Manganese superoxide dismutase dimorphism relationship with severity and prognosis in cardiogenic shock due to dilated cardiomyopathy.

The aim was to determine (a) Ala-16Val-SOD2 dimorphisms; (b) allelic frequency and phenotype of a common Pro-Leu polymorphism in GPx1, in a cohort of patients with a cardiogenic shock (CS) due to dilated cardiomyopathy without acute coronary syndrome. Consecutive patients with de novo CS that worsened a dilated (DCM) or ischemic (ICM) cardiomyopathy. Congenital heart disease, pacemaker and other shock aetiologies were excluded. To determine oxidative stress (OS), this study evaluated lipid peroxidation, protein oxidation and erythrocyte GPx, SOD and catalase activities. Ala16Val-SOD2 (dbSNP: rs4880) and Pro198Leu-GPx1 (dbSNP: rs1050450) polymorphisms were studied by allelic discrimination using fluorogenic probes and the 5'nuclease (TaqMan) assay. Twenty-four patients (with ICM (n = 8) or DCM (n = 16), age = 57.5 ± 10.7 years, LVEF = 25.3 ± 8.5%, NT-proBNP levels = 8540 ± 1703 ng/L) were included during a 15 month follow-up. OS parameters were significantly higher in patients than in controls. Distribution of MnSOD genotypes was 47% Val/Val-variant, 29.5% Ala/Val and 23.5% Ala/Ala-variants. Severity of CS was more important in patients with Val/Val-variant and can be put in parallel with NT-proBNP levels (Val/Val-variant: 11 310 ± 3875 ng/L vs Ala/Ala-variant: 6486 ± 1375 ng/L and Ala/Val-variant: 6004 ± 2228 ng/L; p < 0.05) and hemodynamic support duration (144.6 vs Ala/Val-variant: 108.8 h and Ala/Ala-variant: 52.5 h; p < 0.05) with a positive correlation (Spearman rho = 0.72, p < 0.05). Moreover, Val/Val-variant significantly influenced the mortality (Spearman rho = 0.67, p < 0.05), but not the morbidity (p = 0.3). Distribution of GPx genotypes was 64% Pro/Pro, 18% Pro/Leu and 18% Leu/Leu. GPx-variants influenced neither GPx activities nor cardiac events. In conclusion, CS was associated with markers of increased OS. GPx polymorphism did not influence the GPx activity. Only the Val-encoding MnSOD allele was significantly correlated with the severity and prognosis of CS.

Prognostic value of admission myeloperoxidase levels in patients with ST-segment elevation myocardial infarction and cardiogenic shock.

Inflammation plays a critical role in acute myocardial infarction. One inflammatory marker is myeloperoxidase (MPO). Its role as a predictor of in-hospital death in patients with ST-segment elevation myocardial infarction (STEMI) presenting with cardiogenic shock (CS) is unclear. Therefore, the aim of this study was to investigate the role of MPO as a predictor of in-hospital death in patients with STEMIs presenting with CS and treated with primary percutaneous coronary intervention. In 38 consecutive patients with CS complicating STEMIs who were treated with primary percutaneous coronary intervention, serum MPO levels were measured at coronary care unit admission using a commercially available enzyme-linked immunosorbent assay. The primary study end point was in-hospital cardiac death. Among the 38 patients included in the study, 20 died during their coronary care unit stays, whereas 18 survived. Compared with patients who survived, patients who died showed, at coronary care unit admission, higher serum MPO levels (81 +/- 28 vs 56 +/- 23 ng/ml, p <0.006). After controlling for different baseline clinical, laboratory, and angiographic variables, baseline serum MPO level was an independent predictor of in-hospital mortality on multivariate analysis (odds ratio 3.9, 95% confidence interval 1.8 to 7.5, p <0.001). In conclusion, admission MPO concentration is an independent predictor of in-hospital mortality in patients with STEMIs presenting with CS.

The tragedy of TRIUMPH for nitric oxide synthesis inhibition in cardiogenic shock: where do we go from here?

