antibodiesas well as ß₂GPI-independent antibodies. ß₂GPIacts as a cofactor for the interaction between ACLA and phospholipids.Antibodies solely directed to ß₂GPI have     

Triiodothyronine therapy in open-heart surgery: from hope to disappointment

A controversy persists as to whether cardiopulmonary bypass(CPB) decreases plasma levels of triiodothyronine (T₃), therebyjustifying peri-operative administration of T₃ to improve haemodynamicrecovery. To examine the effects of T₃ therapy on post-CPB haemodynamicsand to determine whether the potential inotropic effects ofT₃ are mediated by an increase in ß-adrenergic responsiveness,a prospective, randomized, double-blind, placebo-controlledstudy was performed in 20 patients undergoing cardiac surgerywith CPB. T₃ or placebo solution (10 patients in each group)was given intravenously at the time of aortic unclamping and4, 8, 12 and 20 h thereafter. End points included (1) thyroidhormone levels measured by radioimmunoassay (2) standard haemodynamicparameters (3) the density of lymphocyte ß-adrenoceptorsmeasured by a radioligand (¹²⁵I-iodocyanopindolol) binding technique. Post-CPB values (cross clamp removal) of T₃ (pg . ml^–1)were not significantly decreased compared with pre-CPB values:3.3±0.2 vs 3.1±0.2 in controls and 3.3±0.4vs 3.7±0.6 in T₃-treated patients, respectively. Thehaemodynamic parameters were no different between the two groupsat any postoperative time point. Likewise, density and affinityof lymphocyte ß-adrenoceptors were not significantlydifferent from pre-operative values in either group. Thus, thereseems to be no sound justification for a routine use of T₃ inpatients undergoing open-heart procedures.     

Interactions Between Cytokines and Neurohormonal Systems in the Failing Heart

The prognosis for patients with congestive heart failure (CHF) has been improved as a result of the use of angiotensin converting enzyme inhibitors and -adrenergic receptor blockers. The success of these therapies underscores the pathogenic role of neurohormonal activation in CHF. Clinical and experimental evidence supports a pathophysiologic role for pro-inflammatory cytokines and nitric oxide (NO) in the effects of angiotensin II and norepinephrine in CHF. Potential mechanism(s) responsible for the effects of these immunomodulators can be explained on the basis of established principles of myocardial excitation contraction coupling (E-C). A novel hypothesis is proposed that cytokines and NO-mediated alterations in E-C coupling contribute to the reversible myocardial depression and -adrenergic desensitization observed in a diverse group of clinical conditions that activate host inflammatory responses, including CHF. Basic studies into cytokine signaling pathways in cardiac myocytes have the potential to provide important new insights relevant to the design of new management strategies for the treatment of congestive heart failure patients.     

An animal model of congestive (dilated) cardiomyopathy: dilatation and hypertrophy of the heart in the chronic stage in DBA/2 mice with myocarditis caused by encephalomyocarditis virus

To investigate whether lesions that develop in the chronic stage of viral myocarditis are similar to those seen in congestive (dilated) cardiomyopathy, we studied myocarditis in inbred strains of DBA/2 mice infected with encephalomyocarditis (EMC) virus. Myocardial necrosis with calcification appeared on day 4. Thereafter, myocardial necrosis became more extensive and mononuclear cell infiltration was evident and was most marked on day 14. On day 90, cellular infiltration had decreased and myocardial fibrosis was prominent. At this stage, the heart weight was significantly greater in the infected mice than in the controls (0.190 +/- 0.028 g vs 0.122 +/- 0.013 g, mean +/- SD) (p less than 0.001) and the cavity dimensions of the left ventricle were larger (1.67 +/- 0.29 mm vs 1.11 +/- 0.20 mm) (p less than 0.001). The diameters of myocardial fibers of the right ventricle, the interventricular septum and the left ventricle were significantly larger than those of the controls (right ventricle, 16.6 +/- 1.8 vs 13.4 +/- 1.5 micrometer; interventricular septum, 17.8 +/- 1.5 vs 13.8 +/- 1.5 micrometer; left ventricle, 19.4 +/- 1.7 vs 14.8 +/- 1.1 micrometer) (p less than 0.001). This study demonstrates that in viral myocarditis in the chronic stage, lesions develop that resemble those seen in congestive cardiomyopathy.     

