Aetiology of resuscitated out-of-hospital cardiac arrest treated at hospital.

INTRODUCTION: Precipitating aetiology of out-of-hospital cardiac arrest (OHCA), as confirmed by diagnostic testing or autopsy, provides important insights into burden of OHCA and has potential implications for improving OHCA survivorship. This study aimed to describe the aetiology of non-traumatic resuscitated OHCAs treated at hospital within a local health network according to available documentation, and to investigate differences in outcome between aetiologies. METHODS: Observational retrospective cohort study of consecutive OHCA treated at hospital within a local health network between 2011-2016. Cases without sustained ROSC (≥20 minutes), unverified cardiac arrest, and retrievals to external acute care facilities were excluded. A single aetiology was determined from the hospital medical record and available autopsy results. Survival to hospital discharge was compared between adjudicated aetiologies. RESULTS: In the 314 included cases, distribution of precipitating aetiology was 53% cardiac, 18% respiratory, 3% neurological, 6% toxicological, 9% other, and 11% unknown. A presumed cardiac pre-hospital diagnosis was assigned in 235 (84%) cases, 20% of which were incorrect after exclusion of unknown cases. Rates of survival to hospital discharge varied significantly across aetiologies: cardiac 64%, respiratory 21%, neurological 0%, toxicological 58%, other 32% (p < 0.001). A two-fold difference in survival was observed between cardiac and non-cardiac aetiologies (64% versus 29%, excluding unknown, p < 0.001). CONCLUSIONS: Non-cardiac aetiologies represented a substantial burden of resuscitated OHCA treated at hospital within a local health network and were associated with poor outcome. The results confirmed that true aetiology was not evident on initial examination in 1 in 5 cases with a pre-hospital cardiac diagnosis.

Controlling angina. Management options.

BACKGROUND: Angina pectoris is a common medical problem in the community requiring a multifaceted approach to treatment in order to improve the quality of life and long term prognosis for the patient. OBJECTIVE: To discuss some of the practical aspects of the medical management of patients with stable angina pectoris, including anti ischaemic medications and secondary prevention strategies. DISCUSSION: Decreasing the risk of rapid progression of atherosclerosis in patients with angina is probably the most important factor in long term management. Also, careful use of anti ischaemic and anti platelet medications may prevent further serious cardiac events and improve quality of life.

Cytokine-mediated apoptosis in cardiac myocytes: the role of inducible nitric oxide synthase induction and peroxynitrite generation.

Increased production of nitric oxide (NO) after induction of the cytokine-inducible isoform of nitric oxide synthase (iNOS or NOS2) in cardiac myocytes and other parenchymal cells within the heart may in addition to contributing to myocyte contractile dysfunction also contribute to the induction of programmed cell death (apoptosis). To investigate the mechanism(s) by which increased NO production leads to apoptosis, we examined the role of NO in primary cultures of neonatal rat ventricular myocytes (NRVMs) after induction by the cytokines interleukin-1beta (IL-1beta) and interferon gamma (IFNgamma) or exposure to the exogenous NO donor S-nitroso-N-acetylcysteine (SNAC) or peroxynitrite (ONOO(-)). Both SNAC (1 mmol/L) and ONOO(-) (100 micromol/L), but not their respective controls (ie, N-acetylcysteine and pH-inactivated ONOO(-)), induced apoptosis in confluent, serum-starved NRVMs at 48 hours. Similarly, incubation of NRVMs with IL-1beta and IFNgamma for 48 hours resulted in an increase in iNOS expression, nitrite production, and programmed cell death. Both the cytokine-induced nitrite accumulation and myocyte apoptosis could be completely prevented by the nonselective NOS inhibitor L-nitroarginine (3 mmol/L) or the specific iNOS inhibitor 2-amino-5, 6-dihydro-6-methyl-4H-1,3-thiazine (AMT, 100 micromol/L). NO-mediated myocyte apoptosis was not attenuated by the inhibition of soluble guanylyl cyclase with ODQ, nor could apoptosis be induced by the incubation of NRVMs with 1 mmol/L 8-bromo-cGMP, a cell-permeant cGMP analogue. However, NO-mediated apoptosis was significantly attenuated by the superoxide dismutase mimetic and ONOO(-) scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP, 100 micromol/L). NO/ONOO(-)-mediated apoptosis was associated with increased expression of Bax with no change in Bcl-2 mRNA abundance. Furthermore, apoptotic cell death was also confirmed in adult rat ventricular myocytes (ARVMs) when grown in heteroculture with IL-1beta- and IFNgamma-treated rat cardiac microvascular endothelial cells. Therefore, cytokine-induced apoptosis in NRVMs and ARVMs is mediated by iNOS induction, ONOO(-), and associated with an increase in Bax levels.