Cardiogenic shock following an acute coronary syndrome (ACS) continues to be associated with significant mortality despite modern reperfusion strategies and inotropic support. There is mounting evidence that an acute inflammatory response accompanies the well documented decrement in left ventricular systolic function associated with cardiogenic shock and that this response may affect outcomes. In the past 2 decades it has also become apparent that nitric oxide (NO), a heteroatomic free radical has numerous biologic activities, among them the maintenance of vascular tone. The production of NO is mediated by three nitric oxide synthases (NOS); the transcription of one of these (NOS2 or inducible NOS [iNOS]) is induced by inflammatory stimuli. The iNOS gene product produces NO at very high and potentially pathologic levels. The up-regulation of iNOS transcription and overproduction of NO have been implicated in the pathogenesis of shock states where excess NO is thought to cause catecholamine resistant vasodilatation and reduced myocardial inotropy, resulting in hypotension and a fall in cardiac output. NO can also react with superoxide to produce peroxynitrate, a molecule directly toxic to the cells via modification of proteins and DNA. Inhibitors of NOS have long been utilized in the laboratory characterization of the NOS. More recently, attempts have been made to determine if the inhibition of NOS might have clinical utility in the setting of circulatory shock. With respect to septic shock, early animal studies and small trials in humans proved encouraging, but a larger trial was terminated early because of a trend toward harm among patients receiving the NO inhibitor. Studies have been undertaken in the setting of cardiogenic shock. Animal studies and small trials with humans again proved encouraging, but the large randomized TRIUMPH trial evaluating tilarginine (NG-monomethyl-L-arginine; L-NMMA) was recently terminated because of a lack of efficacy. These studies evaluated compounds with little selectivity for iNOS and their failure may have been due, in part, to the inhibition of the other NOS isoforms. In this review, we describe the biochemistry of NO synthesis, the regulation of NO production, and the clinical trials evaluating the efficacy of NOS inhibition with an eye to future trials with more selective inhibitors of iNOS.

Effect of nitric oxide synthase inhibition on haemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study.

AIMS: Previous studies suggested haemodynamic benefits and, possibly, mortality reduction with the use of nitric oxide synthase (NOS) inhibition in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). We assessed preliminary efficacy and safety of four doses of l-n-monomethyl-arginine (l-NMMA), a non-selective NOS inhibitor, in patients with AMI complicated by CS despite an open infarct-related artery. METHODS AND RESULTS: Patients (n = 79) were randomly assigned to a bolus and 5 h infusion of placebo or 0.15, 0.5, 1.0, or 1.5 mg/kg of l-NMMA. The primary outcome measure was absolute change in mean arterial pressure (MAP) at 2 h. Fifteen minutes after study drug initiation, mean change in MAP was -4.0 mmHg in the placebo group and 5.8 (P = 0.02), 4.8 (P = 0.02), 5.1 (P = 0.07), and 11.6 (P < 0.001) mmHg in the four l-NMMA groups, respectively (all vs. placebo). Mean change in MAP at 2 h was -0.4, 4.4, 1.8, -4.1, and 6.8 mmHg in the placebo and four l-NMMA groups, respectively (all P = NS). CONCLUSION: l-NMMA resulted in modest increases in MAP at 15 min compared with placebo but there were no differences at 2 h.

Effects of nitric oxide synthase inhibition on the cardiovascular response to low output shock.

OBJECTIVE: To study the role of nitric oxide in the cardiovascular response to a model of a low output syndrome. DESIGN: Prospective animal study. SETTING: Animal research laboratory. SUBJECTS: Sheep anesthetized with pentobarbital, mechanically ventilated, and monitored with pulmonary arterial and peripheral arterial catheters. INTERVENTIONS: A low output state was induced by inflating a balloon-tip catheter placed in the right atrium. Cardiac index was maintained at 1 L/min/m2 throughout the experiment in three groups of sheep: a) control (n=6) b)LNNA group (pretreated with the nitric oxide synthase inhibitor N omega-nitro-L-arginine [LNNA, 100 mg/kg, iv bolus, n=6); and c) dexamethasone group (pretreated with dexamethasone (6 mg/kg, intravenous bolus, n=6). Dexamethasone is an inhibitor of the induction of nitric oxide synthase. LNNA or dexamethasone were administered 15 mins before inducing the low output state. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and oxygen transport variables, and plasma lactate and pyruvate concentrations, were measured at baseline and during the next 3 hrs. For a comparable decrease in cardiac index and oxygen delivery in all groups, the LNNA group had less hypotension and a more marked increase in systemic vascular resistance as compared with the control group. Oxygen consumption and oxygen extraction were higher in the LNNA group as compared with the control group at 30 and 60 mins. Plasma lactate concentration increased significantly less in the LNNA group than in the control and the dexamethasone groups during the observation period. CONCLUSIONS: Inhibition of nitric oxide synthesis during a severe low output state in sheep is associated with a better hemodynamic response, as evidenced by a greater vasoconstriction, and signs of less marked tissue hypoxia. It is likely that inhibition of nitric oxide synthesis in this model leads to an imbalance between the tonic relaxing action of nitric oxide and the influences of vasoconstrictor agents.

