Cirrhotic cardiomyopathy

During the course of cirrhosis, there is a progressive deterioration of cardiac function manifested by the disappearance of the hyperdynamic circulation due to afailure in heart function with decreased cardiac output. This is due to a deterioration in inotropic and chronotropic function which takes place in parallel with a diastolic dysfunction and cardiac hypertrophy in the absence of other known cardiac disease. Other findings of this specific cardiomyopathy include impaired contractile responsiveness to stress stimuli and electrophysiological abnormalities with prolonged QT interval. The pathogenic mechanisms of cirrhotic cardiomyopathy include impairment of the b-adrenergic receptor signalling, abnormal cardiomyocyte membrane lipid composition and biophysical properties, ion channel defects and overactivity of humoral cardiodepressant factors. Cirrhotic cardiomyopathy may be difficult to determine due to the lack of a specific diagnosis test. However, an echocardiogram allows the detection of the diastolic dysfunction and the E/e′ ratio may be used in the followup progression of the illness. Cirrhotic cardiomyopathy plays an important role in the pathogenesis of the impairment of effective arterial blood volume and correlates with the degree of liver failure. A clinical consequence of cardiac dysfunction is an inadequate cardiac response in the setting of vascular stress that may result in renal hypoperfusion leading to renal failure. The prognosis is difficult to establish but the severity of diastolic dysfunction may be a marker of mortality risk. Treatment is non-specific and liver transplantation may normalize the cardiac function.

Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure

In advanced heart failure(HF), chronic inotropic therapy with intravenous milrinone, a phosphodiesterase Ⅲ inhibitor, is used as a bridge to advanced management that includes transplantation, ventricular assist device implantation, or palliation. This is especially true when repeated attempts to wean off inotropic support result in symptomatic hypotension, worsened symptoms, and/or progressive organ dysfunction. Unfortunately, patients in this clinical predicament are considered hemodynamically labile and may escape the benefits of guidelinedirected HF therapy. In this scenario, chronic milrinone infusion may be beneficial as a bridge to introduction of evidence based HF therapy. However, this strategy is not well studied, and in general, chronic inotropic infusion is discouraged due to potential cardiotoxicity that accelerates disease progression and proarrhythmic effects that increase sudden death. Alternatively, chronic inotropic support with milrinone infusion is a unique opportunity in advanced HF. This review discusses evidence that long-term intravenous milrinone support may allow introduction of beta blocker(BB) therapy. When used together, milrinone does not attenuate the clinical benefits of BB therapy while BB mitigates cardiotoxic effects of milrinone. In addition, BB therapy decreases the risk of adverse arrhythmias associated with milrinone. We propose that advanced HF patients who are intolerant to BB therapy may benefit from a trial of intravenous milrinone as a bridge to BB initiation. The discussed clinical scenarios demonstrate that concomitant treatment with milrinone infusion and BB therapy does not adversely impact standard HF therapy and may improve left ventricular function and morbidity associated with advanced HF.

Should dopamine be the first line inotrope in the treatment of neonatal hypotension? Review of the evidence

AIM: To determine if dopamine is effective in treating neonatal hypotension and safe to use comparing to other inotropes. METHODS: This is a review of evidence on inotropic treatment of neonatal hypotension. Databases searched were MEDLINE and the Cochrane Library, a total of 134 studies were identified. Only studies with high quality evidence(level 1a and b and 2a) were included. After review, only eight studies were included in the final analysis. Pooled risk ratios derived for each outcome [Mantel-Haenzel(M-H) fixed effect] with CI, as reported in the Cochrane reviews were plotted in forest plot form. RESULTS: Eight articles met inclusion criteria, which all included treatment in preterm infants. Dopamine increased mean arterial blood pressure(BP)(n = 163; r = 0.88, 95%CI: 0.76 to 0.94) and systolic BP(n = 142; r = 0.81, 95%CI: 0.42 to 0.94) comparing to placebo. Dopamine has been shown overall to be statistically more effective in increasing BP than dobutamine(n = 251, r = 0.26, 95%CI: 0.20-0.32). However there were no differences in short term outcomes(periventricular leucomalacia, periventricular haemorrhage) and mortality between both drugs. There is no statistical evidence of dopamine being more effective than adrenaline or corticosteroids. There was no difference in morbidity and mortality outcomes when dopamine was compared to hydrocortisone(RR 1.81, 95%CI: 0.18 to 18.39) or adrenaline. CONCLUSION: In preterms, dopamine is the most studied drug, and we suggest it could be used as first line treatment in hypotension.