Inducible nitric oxide synthase and tumor necrosis factor in animal models of myocardial necrosis induced by coronary artery ligation or isoproterenol injection.

BACKGROUND: Increased expression of inducible nitric oxide synthase (iNOS) has been described in humans with cardiomyopathies. Most animal models of ischemia-induced heart failure use the surgical ligation of coronary arteries. However, studies of iNOS expression in these models may be confounded by a robust immune response because of the surgical procedure itself leading to iNOS expression in the heart, as well as in other tissues. METHODS AND RESULTS: iNOS expression was studied in adult male rats injected subcutaneously with either 250 mg/kg of isoproterenol (ISO) or vehicle on 2 consecutive days. This approach induces diffuse myocardial necrosis and leads to the development of a dilated cardiomyopathy. Hearts from ISO-injected animals harvested at 6 weeks had evidence of apical and subendocardial scarring. These hearts showed a 9.6-fold (left ventricle [LV], P = .004) and an 11.9-fold (right ventricle, P = .002) increase in the expression of tumor necrosis factor (TNF), and a 6.8-fold increase (LV, P = .0183) in iNOS messenger RNA compared with vehicle-injected controls. iNOS protein also was detectable by immmunoprecipitation in left ventricular muscle from ISO-injected animals, as well as by immunohistochemical analysis. CONCLUSION: Expression of TNF and iNOS in the heart is increased in an experimental model of dilated cardiomyopathy that minimizes the confounding effects of surgery, supporting a role for the activation of innate immunity signaling pathways in the pathogenesis of heart failure.

Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane.

-The clinical efficacy of anthracycline antineoplastic agents is limited by a high incidence of severe and usually irreversible cardiac toxicity, the cause of which remains controversial. In primary cultures of neonatal and adult rat ventricular myocytes, we found that daunorubicin, at concentrations /=10 micromol/L induced necrotic cell death within 24 hours, with no changes characteristic of apoptosis. To determine whether reactive oxygen species play a role in daunorubicin-mediated apoptosis, we monitored the generation of hydrogen peroxide with dichlorofluorescein (DCF). However, daunorubicin (1 micromol/L) did not increase DCF fluorescence, nor were the antioxidants N-acetylcysteine or the combination of alpha-tocopherol and ascorbic acid able to prevent apoptosis. In contrast, dexrazoxane (10 micromol/L), known clinically to limit anthracycline cardiac toxicity, prevented daunorubicin-induced myocyte apoptosis, but not necrosis induced by higher anthracycline concentrations (>/=10 micromol/L). The antiapoptotic action of dexrazoxane was mimicked by the superoxide-dismutase mimetic porphyrin manganese(II/III)tetrakis(1-methyl-4-peridyl)porphyrin (50 micromol/L). The recognition that anthracycline-induced cardiac myocyte apoptosis, perhaps mediated by superoxide anion generation, occurs at concentrations well below those that result in myocyte necrosis, may aid in the design of new therapeutic strategies to limit the toxicity of these drugs.

Modulation of the endothelial nitric-oxide synthase-caveolin interaction in cardiac myocytes. Implications for the autonomic regulation of heart rate.

The endothelial isoform of nitric oxide synthase (eNOS) is dually acylated and thereby targeted to signal-transducing microdomains termed caveolae. In endothelial cells, eNOS interacts with caveolin-1, which represses eNOS enzyme activity. In cardiac myocytes, eNOS associates with the muscle-specific caveolin-3 isoform, but whether this interaction affects NO production and regulates myocyte function is unknown. We isolated neonatal cardiac myocytes from mutant mice with targeted disruption of the eNOS gene and transfected them with wild-type (WT) eNOS or myristoylation-deficient (myr-) eNOS mutant cDNA. In myocytes expressing WT eNOS, the muscarinic cholinergic agonist carbachol completely abrogated the spontaneous beating rate and induced a 4-fold elevation of the cGMP level. By contrast, in the myr- eNOS myocytes, carbachol failed to exert its negative chronotropic effect and to increase cGMP levels. We then used a reversible permeabilization protocol to load intact neonatal rat myocytes with an oligopeptide corresponding to the caveolin-3 scaffolding domain. This peptide completely and specifically inhibited the carbachol-induced negative chronotropic effect and the accompanying cGMP elevation. Thus, our results suggest that acylated eNOS may couple muscarinic receptor activation to heart rate control and indicate a key role for eNOS/caveolin interactions in the cholinergic modulation of cardiac myocyte function.