[Acute liver failure secondary to cardiogenic shock in patients with congestive heart failure]. / Falência hepática aguda secundária a choque cardiogênico em portadores de insuficiência cardíaca congestiva.

Fulminant hepatic failure is a complication of severe cardiocirculatory failure, with high morbidity and mortality, and is frequently misdiagnosed as fulminant viral hepatitis. We report three cases of patients with chronic severe heart failure who developed cardiogenic shock complicated by elevation of aminotransferase levels above 1,000 soon after the most severe episode of hypotension. All the three patients presented regression of hepatic enzymes 72h after admission. Two patients developed hepatic encephalopathy and renal failure. One underwent the implantation of an artificial left ventricle, followed by orthotopic heart transplantation. One died of systemic multiple organ failure, after he had showed improvement on his hepatic profile, and one was sent to the ward, after 15 days with marked improvement on his clinical status and no signs of hepatic disease.

Falência hepática aguda secundária a choque cardiogênico em portadores de insuficiência cardíaca congestiva / Acute Liver Failure Cardiogenic Shock in Patients with Congestive Heart Failure

Fulminant hepatic failure is a complication of severe cardiocirculatory failure, with high morbidity and mortality, and is frequently misdiagnosed as fulminant viral hepatitis. We report three cases of patients with chronic severe heart failure who developed cardiogenic shock complicated by elevation of aminotransferase levels above 1,000 soon after the most severe episode of hypotension. All the three patients presented regression of hepatic enzymes 72h after admission. Two patients developed hepatic encephalopathy and renal failure. One underwent the implantation of an artificial left ventricle, followed by orthotopic heart transplantation. One died of systemic multiple organ failure, after he had showed improvement on his hepatic profile, and one was sent to the ward, after 15 days with marked improvement on his clinical status and no signs of hepatic disease

Atypical patterns of lactate dehydrogenase isoenzymes in acute myocardial infarction.

Total lactate dehydrogenase (LD; EC 1.1.1.27) activity in serum and LD isoenzymes were quantified in 190 patients with acute myocardial infarction (AMI) 24, 48, and 72 h after admission. In 90% of the 570 blood specimens an LD isoenzyme pattern typical of AMI (LD-1/LD-2 greater than 0.76) was found. The other 56 blood specimens showed an LD isoenzyme pattern atypical of AMI (LD-1/LD-2 less than 0.76). They were divided into three groups: 28 specimens with isomorphic pattern (relative increase in all five LD isoenzymes); 18 with relatively increased LD-3 proportion (greater than 35%); and 10 specimens with increased LD-5 proportion (greater than 10%). No difference was found in mean total LD activity in serum between the typical isoenzyme group and the three atypical groups. The LD isomorphic pattern was found in 60% of AMI patients complicated by cardiogenic shock. Fifty percent of AMI patients admitted with pulmonary edema showed increased LD-3 proportion and half of the patients with AMI and congestive heart failure, predominant right, demonstrated increased LD-5 proportion. We conclude that although most patients with AMI present at diagnosis with a typical LD isoenzyme pattern, it is important to recognize that some may present with atypical LD isoenzyme patterns, which may be associated with specific AMI complications.

The correlation between CK MB curve type and the clinical course of recent myocardial infarction.

In 265 patients with acute myocardial infarction (MI) for whom the 72-hour CK MB curve was obtained, three types of a curve were found: with a single and early 16 h peak value (type A), with a single late 16 h peak value (type B), and with a double peak (type C). Type A of the CK MB curve was found in 32% of patients with acute MI, type B in 55% and type C in 13%. There were no significant differences of CK MB max between the type groups. Infarct size differed significantly between groups (A-29 +/- 19, B-35 +/- 22, C-53 +/- 30 g Eq CK MB). In-hospital mortality also differed significantly particularly between type C (31%) and type A groups (5%). Nitroglycerin or practolol given intravenously during the first 48 hours changed the CK MB curve mainly by decreasing CK MB max as compared to controls treated conventionally. There was no effect of treatment with either nitroglycerin or practolol on the clinical course in patients with type A CK MB curve. There is a good correlation between the CK MB curve type and the clinical course of MI. Nitroglycerin or practolol decreased the infarct size only in patients with either B or C type of CK MB curve, having no influence in patients with a mild form of acute MI (type A).

