Letter by Opie and Selker regarding article, "Reperfusion starts in the ambulance".
Explore the source record for details and available documents.
Ambulances↗
Biomedical subjects
Lionel H Opie
Publications and source records attributed to Lionel H Opie.
Diazoxide-induced respiratory inhibition - a putative mitochondrial K(ATP) channel independent mechanism of pharmacological preconditioning.
The ischemic preconditioning biological phenomenon has been explored to identify putative pharmacologic agents to mimic this cytoprotective program against cellular ischemic injury. Diazoxide administration confers this cytoprotection, however, whether this is via direct activation of the putative mitochondrial K(ATP) (mK(ATP)) channel which was originally proposed has been questioned. Here, we present data supporting an alternate hypothesis evoking mitochondrial respiratory inhibition rather than mK(ATP) channel activation, as a mediating event in the diazoxide-activated cytoprotective program. Mitochondrial respiration and reactive oxygen species (ROS) production was measured in digitonin-permeabilized C2C12 myotubes, allowing for the modulation of mK(ATP) conductance by changing the potassium concentration of the medium (0-130 mM). Diazoxide dose-dependently attenuated succinate-supported respiration, an effect that was independent of mK(ATP) channel conductance. Similarly, 5-hydroxydecanoate (5-HD), a putative mK(ATP) channel blocker, released diazoxide-induced respiratory inhibition independently of potassium concentration. Since diazoxide-induced cytoprotection and respiratory inhibition are both integrally linked to ROS generation we repeated above experiments following ROS generation using DCF fluorescence. Cytoprotective doses of diazoxide increased ROS generation independently of potassium concentration and 5-HD inhibited ROS production under the same conditions. Collectively these data support the hypothesis that diazoxide-mediated cytoprotection is independent of the conductance of the mK(ATP) channel and rather implicate mitochondrial respiratory inhibition-triggered ROS signaling.
Adenosine Triphosphate↗
Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure.
BACKGROUND: Metabolic modulators that enhance myocardial glucose metabolism by inhibiting free fatty acid (FFA) metabolism may improve cardiac function in heart failure patients. We studied the effect of acute FFA withdrawal on cardiac function in patients with heart failure caused by idiopathic dilated cardiomyopathy (IDCM). METHODS AND RESULTS: Eighteen fasting nondiabetic patients with IDCM (14 men, 4 women, aged 58.8+/-8.0 years, ejection fraction 33+/-8.8%) and 8 matched healthy controls underwent examination of myocardial perfusion and oxidative and FFA metabolism, before and after acute reduction of serum FFA concentrations by acipimox, an inhibitor of lipolysis. Metabolism was monitored by positron emission tomography and [15O]H2O, [11C]acetate, and [11C]palmitate. Left ventricular function and myocardial work were echocardiographically measured, and efficiency of forward work was calculated. Acipimox decreased myocardial FFA uptake by >80% in both groups. Rate-pressure product and myocardial perfusion remained unchanged, whereas stroke volume decreased similarly in both groups. In the healthy controls, reduced cardiac work was accompanied by decreased oxidative metabolism (from 0.071+/-0.019 to 0.055+/-0.016 min(-1), P<0.01). In IDCM patients, cardiac work fell, whereas oxidative metabolism remained unchanged and efficiency fell (from 35.4+/-12.6 to 31.6+/-13.3 mm Hg x L x g(-1), P<0.05). CONCLUSIONS: Acutely decreased serum FFA depresses cardiac work. In healthy hearts, this is accompanied by parallel decrease in oxidative metabolism, and myocardial efficiency is preserved. In failing hearts, FFA depletion did not downregulate oxidative metabolism, and myocardial efficiency deteriorated. Thus, failing hearts are unexpectedly more dependent than healthy hearts on FFA availability. We propose that both glucose and fatty acid oxidation are required for optimal function of the failing heart.
Aged↗
Cardiovascular disease prevention with a multidrug regimen in the developing world: a cost-effectiveness analysis.