Reversible S-nitrosation of creatine kinase by nitric oxide in adult rat ventricular myocytes.

We have previously demonstrated that the nitric oxide (NO) donor S-nitroso-N-acetylcysteine (SNAC) reversibly decreases the activity of creatine kinase (CK) in an isolated rat heart preparation, markedly suppressing myocardial contractile responsiveness to an inotropic challenge. We wished to further examine the role of exogenous and endogenous sources of NO species on S-nitrosation of CK and subsequent enzyme activity in adult rat ventricular myocytes (ARVM). Two S-nitrosothiol groups were formed in the CK dimer after nitrosation of rabbit skeletal muscle CK in solution. CK inactivation due to S-nitrosation was time- and concentration-dependent in solution and in ARVM lysate for both NO donors S-nitroso-N-acetylpenicillamine (SNAP) and SNAC, and was rapidly reversible with the sulfhydryl dithiothreitol (DTT). Similarly, SNAC or SNAP dose-dependently decreased CK activity in intact ARVM, which was further attenuated by increasing the metabolic activity of the cells with electrical pacing for 1 h. Co-cultures of ARVM with interleukin 1 beta (IL-1 beta)- and interferon gamma (IFN gamma)-pretreated cardiac microvascular endothelial cells (CMEC) caused no detectable decline in myocyte CK activity. Increasing GSH levels attenuated the decline in myocyte CK activity with SNAC, while decreases in myocyte GSH levels enhanced the inhibitory effect of SNAC on intact myocyte CK activity. These data indicate that the degree of inhibition of cardiac myocyte CK by NO is dependent on the extent of myocyte metabolic activity and the intracellular GSH content.

Human ventricular myocytes in vitro exhibit both early and delayed preconditioning responses to simulated ischemia.

Myocardial tissue has been demonstrated to exhibit, in response to brief periods of ischemia, both an immediate period of cytoprotection [i.e. early or "first window" preconditioning response (EPR)], and a later period of cytoprotection [i.e. delayed or "second window" preconditioning response (DPR)], when exposed to a subsequent prolonged hypoxic insult. EPR has been documented in vitro in isolated cardiac myocytes, as well as in situ in intact hearts or trabeculae, for a number of vertebrate species, including humans. However, there are no reports to date of DPR in human cardiac myocytes. To address this question, human ventricular myocytes (HVM) primary isolates were prepared from fetal ventricular muscle, grown to confluency, and studied in primary culture in serum-free medium (> 90%) ventricular myocytes as determined by immunohistochemical analysis with an anti-myosin chain antibody). Using cell viability as determined by trypan blue exclusion, an EPR response could readily be detected following 15, 30, or 60 min of simulated ischemia (SI) in a hypoxic (< 1 tau pO2) buffer containing 11 mmol/l 2-deoxyglucose, followed by a prolonged (c. 17 h) SI challenge. In addition, HVM exposed to 60 min of SI, followed after 24 h by a period of SI, also exhibited a "second window" DPR (80 +/- 10% compared to 71 +/- 11% survival, in preconditioned and non-preconditioned cultures; P < 0.05; n = 18 independent experiments). Thus, in response to short periods of SI, human ventricular myocytes in vitro exhibit both "first window" and "second window" cytoprotective responses to subsequent, prolonged ischemic stress.

Muscarinic cholinergic regulation of cardiac myocyte ICa-L is absent in mice with targeted disruption of endothelial nitric oxide synthase.

Cardiac myocytes have been shown to express constitutively endothelial nitric oxide synthase (eNOS) (nitric oxide synthase 3), the activation of which has been implicated in the regulation of myocyte L-type voltage-sensitive calcium channel current (ICa-L) and myocyte contractile responsiveness to parasympathetic nervous system signaling, although this implication remains controversial. Therefore, we examined the effect of the muscarinic cholinergic agonist carbachol (CCh) on ICa-L and contractile amplitude in isoproterenol (ISO)-prestimulated ventricular myocytes isolated from adult mice, designated eNOSnull mice, with targeted disruption of the eNOS gene. Although both eNOSnull and wild-type (WT) ventricular myocytes exhibited similar increases in ICa-L in response to ISO, there was no measurable suppression of ICa-L by CCh in cells from eNOSnull mice, in contrast to cells from WT mice. These results were reflected in the absence of an effect of CCh on the positive inotropic effect of ISO in eNOSnull myocytes. Also, unlike myocytes from WT animals, eNOSnull myocytes failed to exhibit an increase in cGMP content in response to CCh. Nevertheless, the pharmacologic nitric oxide donors 3-morpholino-sydnonimine and S-nitroso-acetyl-cystein increased cGMP generation and suppressed ISO-augmented ICa-L in eNOSnull cells, suggesting that the signal transduction pathway(s) downstream of eNOS remained intact. Of importance, activation of the acetylcholine-activated K+ channel by CCh was unaffected in atrial and ventricular eNOSnull myocytes. These results confirm the obligatory role of eNOS in coupling muscarinic receptor activation to cGMP-dependent control of ICa-L in cardiac myocytes.