Heart failure: Effects of beta receptor antagonists on left ventricular function in patients with clinical evidence of heart failure after myocardial infarction. A double-blind comparison of metoprolol and xamoterol Echocardiographic results from the Metoprolol and Xamoterol Infarction Study (MEXIS)

Two hundred and ten patients with clinical evidence of heartfailure, developing after an acute myocardial infarction, wererandomized to treatment with the ß₁ antagonist metoprolol50–100mg b.i.d. (n=106) or the ß₁ partial agonistxamoterol 100–200 mg bid. (n=104). Left ventricular systolicand diastolic function were assessed with echocardiography andtransmitral Doppler cardiography before and after 3 and 12 monthsof double-blind treatment. E-point septal separation and percent left ventricular fractional shortening were used as indicesof systolic function. The ratio between peak early and latemitral diastolic flow (E/A ratio) and isovolumic relaxationtime were used as indices of diastolic function. In the xamoterol group, there was a deterioration in E-pointseptal separation (P<0·05). A difference between thetreatment groups was present both at 3 months (E-point septalseparation 11·4 vs 13·0 mm, P<0·0l,fractional short ening 271 vs 252%, P<005) and 12 months(E-point septal separation Ill vs 13·2 mm, P<0·05fractional shortening 26·9 vs 25·0%, P<0·05).E/A ratio increased in the metoprolol group (P<0·05)but not in the xamoterol group. At 3 months there was a significantdifference (0·85 vs 0·67, P<0·005 betweenthe groups but not at 12 months. In comparison with the ß₁-receptor antagonist metoprolol,the ß₁ partial agonist xamoterol impaired left ventricularsystolic function in patients with clinical evidence of heartfailure after an acute myocardial infarction.     

Cellular and molecular bases for the immunopathology of the myocardial cell damage involved in acute viral myocarditis with special reference to dilated cardiomyopathy.

Cell-mediated autoimmunity has been strongly implicated in the pathogenesis of the myocardial cell damage involved in viral myocarditis. To investigate the cellular and molecular bases of both target cells and effector cells for cell-mediated cytotoxicity involved in viral myocarditis and dilated cardiomyopathy, we first examined the expression of major histocompatibility complex (MHC) antigens and a cell adhesion molecule, intercellular adhesion molecule-1 (ICAM-1) in myocardial cells of a murine model of viral myocarditis and in patients with acute myocarditis and dilated cardiomyopathy. Secondly, we analyzed the characteristics of the infiltrating cells in the heart, especially the expression of a cytolytic factor, perforin. We found that Coxsackievirus B3 (CVB3)-induced murine acute myocarditis resulted in enhanced expression of MHC (class I) antigens and ICAM-1 on myocardial cells, and that perforin was abundantly expressed in NK (natural killer)-like large granular lymphocytes (LGL), which represent the main infiltrating cell type in the early stage. Immunoelectron microscopic study showed killer cells directly damaging cardiac myocytes by the release of perforin. Perforin was also expressed in the infiltrating cells in the heart of a patient with acute myocarditis. Both MHC antigens and ICAM-1 were clearly expressed in the hearts of patients with acute myocarditis and dilated cardiomyopathy. These data provided direct evidence that cell-mediated cytotoxicity plays a critical role in the myocardial cell damage involved in viral myocarditis.     

Denopamine,a β1-adrenergic agonist,prolongs survival in a murine model of congestive heart failure induced by viral myocarditis: suppression of tumor necrosis factor-α production in the heart