BACKGROUND: Cardiovascular disease is the leading cause of death, with 80% of cases occurring in developing countries. We therefore aimed to establish whether use of evidence-based multidrug regimens for patients at high risk for cardiovascular disease would be cost-effective in low-income and middle-income countries. METHODS: We used a Markov model to do a cost-effectiveness analysis with two combination regimens. For primary prevention, we used aspirin, a calcium-channel blocker, an angiotensin-converting-enzyme inhibitor, and a statin, and assessed them in four groups with different thresholds of absolute risks for cardiovascular disease. For secondary prevention, we assessed the same combination of drugs in one group, but substituted a beta blocker for the calcium-channel blocker. To compare strategies, we report incremental cost-effectiveness ratios (ICER), in US dollars per quality-adjusted life-year (QALY). FINDINGS: We recorded that preventive strategies could result in a 2-year gain in life expectancy. Across six developing World Bank regions, primary prevention yielded ICERs of US746-890 dollars/QALY gained for patients with a 10-year absolute risk of cardiovascular disease greater than 25%, and 1039-1221 dollars/QALY gained for those with an absolute risk greater than 5%. ICERs for secondary prevention ranged from 306 dollars/QALY to 388 dollars/QALY gained. INTERPRETATION: Regimens of aspirin, two blood-pressure drugs, and a statin could halve the risk of death from cardiovascular disease in high-risk patients. This approach is cost-effective according to WHO recommendations, and is robust across several estimates of drug efficacy and of treatment cost. Developing countries should encourage the use of these inexpensive drugs that are currently available for both primary and secondary prevention.
Adult↗
Donepezil for severe Alzheimer's disease.
Explore the source record for details and available documents.
Alzheimer Disease↗
Postconditioning for protection of the infarcting heart.
Explore the source record for details and available documents.
Animals↗
Controversies in ventricular remodelling.
Ventricular remodelling describes structural changes in the left ventricle in response to chronic alterations in loading conditions, with three major patterns: concentric remodelling, when a pressure load leads to growth in cardiomyocyte thickness; eccentric hypertrophy, when a volume load produces myocyte lengthening; and myocardial infarction, an amalgam of patterns in which stretched and dilated infarcted tissue increases left-ventricular volume with a combined volume and pressure load on non-infarcted areas. Whether left-ventricular hypertrophy is adaptive or maladaptive is controversial, as suggested by patterns of signalling pathways, transgenic models, and clinical findings in aortic stenosis. The transition from apparently compensated hypertrophy to the failing heart indicates a changing balance between metalloproteinases and their inhibitors, effects of reactive oxygen species, and death-promoting and profibrotic neurohumoral responses. These processes are evasive therapeutic targets. Here, we discuss potential novel therapies for these disorders, including: sildenafil, an unexpected option for anti-transition therapy; surgery for increased sphericity caused by chronic volume overload of mitral regurgitation; an antifibrotic peptide to inhibit the fibrogenic effects of transforming growth factor beta; mechanical intervention in advanced heart failure; and stem-cell therapy.
Animals↗
Controversies in atrial fibrillation.
Atrial fibrillation is the most common sustained cardiac arrhythmia, and contributes greatly to cardiovascular morbidity and mortality. Many aspects of the management of atrial fibrillation remain controversial. We address nine specific controversies in atrial fibrillation management, briefly focusing on the relations between mechanisms and therapy, the roles of rhythm and rate control, the definition of optimum rate control, the need for early cardioversion to prevent remodelling, the comparison of electrical with pharmacological cardioversion, the selection of patients for long-term oral anticoagulation, the roles of novel long-term anticoagulation approaches and ablation therapy, and the potential usefulness of upstream therapy targeting substrate development. The background of every controversy is reviewed and our opinions expressed. Here, we hope to inform physicians about the most important controversies in this specialty and stimulate investigators to address unresolved issues.
Aged↗
Controversies in hypertension.
Hypertension remains the most common risk factor for cardiovascular morbidity and mortality. Its incidence is rising in both ageing and obese populations, but its control remains inadequate worldwide. We address several persisting controversies that may interfere with appropriate management of hypertension. They include: the reasons behind the increasing incidence of hypertension and the possible ways to slow the process, especially by lifestyle changes; the need for overall cardiovascular risk assessment; the major issues in the decision to institute drug therapy and the choice of drugs; and the importance of screening for various identifiable causes. We provide the background for these controversies, followed by some opinions on how to guide practitioners to offer more effective management of hypertension.