Nitric oxide inhibits creatine kinase and regulates rat heart contractile reserve.

Cardiac myocytes express both constitutive and cytokine-inducible nitric oxide syntheses (NOS). NO and its congeners have been implicated in the regulation of cardiac contractile function. To determine whether NO could affect myocardial energetics, 31P NMR spectroscopy was used to evaluate high-energy phosphate metabolism in isolated rat hearts perfused with the NO donor S-nitrosoacetylcysteine (SNAC). All hearts were exposed to an initial high Ca2+ (3.5 mM) challenge followed by a recovery period, and then, either in the presence or absence of SNAC, to a second high Ca2+ challenge. This protocol allowed us to monitor simultaneously the effect of SNAC infusion on both contractile reserve (i.e., baseline versus high workload contractile function) and high-energy phosphate metabolism. The initial high Ca2+ challenge caused the rate-pressure product to increase by 74 +/- 5% in all hearts. As expected, ATP was maintained as phosphocreatine (PCr) content briefly dropped and then returned to baseline during the subsequent recovery period. Control hearts responded similarLy to the second high Ca2+ challenge, but SNAC-treated hearts did not demonstrate the expected increase in rate-pressure product. In these hearts, ATP declined significantly during the second high Ca2+ challenge, whereas phosphocreatine did not differ from controls, suggesting that phosphoryl transfer by creatine kinase (CK) was inhibited. CK activity, measured biochemically, was decreased by 61 +/- 13% in SNAC-treated hearts compared to controls. Purified CK in solution was also inhibited by SNAC, and reversal could be accomplished with DTT, a sulfhydryl reducing agent. Thus, NO can regulate contractile reserve, possibly by reversible nitrosothiol modification of CK.

N-acetylcysteine in combination with nitroglycerin and streptokinase for the treatment of evolving acute myocardial infarction. Safety and biochemical effects.

BACKGROUND: N-acetylcysteine (NAC) has been shown to potentiate the effects of nitroglycerin (NTG) and to have antioxidant activity. This is the first study to assess the safety and effect of NAC in the treatment of evolving acute myocardial infarction (AMI). METHODS AND RESULTS: Patients with AMI received either 15 g NAC infused over 24 hours (n = 20) or no NAC (n = 7), combined with intravenous NTG and streptokinase. Peripheral venous plasma malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione concentrations, and rate of reperfusion (using continuous ST-segment analysis) were measured. Cardiac catheterization was performed between days 2 and 5. No significant adverse events occurred. Less oxidative stress occurred in patients treated with NAC than in patients not receiving NAC (GSH to GSSG ratio 44 +/- 25 versus 19 +/- 13 at 4 hours, P < .05). NAC concentration (mean 172 +/- 79 mumol/L at 4 hours) was correlated to GSH concentration (P = .006). MDA concentrations were lower (P = .001) over the first 8 hours of treatment with NAC. There was a trend toward more rapid reperfusion (median 58 minutes, 95% confidence interval [CI] 48 to 98 minutes versus median 95 minutes, 95% CI 59 to 106 minutes; P = .17) and better preservation of left ventricular function (cardiac index 3.4 +/- 0.8 versus 2.6 +/- 0.27 L.min.m2, P = .009) with NAC treatment. CONCLUSIONS: NAC in combination with NTG and streptokinase appeared to be safe for the treatment of evolving AMI and was associated with significantly less oxidative stress, a trend toward more rapid reperfusion, and better preservation of left ventricular function.

Streptokinase-induced transient aggravation of myocardial injury.

