Number 24, 2004
Angina Pectoris

Featured research

NECA and bradykinin at reperfusion reduce infarction in rabbit hearts by signaling through PI3K, ERK, and NO
Yang X-M, Krieg T, Cui L, Downey JM, Cohen MV.J Mol Cell Cardiol. 2004;36:411–421.

This study compared the signal transduction pathways responsible for the anti-infarct effect of the A₁/A₂ adenosine receptor agonist 5′-N-ethyl carboxamido adenosine (NECA) and bradykinin. Receptor agonists were administered to isolated rabbit hearts, starting 25min after the onset of a 30-min period of ischemia and continuing into the 2-h reperfusion period. The results show that both NECA and bradykinin significantly decrease infarct size when administered at reperfusion. They do so through a mechanism that involves activation of phosphatidylinositol 3-kinase (PI3K), nitric oxide, and extracellular regulated kinase (ERK).

Commentary
Although mimetics of ischemic and pharmacological preconditioning are very effective at limiting infarction during an ischemic insult, the requirement for pretreatment has greatly limited their clinical usefulness, because patients with acute myocardial infarction mainly present after the onset of coronary occlusion. What is needed is a cardioprotective intervention that can be applied after ischemia has begun. Adenosine, the first preconditioning mimetic identified, was initially examined in this setting, with very mixed results. In contrast to the inconsistent data with adenosine, AMP579, an adenosine agonist with nearly equivalent affinities for A₁ and A_2A receptors, has without exception salvaged ischemic myocardium when administered at the time of reperfusion. The authors observed that NECA, a closely related compound, salvaged ischemic myocardium when infused for 70min, beginning 5min before reperfusion in isolated rabbit hearts. The salutary effect of NECA depended on A₂ receptors in addition to PI3K, nitric oxide synthase (NOS), and ERKs 1/2. Bradykinin was equally as effective as NECA, and inhibitor studies indicated that its protection was also dependent on PI3K, NOS, and ERKs 1/2. These findings challenge the concept that preconditioning mimetic agents must be administered before reperfusion in order to protect. Bradykinin protected at reperfusion by utilizing the same pathway, PI3K and NOS, that it uses to trigger preconditioning. The authors therefore speculate that other preconditioning mimetics such as opioids, angiotensin, norepinephrine, and endothelin [1] may also be protective in this setting, and the effects of these agents will be the subject of future studies. As noted, protection by both bradykinin and NECA at reperfusion was dependent on PI3K and NOS. However, ERK, which is used in multiple signaling units, has not been associated with either PI3K or NOS, so that at present it is not clear why ERK activation causes cardioprotection. Nevertheless, both NECA and bradykinin administered at reperfusion protect through a common signaling pathway. Moreover, as bradykinin at reperfusion protects through part of the same pathway that it uses to precondition the heart, it is likely that other preconditioning mimetics may protect when administered at reperfusion.

REFERENCES

Danielle Feuvray

Metabolic manipulation in ischemic heart disease: a novel approach to treatment
Lee L, Horowitz J, Frenneaux M. Eur Heart J 2004;25:634–641.

Antianginal drugs that exert their anti-ischemic effects primarily by altering myocardial metabolism have recently attracted attention. They have the potential to relieve symptoms in patients with refractory angina who are already on ‘optimal’ medical therapy and have disease that is not amenable to revascularization, making these drugs an attractive addition to therapy, particularly for the elderly population. In some cases, they may even be used as first-line treatment. These drugs increase glucose metabolism at the expense of free fatty acid metabolism, enhancing oxygen efficiency during myocardial ischemia. They have been demonstrated to reduce ischemia in several clinical trials, but their use remains limited. This review aims to draw attention to these ‘metabolic’ antianginal drugs while surveying the evidence supporting their use and mode of action. Four metabolic antianginal drugs are reviewed: perhexiline, trimetazidine, ranolazine, and etomoxir. We also discuss the metabolic actions of glucose–insulin–potassium and β-blockers and describe myocardial metabolism during normal and ischemic conditions. The potential of these metabolic agents may extend beyond the treatment of ischemia secondary to coronary artery disease. They offer significant promise for the treatment of symptoms caused by inoperable aortic stenosis, hypertrophic cardiomyopathy, and chronic heart failure.