Adult↗
Controversies in cardiology.
Explore the source record for details and available documents.
Cardiology↗
Controversies in stable coronary artery disease.
Coronary heart disease is still highly prevalent worldwide, and stable angina pectoris is one of its more common presentations. Three major controversies are risk factor management, drug therapy, and intervention. As well as the major risk factors stated by the Framingham study and European guidelines, other factors include abdominal obesity, metabolic syndrome, and psychological stress. How should these additional factors be rated? With respect to drug therapy, apart from aspirin, all patients with stable angina should be assessed for statin treatment. Although statins will reduce coronary events by about one third in patients with vascular disease, the absolute benefit depends on the absolute risk. Non-controversially, all patients should be considered for angiotensin-converting-enzyme inhibitors. The concept that beta blockers are protective from future coronary events can be disputed. Percutaneous coronary intervention can relieve symptoms without extending lifespan beyond medical therapy. However, strong mortality data favour coronary-artery bypass grafting in individuals with triple-vessel or even double-vessel disease. Thus, effort angina needs comprehensive assessment, lifestyle changes, and treatment tailored to the individual patient.
Adolescent↗
Adverse effects of free fatty acid associated with increased oxidative stress in postischemic isolated rat hearts.
The mechanisms of the adverse effects of free fatty acids on the ischemic-reperfused myocardium are not fully understood. Long-chain fatty acids, including palmitate, uncouple oxidative phosphorylation and should therefore promote the formation of oxygen-derived free radicals, with consequent adverse effects. Conversely, the antianginal agent trimetazidine (TMZ), known to inhibit cardiac fatty acid oxidation, could hypothetically lessen the formation of reactive oxygen species (ROS) and thus improve reperfusion mechanical function. Isolated perfused rat hearts underwent 30 min of total global ischemia followed by 30 min of reperfusion. Hearts were perfused with glucose 5.5 mmol/l or palmitate 1.5 mmol/l with or without TMZ (100 micromol/l). Ascorbyl free radical (AFR) release during perfusion periods was measured by electron spin resonance as a marker of oxidative stress. Post-ischemic recovery in the palmitate group of heart was lower than in the glucose group with a marked rise in diastolic tension and reduction in left ventricular developed pressure (Glucose: 85 +/- 11 mmHg; Palmitate: 10 +/- 6 mmHg; p < 0.001). TMZ decreased diastolic tension in both glucose- and in palmitate-perfused hearts. Release of AFR within the first minute of reperfusion was greater in palmitate-perfused hearts and in hearts perfused with either substrate, this marker of oxidative stress was decreased by TMZ (expressed in arbitrary units/ml; respectively: 8.49 +/- 1.24 vs. 1.06 +/- 0.70 p < 0.05; 12.47 +/- 2.49 vs. 3.37 +/- 1.29 p < 0.05). Palmitate increased the formation of ROS and reperfusion contracture. TMZ, a potential inhibitor of palmitate-induced mitochondrial uncoupling, decreased the formation of free radicals and improved postischemic mechanical dysfunction. The novel conclusion is that adverse effects of fatty acids on ischemic-reperfusion injury may be mediated, at least in part, by oxygen-derived free radicals.
Animals↗
Effect of losartan versus candesartan on uric acid, renal function, and fibrinogen in patients with hypertension and hyperuricemia associated with diuretics.