We examined the relationship between streptokinase infusion, intensity of myocardial injury and systemic hypotension in patients receiving streptokinase for treatment of evolving acute myocardial infarction. Twenty consecutive patients treated with streptokinase for evolving acute myocardial infarction received continuous blood pressure and S-T segment monitoring of the 12 lead electrocardiogram (ECG) for at least 5 h, commencing prior to commencement of the streptokinase infusion. Aggravation of injury, manifested both by episodic increases in S-T segment elevation on the electrocardiogram (ECG) (P < 0.001), and in mean S-T segment elevation (P < 0.05) occurred within the first 20 min after initiation of streptokinase infusion. Hypotension also occurred transiently in most patients, with a mean minimum systolic blood pressure of 92 +/- 22 (S.D.) mmHg occurring 16 +/- 5 min after commencement of streptokinase. There was no correlation between the extent of aggravation of injury and that of hypotension. All patients showed ECG evidence of reperfusion, with a reduction of S-T elevation in the reference lead to 50% of maximal value, after a median of 62 min (range 9-174 min). It is concluded that streptokinase aggravates injury prior to reperfusion, although probably not via the induction of hypotension: It is possible that this effect contributes to the 'early hazard' of thrombolytic therapy.

The prevalence of ST-segment depression on ambulatory electrocardiographic monitoring during daily life in high-risk asymptomatic police officers.

BACKGROUND: In individuals with no known ischaemic heart disease, the prevalence and significance of ST-segment depression on ambulatory electrocardiographic monitoring is unclear. We therefore determined the prevalence of ST-segment depression among middle-aged male police officers, an occupational group in whom an increased risk of ischaemic heart disease has been reported, who also had multiple individual coronary risk factors but no known ischaemic heart disease. METHODS: Full-time male police offices aged 45 years or more with at least two coronary risk factors but no known ischaemic heart disease performed a 24h ambulatory electrocardiographic monitor, timed to include a shift of work. The number and duration of episodes of ST-segment depression were determined. In those in whom ST-segment depression was detected, exercise thallium scintigraphy and repeat 24h ambulatory electrocardiographic monitoring were performed. RESULTS: The prevalence of ST-segment depression on 24h ambulatory electrocardiographic monitoring, including an 8h period of normal work, was 3.4% (95% confidence interval 1.3-8.3%). Exercise thallium scintigraphy was carried out in those in whom ST-segment depression had been detected. Despite two participants developing ST-segment depression during exercise, no evidence of myocardial ischaemia was observed on the perfusion scan. Therefore, the prevalence of ST-segment depression on ambulatory electrocardiographic monitoring in this asymptomatic but high-risk population was low and, when it did occur, no exercise-induced myocardial ischaemia was observed. CONCLUSION: These results suggest that ST-segment depression on ambulatory electrocardiographic monitoring in asymptomatic subjects may not represent myocardial ischaemia. The use of this parameter to screen asymptomatic populations for ischaemic heart disease is therefore highly questionable.

Silent ischemia after uncomplicated myocardial infarction: lack of incremental clinical significance.

To determine the potential utility of the detection of silent myocardial ischemia after acute myocardial infarction for clinical decision making, we investigated the hypothesis that the occurrence of silent myocardial ischemia on ambulatory electrocardiographic (EGG) monitoring after acute myocardial infarction is independently predictive of adverse outcome in patients in whom conventional clinical and investigative parameters indicate favourable prognosis on medical therapy. Among 465 consecutive patients admitted to our Coronary Care Unit with acute myocardial infarction, 42 patients (39% of those eligible) were randomly selected for study. Twenty-four hour ambulatory ECG monitoring was carried out 13 +/- 10 (standard deviation) days post-acute myocardial infarction. Ninety-eight percent of patients were receiving prophylactic anti-ischemic medications and 81% on aspirin. Silent myocardial ischemia was detected in 14%. During the follow-up period of 16 +/- 3 months, acute ischemic events occurred in 33% of those with silent myocardial ischemia and 19% of those without previous silent myocardial ischemia (P = 0.59). The sensitivity of the test for prediction of future acute ischemic events was 22% (95% confidence interval: 3-60%), specificity 87% (95% confidence interval: 72-97%), positive predictive value 33% (95% confidence interval: 4-78%) and negative predictive value 81% (95% confidence interval: 64-92%). Therefore the detection of ambulatory silent myocardial ischemia after acute myocardial infarction is not of sufficient incremental value as a predictor of the occurrence of adverse cardiac events to justify its routine clinical use in this subgroup of patients.

Sotalol-induced torsade de pointes: management with magnesium infusion.

A 69 year old woman was treated with sotalol (320 mg daily) for intermittent atrial fibrillation. Sotalol was initially well tolerated and reversion to sinus rhythm with sinus bradycardia occurred 4 weeks after initiation of therapy. Shortly thereafter, the patient developed recurrent syncope due to torsade de pointes. This was treated successfully with intravenous magnesium infusion and withdrawal of sotalol. Subsequently, the atrial fibrillation was adequately managed using amiodarone, with no recurrence of torsade de pointes. Development of bradycardia associated with reversion to sinus rhythm represents a potential cause of 'late' pro-arrhythmic effects of sotalol.