Inotropic Requirement in Patients Undergoing Coronary Artery Bypass Grafting (CABG) in RSUP Dr. Hasan Sadikin Bandung in 2014-2016

Inotropic agents are indicated to treat ventricular dysfunction that frequently found post-CABG surgery. However, the use of inotropic isn’t free from disadvantageous side effects and is related to higher morbidity and mortality in post-CABG surgery patients. Several risk factors are known to affect higher need for inotropic agents’?post-CABG surgery. This study aims to discover the inotropic?requirement in patients undergoing CABG surgery based on age, sex, preoperative left ventricular ejection?fraction?(LVEF),?comorbidities,?cross clamping time (CCT), and cardiopulmonary bypass (CPB) duration in Hasan Sadikin General Hospital Bandung in 2014-2016. This study is a descriptive cross-sectional study done retrospectively through medical records. This study found the inotropic?requirement?post-CABG surgery was?130 patients (74.3%). The inotropic?requirement?based on age was?28 patients (80.0%) > 65 years old,?112 patients (75.7%) were?male, 18 patients (66.7%) were?female, 19 patients (100%) with ?LVEF, 41?patients (85.4%) with DM, 20 patients (90.9%) with CKD, 44?patients (93.6%) with >90 minute CCT, 37?patients (90.2%) with >120 minute duration CPB. In conclusion, there was a higher inotropic?requirement in?patients with age > 65 years?old,?preoperative LVEF??comorbidities,?CPB duration > 120 minutes and CCT > 90 minutes.

Severity of Symptoms of Systemic Inflammatory Response Syndrome and Congestive Heart Failure Caused by Chronic Aortic Stenosis and Its Pharmacological Correction

Systemic inflammatory response syndrome (SIRS) is one of the key accompanied states that worsens severity of congestive heart failure (CHF) and leads refractory CHF to conventional therapy. We investigated whether the cessation of the symptoms and signs of SIRS prevents the progression of the CHF caused by chronic aortic stenosis in rabbits. 8 weeks after induced CHF by left descending coronary artery stenosis, all animals were randomly assigned into 3 groups: control (CG)—without therapy (infusion of 0.9% NaCl);main I— receive mg/kg of Adenocin®dissolved in water for injection i.v., once daily and main II—animals receive 0.25 mg/kg enalapril i.m, furosemide 1.0 mg/kg i.v. (bolus) and pimobendan 0.1 mg/kg i.v. once daily. All animals were euthanized after 14 days of the beginning of treatment. Long-term aortic stenosis leads to a simultaneously developing of CHF, diagnosed by developing cardiac hypertrophy, increased level of BNP and myocardial oedema and SIRS, confirmed by increasing markers and symptoms of endotoxemia, tissue dysoxia and decreasing reserve ability of intrinsic defense systems. Restoration of myocardium redox-potential and level of NAD under treatment with Adenocin®leads unlike combined treatment with enalapril, furosemide and pimobendan to restoration, the regulatory pathways of TNF-α synthesis, cessation of the hypoxic/ischemic, lysosomal dysfunction and free radical-induced damage in myocardium and symptoms of CHF. Potential important link between cellular metabolism (hypoxia/ischemia), endotoxemia and disturbances in intrinsic defense system is the level of redox-potentail, NAD/NADH in myocardium. Influence of oxidized form of NAD-containing positive inotropic drug Adenocin®leads to the decreasing symptoms of CHF and beneficial action occurs on all the key links of SIRS.