BACKGROUND: Hyperuricemia may counter benefits of blood pressure (BP) reduction, although this is controversial. METHODS: We examined the effects of candesartan and losartan on uric acid, creatinine, and fibrinogen. Patients with hypertension and serum uric acid > or = 0.42 mmol/L (7 mg/dL) associated with diuretics were randomized to receive losartan 50 to 100 mg or candesartan 8 to 16 mg for 24 weeks. At randomization and after 24 weeks, systolic and diastolic BP, serum uric acid, creatinine, and fibrinogen were measured. RESULTS: A total of 59 patients were entered into the study (30 in the losartan and 29 in the candesartan group). Mean systolic and diastolic BP were reduced in the candesartan group, from 156 mm Hg at baseline to 132 mm Hg at 24 weeks, and from 90.9 to 80.8 mm Hg respectively, P < .0001), and in the losartan group from 150.3 to 132 mm Hg and from 89.6 to 77.6 respectively, P < 0001). Overall mean values of fibrinogen levels were again reduced from 4.39 g/L at baseline to 4.01 g/L at 24 weeks (P < .02). Mean values of serum uric acid in the losartan and candesartan groups were similar at baseline (0.44 and 0.46 mmol/L, respectively), but they were lower in the losartan group after 24 weeks (0.39 and 0.48 mmol/L, P = .01). Twelve patients (44%) in the candesartan group had a 10% increase in serum creatinine compared with four patients (14.2%) in the losartan group (P < .02). CONCLUSIONS: Candesartan and losartan lowered BP, but only losartan reduced uric acid. The lowering of fibrinogen in both groups may explain the reduction in stroke with angiotensin receptor blockers. The effect of persistent hyperuricemia on renal function requires further study.
Antihypertensive Agents↗
Ceramide attenuates hypoxic cell death via reactive oxygen species signaling.
We have previously demonstrated that tumor necrosis factor alpha (TNFalpha), a cytokine known to be induced by ischemia, independently promotes preconditioning in part via ceramide generation. As reactive oxygen species (ROS) signaling is evoked by ischemic preconditioning, by TNFalpha and by ceramide we reasoned that ceramide-induced preconditioning is ROS-mediated. Fibroblastic L-cells were subjected to 8 hours simulated ischemia and were preconditioned by pretreatment with cell permeable c2 ceramide (1 microM) with or without the antioxidant N-mercaptopropionyl glycine (MPG; 1 mM). Pretreatment with ceramide reduced lactate dehydrogenase release at the end of the simulated ischemia but this cytoprotective effect was lost in the presence of MPG. Concurrent temporal ROS generation was measured using confocal microscopy on cells stained with dichlorofluorescein diacetate (DCF-DA). Ceramide increased ROS production after 30 minutes and this induction was decreased by MPG. Incubation of ceramide with cyclooxygenase-2 inhibitor, NS 398 (10 microM), or with a mitochondrial respiratory chain inhibitor, rotenone (10 microM) reduced the cytoprotective effect of ceramide in parallel with a partial diminution in ROS generation. In contrast, inhibition of other ROS-producing systems including nitric oxide synthase, xanthine oxidase, or NADPH oxidase failed to modulate ceramide-induced cytoprotection. Collectively, these data demonstrate that ceramide induces a cell survival program through ROS signaling activated, in part, via cyclooxygenase and the mitochondrial respiratory chain.
Animals↗
How strong is the evidence for use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis.
OBJECTIVE: To quantify the effect of first-line antihypertensive treatment with beta-blockers on mortality, morbidity and withdrawal rates, compared with the other main classes of antihypertensive agents. METHODS: We identified eligible trials by searching the Cochrane Controlled Trials Register, Medline, Embase, reference lists of previous reviews, and contacting researchers. We extracted data independently in duplicate and conducted meta-analysis by analysing trial participants in groups to which they were randomized, regardless of subsequent treatment actually received. RESULTS: Thirteen trials with 91,561 participants, meeting inclusion criteria, compared beta-blockers to placebo (four trials; n = 23,613), diuretics (five trials; n = 18,241), calcium-channel blockers (CCBs) (four trials; n = 44,825), and renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (three trials; n = 10,828). Compared to placebo, beta-blockers reduced the risk of stroke (relative risk 0.80; 95% confidence interval 0.66-0.96) with a marginal fall in total cardiovascular events (0.88, 0.79-0.97), but did not affect all-cause mortality (0.99, 0.88-1.11), coronary heart disease (0.93, 0.81-1.07) or cardiovascular mortality (0.93, 0.80-1.09). The effect on stroke was less than that of CCBs (1.24, 1.11-1.40) and RAS inhibitors (1.30, 1.11-1.53), and that on total cardiovascular events less than that of CCBs (1.18, 1.08-1.29). In addition, patients on beta-blockers were more likely to discontinue treatment than those on diuretics (1.80; 1.33-2.42) or RAS inhibitors (1.41; 1.29-1.54). CONCLUSION: Beta-blockers are inferior to CCBs and to RAS inhibitors for reducing several important hard end points. Compared with diuretics, they had similar outcomes, but were less well tolerated. Hence beta-blockers are generally suboptimal first-line antihypertensive drugs.