[Activity of various organ-specific liver enzymes in patients with myocardial infarction complicated by cardiogenic shock]. / Aktivnost' nekotorykh organospetsificheskikh fermentov pecheni u bol'nykh infarktom miokarda, oslozhnennym kardiogennym shokom.

The activity of some organ specific enzymes of the liver subcellular structures in the blood serum was examined in 56 patients with cardiogenic shock. The correlation between the gravity of clinical signs of cardiogenic shock and blood enzyme degree was revealed. It was concluded that biochemical criteria could be used in the diagnosis of irreversible changes in the liver in cardiogenic shock.

Shock-induced damage to mitochondrial function and some cellular antioxidant mechanisms in humans.

The effects of circulatory shock on skeletal muscle mitochondrial oxidative activity in various substrates and cytochrome oxidase activity have been investigated using samples of muscle obtained by the needle biopsy technique from human subjects. The effect of shock on superoxide dismutase activity and glutathione content of skeletal muscle was also examined. The results show that there is a large decrease in cytochrome oxidase activity during shock and also in the capacity of the mitochondria to oxidize either succinate, or pyruvate, or palmitoyl carnitine. There is a fall in the tissue content of superoxide dismutase and in the total glutathione present. Furthermore, an increased oxidized glutathione content causes a decrease in the molar ratio of reduced to oxidized glutathione present in the muscle. These findings suggest that mitochondrial electron transport chain (ETC) oxidative damage can play a relevant role in the pathogenesis of circulatory shock and support the hypothesis of oxygen-free radical involvement in the cellular injury.

Relationship between serum CK-MB-estimated acute myocardial infarct size and clinical complications.

The relationship between acute myocardial infarct (AMI) size and morbidity and mortality was estimated in 317 patients followed for one year or until death. Infarct size was estimated from serum creatine kinase (CK)-MB levels measured thrice daily. The incidence of ventricular arrhythmias, congestive heart failure, cardiogenic shock, and the cardiac performance during exercise were studied during hospitalization. Hospital mortality and one-year mortality were registered. A positive correlation was found between serum CK-MB-estimated infarct size and the incidence of ventricular arrhythmias (p less than 0.05). Patients with congestive heart failure and patients with cardiogenic shock had significantly larger infarct size than patients without (p less than 0.05-0.01), although there was a substantial overlap. During exercise test the rise in systolic blood pressure correlated negatively and the rise in heart rate correlated positively to estimated infarct size (p less than 0.01). Both hospital mortality and one-year mortality were significantly related to estimated infarct size (p less than 0.01). Thus the infarct size, as estimated from serum CK-MB, seems to be of importance for development of the most common and serious complications after AMI.

Mitochondrial creatine kinase. A poor prognostic sign.

A serum creatine kinase (CK) isoenzyme band cathodic to MM, thought to represent mitochondrial CK, was found in eight patients in shock, six of whom died within 12 days. Severe tissue damage appears to be required to release this isoenzyme to detectable levels in the serum.

Plasma adrenaline and noradrenaline concentrations and dopamine-beta-hydroxylase activity in myocardial infarction with and without cardiogenic shock.

In patients with myocardial infarction, with or without cardiogenic shock, plasma noradrenaline and adrenaline concentrations are increased. However, plasma noradrenaline concentrations are considerably higher in patients with cardiogenic shock when compared with those with uncomplicated myocardial infarction. Plasma noradrenaline and adrenaline concentrations showed a sustained increase until death in patients with cardiogenic shock whereas those concentrations were back to normal levels by the end of the third day in patients with uncomplicated myocardial infarction. Plasma dopamine-beta-hydroxylase activities in both the groups were within normal range and did not show any significant variation throughout the period of study.

The loss of electrically active myocardium in cardiogenic shock.

A method of precordial mapping of RS ratio changes and the appearance of Q waves that occur in acute myocardial infarction has been developed. The serial changes of R and Q waves in 40 patients suffering uncomplicated anterior infarction shows that the loss of electrically active myocardium occurs within 6 h from the onset of chest pain. The total precordial ECG changes of R and Q waves in 5 patients suffering anterior infarction and cardiogenic shock showed that the loss of electrically active myocardium continues after 6 h from the onset of chest pain, and is significantly different from the uncomplicated group. This was supported by the serial plasma MBCK activity determinations which suggest more than one episode of necrosis.