Objectives. This study was designed to examine the effects of denopamine, a selective β1-adrenergic agonist, in a murine model of congestive heart failure (CHF) due to viral myocarditis.Background. Positive inotropic agents are used to treat severe heart failure due to myocarditis. However, sympathomimetic agents have not been found beneficial in animal models of myocarditis.Methods. In vitro: The effects of denopamine on lipopolysaccharide-induced tumor necrosis factor-α (TNF-α) production was studied in murine spleen cells. In vivo: Four-week-old DBA/2 mice were inoculated with the encephalomyocarditis virus (day 0). Denopamine (14 μmol/kg), denopamine (14 μmol/kg) with a selective β1-blocker metoprolol (42 μmol/kg), or denopamine (14 μmol/kg) with metoprolol (84 μmol/kg) was given daily, and control mice received the vehicle only. Survival and myocardial histology on day 14 and TNF-α levels in the heart on day 6 were examined.Results. In the in vitro study, TNF-α levels in treated cells were significantly lower than in controls (p < 0.05). In the in vivo study treatment with denopamine significantly improved the survival of the animals (14 of 25 (56%) treated, vs 5 of 25 (20%) control mice), attenuated myocardial lesions, and suppressed TNF-α production (66.5 ± 7.5 pg/mg of heart in treated mice vs 113.5 ± 15.1 pg/mg of heart in control mice, mean ± SE). There was a strong linear relationship between mortality and TNF-α levels (r = 0.98, n = 4, p < 0.05). These in vitro and in vivo effects of denopamine were significantly inhibited by metoprolol.Conclusions. These results suggest that denopamine may exert its beneficial effects, in part, by suppressing the production of TNF-α via β1-adrenoceptors.     

β-Adrenergic Signal Transduction Pathway in Developing and Aging Hearts

The β-adrenergic signal transduction pathway in the heart consists of three major components, namely β-adrenergic receptors, guanine nucleotide-binding proteins (G-proteins), and adenylyl cyclase.β-adrenergic receptors, which recognize and bind catecholamines in the myocardium, are primarily of two types: β1-adrenoceptors andβ2-adrenoceptors. Two major types of G-proteins, namely stimulatory (Gs) and inhibitory (Gi) proteins, are expressed in the heart. Although five isoforms of adenylyl cyclase have been detected in the heart, type Vand type VI are present in abundance. While β-adrenergic receptors are coupled to adenylyl cyclase through Gs-proteins, Gi-proteins are known to regulate the adenylyl cyclase activity. β-adrenergic receptors are regulated by β-adrenoceptor kinase and β-arrestin present in the myocardium. Although β-adrenoceptors have been detected in fetal heart, their coupling with Gs-proteins and adenylyl cyclase is weak during early embryonic and fetal life. β2-adrenoceptors, unlikeβ1-adrenoceptors, have been shown to play an important role in catecholamine action in neonatal hearts in comparison to the adult myocardium. Both types V and VI of adenylyl cyclase are expressed weakly in neonatal heart, but type V isoform is predominant in the adult heart. The attenuated responses of the aging heart to catecholamines are explained on the basis of depressed adenylyl cyclase and increased Gi-protein contents since no changes in β-adrenoceptors or Gs-proteins were seen in the aged myocardium. The status of different components of the β-adrenergicreceptor system in both fetal and aging hearts is considered to provide clues regarding defects in the signal transduction mechanisms in heart failure. This revised version was published online in July 2006 with corrections to the Cover Date.     

Haemodynamic and cardiac metabolic effects of the new {beta}1 agonist prenalterol in patients with cardiac failure

Prenalterol, a ß₁ selective agonist, exerts a positiveinotropic action in animal studies as well as in human volunteersand is effective when administered orally. To assess its immediatehaemodynamic and myocardial metabolic effects, we studied theresponse to prenalterol (50 and 100 µg kg^–1 givenintravenously by cardiac catheterization) in 15 patients withcongestive heart failure secondary to coronary artery diseaseor non-ischaemic cardiomyopathy. At peak effect, cardiac indexincreased from 2.6 ± 0.5 to 3.2 ± 0.81 min^–1m² (mean ± S.D.) (P <0.001); peak rate of left ventricularpressure development rose from 963 ± 242 to 1335 ±411 mmHg s^–1 (P < 0.001); left ventriuclar end-diastolicpressure fell from 25 ± 6 to 17 ± 7 mgHg (P <0.001);coronary sinus blood flow increased from 113 ± 39 to148 ± 55 ml min^–1 (P <0.01); myocardial oxygenconsumption was augmented from 12.7 ± 3.9 to 16.4 ±5.8 ml min^–1 (P < 0.001); and heart rate increasedslightly (from 76 ± 12 to 86 ± 14 beats min^–1;(P <0.05)). No significant changes occurred in left ventricularsystolic pressure, stroke volume index, myocardial lactate extractionrate and myocardial arteriovenous oxygen difference, and nopatients developed angina, ECG changes or ventricular arrhythmias.Infusion of prenalterol effectively improved haemodynamic functionand cardiac metabolism in cardiomyopathy. Therefore this agentdeserves further investigation to evaluate its possible rolefor the long-term therapy of patients with chronic heart failure.     