Adrenergic beta-Antagonists↗
Pharmacological preconditioning with tumor necrosis factor-alpha activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signal-regulated kinase).
BACKGROUND: We previously reported that tumor necrosis-factor-alpha (TNF-alpha) can mimic classic ischemic preconditioning (IPC) in a dose- and time-dependent manner. Because TNF-alpha activates the signal transducer and activator of transcription-3 (STAT-3), we hypothesized that TNF-alpha-induced preconditioning requires phosphorylation of STAT-3 rather than involving the classic prosurvival kinases, Akt and extracellular signal-regulated kinase (Erk) 1/2, during early reperfusion. METHODS AND RESULTS: Isolated, ischemic/reperfused rat hearts were preconditioned by either IPC or low-dose TNF-alpha (0.5 ng/mL). Western blot analysis confirmed that IPC phosphorylated Akt and Erk 1/2 after 5 minutes of reperfusion (Akt increased by 34+/-6% and Erk, by 105+/-28% versus control; P<0.01). Phosphatidylinositol 3-kinase/Akt inhibition (wortmannin) or mitogen-activated protein kinase-Erk 1/2 kinase inhibition (PD-98059) during early reperfusion abolished the infarct-sparing effect of IPC. In contrast, TNF-alpha preconditioning did not phosphorylate these kinases (Akt increased by 7+/-7% and Erk, by 17+/-14% versus control; P=NS). Neither wortmannin nor PD-98059 inhibited TNF-alpha-mediated cardioprotection. However, TNF-alpha and IPC both phosphorylated STAT-3 and the proapoptotic protein Bcl-2 antagonist of cell death (BAD) (STAT-3 increased by 58+/-17% with TNF-alpha or by 68+/-12% with IPC; BAD increased by 75+/-8% with TNF-alpha or by 205+/-20% with IPC; P<0.01 versus control), thereby activating the former and inactivating the latter. The STAT-3 inhibitor AG 490 abolished cardioprotection and BAD phosphorylation with both preconditioning stimuli. CONCLUSIONS: Activation of the classic prosurvival kinases (Akt and Erk 1/2) is not essential for TNF-alpha-induced preconditioning in the early reperfusion phase. We show the existence of an alternative protective pathway that involves STAT-3 activation specifically at reperfusion in response to both TNF-alpha and classic IPC. This novel prosurvival pathway may have potential therapeutic significance.
Animals↗
Cost-effectiveness analysis of hypertension guidelines in South Africa: absolute risk versus blood pressure level.
BACKGROUND: Hypertension is responsible for more deaths worldwide than any other cardiovascular risk factor. Guidelines based on blood pressure level for initiation of treatment of hypertension may be too costly compared with an approach based on absolute cardiovascular disease (CVD) risk, especially in developing countries. METHODS AND RESULTS: Using a Markov CVD model, we compared 6 strategies for initiation of drug treatment--2 different blood pressure levels (160/95 and 140/90 mm Hg) and 4 different levels of absolute CVD risk over 10 years (40%, 30%, 20%, and 15%)--with one of no treatment. We modeled a hypothetical cohort of all adults without CVD in South Africa, a multiethnic developing country, over 10 years. The incremental cost-effectiveness ratios for treating those with 10-year absolute risk for CVD >40%, 30%, 20%, and 15% were 700 dollars, 1600 dollars, 4900 dollars, and 11,000 dollars per quality-adjusted life-year gained, respectively. Strategies based on a target blood pressure level were both more expensive and less effective than treatment decisions based on the strategy that used absolute CVD risk of >15%. Sensitivity analysis of cost of treatments, prevalence estimates of risk factors, and benefits expected from treatment did not change the ranking of the strategies. CONCLUSIONS: In South Africa, current guidelines based on blood pressure levels are both more expensive and less effective than guidelines based on absolute risk of cardiovascular disease. The use of quantitative risk-based guidelines for treatment of hypertension could free up major resources for other pressing needs, especially in developing countries.
Adult↗