Contribution of mammalian target of rapamycin in the pathophysiology of cirrhotic cardiomyopathy

AIM: To explore the role of mammalian target of rapamycin(m TOR) in the pathogenesis of cirrhotic cardiomyopathy and the potential of rapamycin to improve this pathologic condition.METHODS: Male albino Wistar rats weighing 100-120 g were treated with tetrachloride carbon(CCl_4) for 8 wk to induce cirrhosis. Subsequently, animals were administered rapamycin(2 mg/kg per day). The QT_c intervals were calculated in a 5-min electrocardiogram. Then, the left ventricular papillary muscles wereisolated to examine inotropic responsiveness to β-adrenergic stimulation using a standard organ bath equipped by Powerlab system. Phosphorylated-m TOR localization in left ventricles was immunohistochemically assessed, and ventricular tumor necrosis factor(TNF)-α was measured. Western blot was used to measure levels of ventricular phosphorylated-m TOR protein.RESULTS: Cirrhosis was confirmed by hematoxylin and eosin staining of liver tissues, visual observation of lethargy, weight loss, jaundice, brown urine, ascites, liver stiffness, and a significant increase of spleen weight(P < 0.001). A significant prolongation in QTc intervals occurred in cirrhotic rats exposed to CCl_4(P < 0.001), while this prolongation was decreased with rapamycin treatment(P < 0.01). CCl_4-induced cirrhosis caused a significant decrease of contractile responsiveness to isoproterenol stimulation and a significant increase in cardiac TNF-α. These findings were correlated with data from western blot and immunohistochemical studies on phosphorylated-m TOR expression in left ventricles. Phosphorylated-m TOR was significantly enhanced in cirrhotic rats, especially in the endothelium, compared to controls. Rapamycin treatment significantly increased contractile force and myocardial localization of phosphorylated-m TOR and decreased cardiac TNF-α concentration compared to cirrhotic rats with no treatment. CONCLUSION: In this study, we demonstrated a potential role for cardiac m TOR in the pathophysiology of cirrhotic cardiomyopathy. Rapamycin normalized the inotropic effect and altered phosphorylated-m TOR expression and myocardial localization in cirrhotic rats.

Synthesis and positive inotropic evaluation of 1-(benzylamino)-3-(4,5-di-hydro[1,2,4]trizaolo[4,3-a]quinolin-7-yloxy)propan-2-ol derivatives

In an attempt to search for more potent positive inotropic agents, a series of 1-（benzylamino）-3-（4,5-dihydro[ 1,2,4]trizaolo[4,3- a]quinolin-7-yloxy）propan-2-ol derivatives was synthesized in four steps using 6-hydroxy-3,4-dihydro-2（1H）-quinolinone as a starting material, and their positive inotropic activities were evaluated by measuring the coronary blood flow （CBF） and the left ventricular pressure （LVP） followed by calculating the rate of pressure development （dp/dtmax values） in the preparation of rat Langendorff＇s heart. Three compounds （5d, 5g, 5j） showed favorable activities, among which 5g was shown the most potent with dp/dtmax value of 9.7% and CBF value of 17.8% at a concentration of 1×10^-5 mol/L in our in vitro study.

Evaluation of Positive Inotropic Activity Induced bya Danazol Derivative in Isolated Rat Heart Model

There is scarce information about the effects of danazol and its derivatives at cardiovascular level. In addition, to date the cellular site and mechanism of action of danazol at the cardiovascular level is very confusing. In order to clarify those phenomena in this study, a danazol derivative was synthesized with the objective of evaluating its activity on perfusion pressure and coronary resistance and comparing this phenomenon with the effect exerted by danazol. The Langendorff technique was used to measure changes on perfusion pressure and coronary resistance in an isolated rat heart model in the absence or presence of danazol and its derivative. Additionally, to characterize the molecular mechanism involved in the inotropic activity induced by danazol derivative was evaluated by measuring left ventricular pressure in the absence or presence of following compounds;flutamide, prazosin, metoprolol, indomethacin and nifedipine. The results showed that danazol derivative significantly increased the perfusion pressure and coronary resistance in comparison with the control conditions and danazol. Additionally, other data indicate that the danazol derivative increases left ventricular pressure in a dose-dependent manner;nevertheless, this phenomenon was significantly inhibited by flutamide. These data suggest that danazol derivative induces positive inotropic activity through of the activation androgen receptor.