Commentary
This is an important and useful review of the metabolic approach to ischemic heart disease. Treatments assessed include β-blockers, glucose–insulin–potassium, perhexiline (which I have not previously considered a metabolic agent), trimetazidine, ranolazine, and etomoxir. Trimetazidine has to date the largest body of information confirming its efficacy and safety. A query concerning its metabolic mode of action was allayed recently and its cause attributed to inappropriate methodology. Ranolazine in high dosage as monotherapy or in combination with either a calcium antagonist or β-blocker has proven anti-ischemic effects. There are slight anxieties about a minor prolongation of the Q–T interval, but no cases of torsades de pointes have been recorded. The potential for these drugs is considerable and long term morbidity and mortality studies are necessary. In addition, it should not be forgotten that trimetazidine can replace oral nitrates in restoring quality of life to men with erectile dysfunction.

Graham Jackon

Anti-ischemic effects and long term survival during ranolazine monotherapy in patients with chronic severe angina
Chaitman BR, Skettino SL, Parker JO, et al, for the MARISA Investigators. J Am Coll Cardiol. 2004;43:1375–1382.

The primary objective of the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial was to determine the dose–response relationship of ranolazine, a new potentially antianginal compound, on symptom-limited exercise duration. Fatty acids increase precipitously in response to stress, including acute myocardial ischemia. Ranolazine is believed to partially inhibit fatty acid oxidation, shift metabolism toward carbohydrate oxidation, and increase the efficiency of oxygen use. Patients (n=191) with angina-limited exercise discontinued antianginal medications and were randomized to groups in a double-blind four-period crossover study of sustained release ranolazine 500, 1000, or 1500mg, or placebo, each administered twice daily for 1 week. Exercise testing was performed at the end of each treatment during both trough and peak ranolazine plasma concentrations. Exercise duration at trough increased with ranolazine 500, 1000, and 1500mg twice daily, by 94, 103, and 116s, respectively, all greater (P <0.005) than the 70s increase with placebo. Dose related increases in exercise duration at peak, in times to 1mm ST-segment depression at trough and peak, and to angina at trough and peak were also demonstrated (all P <0.005). Ranolazine had negligible effects on heart rate and blood pressure. One-year survival rate combining data from the MARISA trial and its open-label follow-on study was 96.3 1.7%. In patients with chronic angina, ranolazine monotherapy was well tolerated and increased exercise performance throughout its dosing interval at all doses studied, without clinically meaningful hemodynamic effects. One-year survival was not less than expected in this high-risk patient population. This metabolic approach to treating myocardial ischemia may offer a new therapeutic option for patients with chronic angina.

Commentary
Inhibiting fatty acid oxidation has recently been demonstrated to have therapeutic benefit in the treatment of angina pectoris and other forms of ischemic heart disease. The inhibition of fatty acid oxidation results in a stimulation of glucose oxidation, resulting in a more oxygen-efficient production of energy in the heart. One approach to inhibiting fatty acid oxidation is with the antianginal drug, trimetazidine, which inhibits a key enzyme of fatty acid β-oxidation, long chain 3-keto acyl coenzyme A thiolase. Trimetazidine, which is available for clinical use as an antianginal agent in more than 80 countries, is the first clinically used agent recognized to act by optimizing energy metabolism in the heart. In this article by Bernard Chaitman and colleagues, the anti-ischemic effect of ranolazine used as monotherapy for angina treatment is described. Ranolazine, which we have shown to inhibit fatty acid oxidation in the heart [1], is the second clinically effective antianginal agent known to act by optimizing energy metabolism. Like trimetazidine, ranolazine exerts antianginal effects when used in combination with hemodynamic agents such as β-blockers, calcium antagonists or nitrates. Although ranolazine has not yet been approved for clinical use, along with trimetazidine it highlights the potential of modulating energy metabolism as an approach to treating ischemic heart disease.

REFERENCES

Gary D. Lopaschuk