Assessment of Ventricular Remodeling in Heart Failure Clinical Trials

Adverse remodeling involves a complicated process of structural and functional changes in the left ventricle (LV). LV remodeling is progressive and, if left unchecked, culminates in heart failure that portends a poor prognosis. Clinical trials in heart failure have employed various techniques to assess ventricular remodeling while focusing on therapeutic-specific strategies to halt or reverse remodeling. These strategies include (1) those designed to reduce wall stress by limiting LV dilatation and reducing LV loading conditions (nitrates and epicardial restraint), (2) those designed to block neurohormonal activation, including angiotensin converting enzyme inhibitors, angiotensin receptor blockers, ??-adrenergic receptor blockers, and aldosterone receptor blockers, (3) ionotropic agents/cardiac glycosides, and (4) cardiac resynchronization therapy. Strategies in development include mechanical assist devices and myocardial regeneration. To date, trials have demonstrated a linkage between indices of remodeling and clinical outcomes measures. Indices of remodeling have facilitated identification of targets for novel pharmaceutical agents and new device therapies.     

Carvedilol increases the production of interleukin-12 and interferon-gamma and improves the survival of mice infected with the encephalomyocarditis virus

OBJECTIVES: This study was designed to examine the effects of carvedilol in a murine model of viral myocarditis induced by encephalomyocarditis virus (EMCV) infection. BACKGROUND: Cytokines play an important role in the pathophysiology of viral myocarditis. Catecholamines influence the production of cytokines via beta-adrenergic receptors, suggesting that beta-adrenergic blockers could modulate the production of cytokines and exert a therapeutic effect in viral myocarditis by blocking the beta-stimulating action of endogenous catecholamines. In clinical trials, the third-generation, nonselective beta-blocker carvedilol was the first among several beta-blockers to reduce mortality in heart failure. However, the effects of carvedilol in acute viral myocarditis and on cytokine production are unknown. METHODS: This study compared the effects of carvedilol, the selective beta(1)-blocker metoprolol, and the nonselective beta-blocker propranolol in a murine model of viral myocarditis induced by EMCV. RESULTS: Carvedilol improved the 14-day survival of the animals, attenuated myocardial lesions on day 7, and increased myocardial levels of interleukin (IL)-12 and interferon (IFN)-gamma, whereas reducing myocardial virus replication. Propranolol also attenuated myocardial lesions, but to a lesser extent, and increased IL-12 and IFN-gamma levels. Metoprolol had no effect in this model. Encephalomyocarditis virus infection increased plasma catecholamine levels. CONCLUSIONS: These results suggest that by blocking the beta(2)-stimulating effects of catecholamines, carvedilol exerts some of its beneficial effects by increasing the production of IL-12 and IFN-gamma. Carvedilol may be effective in patients with viral myocarditis by boosting IL-12 and IFN-gamma production.     

Role of substance P in viral myocarditis in mice

Substance P (SP) is widely expressed in the central nervous system and in peripheral tissues such as myocardial nerves. We examined SP in viral myocarditis in mice induced by encephalomyocarditis virus (EMCV). Localization of SP in the hearts was examined immunohistochemically, and concentrations of SP in hearts and sera were measured by enzyme immunoassay. Substance P levels and density of SP-containing cells in murine hearts on day 6 after EMCV inoculation were decreased compared with those in normal controls. There was a negative correlation between SP levels in the hearts and ratio of heart weight to body weight of the mice at 6 days. Circulating SP levels were decreased in mice on day 6 after EMCV inoculation, and further decreased on day 14. Substance P in hearts and sera is decreased in viral myocarditis in mice, suggesting that SP may play a role in the pathogenesis of viral myocarditis, and that interaction of the neuropeptide nervous system and mast-cell immune system is important in the pathogenesis of viral myocarditis.