Correlation of cardiac troponin T levels with inotrope requirement,hypoxic-ischemic encephalopathy,and survival in asphyxiated neonates

BACKGROUND Cardiac involvement in neonates with perinatal asphyxia not only complicates perinatal management but also contributes to increased mortality.AIM To assess cardiac troponin T(cTnT)levels in asphyxiated neonates and their correlation with echocardiography findings,inotrope requirement,hypoxicischemic encephalopathy(HIE)stages,and mortality.METHODS cTnT levels,echocardiographic findings,the requirement of inotropes,HIE stages,and outcome were studied in neonates of gestational age≥34 wk with perinatal asphyxia.RESULTS Among 57 neonates with perinatal asphyxia,male gender,cesarean section,forceps/vacuum-assisted vaginal delivery and late preterm included 33(57.9%),23(40.4%),3(5.3%),and 12(21.1%)respectively.The mean gestational age was 38.4 wk(1.6 wk).HIE stages I,II,and III were observed in 7(12.3%),37(64.9%),and 9(15.8%)neonates respectively.26(45.6%)neonates had echocardiographic changes and 19(33.3%)required inotropes.cTnT levels were elevated in 41(71.9%)neonates[median(IQR);0.285(0.211-0.422)ng/mL].The Median cTnT level showed an increasing trend with increasing changes in echocardiography(P=0.002).Two neonates with mitral regurgitation and global hypokinesia had the highest cTnT levels(1.99 and 0.651 ng/mL).Of 31 neonates with normal echocardiography,18(58.06%)showed elevated cTnT.cTnT levels were significantly higher in those who required inotropic support than those who did not(P=0.007).Neonates with HIE stage III had significantly higher cTnT levels compared to those with HIE stage I/II(P=0.013).Survivors had lower median cTnT levels[0.210(0.122-0.316)ng/mL]than who succumbed[0.597(0.356-1.146)ng/mL].CONCLUSION cTnT levels suggestive of cardiac involvement were observed in 71.9%of asphyxiated neonates.cTnT levels correlated with echocardiography findings,inotrope requirement,HIE stages,and mortality.

The inotropic score as a predictor of mortality in neonates after complex cardiac surgery

Background Neonates undergoing cardiac surgery are at high risk of postoperative mortality.It is necessary to identify clinical factors that are indicative of in-hospital mortality.The study investigated the predictive value of inotropic score(IS)and vasoactive-inotropic score(VIS)for mortality in neonates after complex cardiac surgery.Methods This was a retrospective analysis of the 214 neonates who underwent complex cardiac surgery for congenital heart disease at a tertiary pediatric cardiac surgery intensive care unit from January 2015 to November 2017.Multiple demographics,intraoperative and postoperative variables were recorded.Multivariate logistic regression and the receiver operating characteristic(ROC)curve were performed to evaluate the relationship between IS/VIS and in-hospital mortality.Results The neonates were divided into two groups according to mortality.Neonates in the non-surviving group(n=16)had higher IS and VIS than those in surviving group(n=198).On multivariable regression analysis,after adjustment for potential confounders,IS but not VIS remained a strong predictor of in-hospital mortality,[initial IS:odds ratio(per 5-score increase):1.68,95%confidence interval:1.16-2.44,P=0.007;maximum IS:odds ratio(per 5-score increase):1.62,95%confidence interval:1.10-2.37,P=0.014].Conclusions In newborns with congenital heart disease,IS but not VIS within 24 hours is helpful for prediction of mortality at the early postoperative period after neonatal complex cardiac surgery.