The challenge of chronic ischemic heart disease

New therapeutic approaches to treat chronic stable angina are being studied.

Issue: November 2008

ByCarl J. Pepine, MD, MACC

Chronic ischemic heart disease, with its associated symptoms and disability, presents a major public health challenge as well as a management dilemma for cardiologists.

Stable angina pectoris is the most prevalent symptomatic form of ischemic heart disease (IHD) present in approximately 10 million Americans. But this likely represents only the “tip of the iceberg” considering difficulties with recognition of chest symptoms and access to medical care capable of making an appropriate diagnosis. In Americans aged 40 to 74 years, the prevalence of angina pectoris is higher in women than men. Considering documented biases relative to women and elderly persons with IHD, these estimates likely underestimate the true burden of stable angina. As our aging population increases in size, ACS death rates continue to decrease. As risk conditions like obesity, metabolic syndrome, diabetes and hypertension become increasingly prevalent, the number of patients with stable angina will continue to grow. Estimates from the United Kingdom indicate that 10% to 20% of women and men aged 65 to 74 years have stable angina, with a doubling each decade since 1980.

Angina affects quality of life in all its dimensions, and unfortunately often persists despite medical and interventional (PCI and CABG) therapies. So despite advances in prevention and management, patients limit their lifestyles to avoid angina, and this represents the management challenge.

To a large extent, this past therapeutic failure reflects our incomplete understanding of the pathophysiologic mechanisms of stable angina. This is evidenced by the fact that essentially all medical therapies targeted reducing myocardial oxygen demand.

New approaches under study

Carl J. Pepine MD, MACC
Carl J. Pepine

A number of new therapeutic approaches to chronic stable angina are under investigation, and a search on ClinicalTrials.gov yielded 160 clinical trials. Interestingly, most of the promising new therapeutic targets focus on mechanisms other than reducing myocardial oxygen demand.

Exciting new potential therapeutic approaches are directed to reduced nitric oxide bioavailability that is a defect central to the chronic coronary syndromes. Two novel drug classes seem to be able to overcome this defect without the limitations of administration of exogenous organic nitrate preparations (eg, lack of responsiveness with continued use) that activate soluble guanylate cyclase (sGC) after bioconversion to nitric oxide: One includes the sGC stimulators (eg, riociguat10, and others) which stimulate sGC directly and enhance the sensitivity of the reduced enzyme to low levels of bioavailable nitric oxide. The other includes the sGC activators which activate the nitric oxide-unresponsive, heme-oxidized or heme-free enzyme. An example is ataciguat, which predominantly stimulates the oxidized form of sGC. Preclinical studies show that ataciguat inhibits platelet activation in a model of acute coronary thrombosis, normalizes platelet activation and restores endothelial and vascular function in a diabetes model, improves endothelial function and reduces plaque in an atherosclerosis model and improves ischemia-induced muscle fatigue in an arterial occlusive disease model.

Based on these data, a randomized, double blind, placebo-controlled trial is underway (the ACCELA Trial) in patients with peripheral arterial occlusive disease. Both of these new classes of drugs reduce BP and in doses that do not reduce BP, they have potential to prevent atherosclerosis as well as thrombosis and inflammation.

Other new targets include vascular smooth muscle relaxation (eg, Rho kinase inhibition13 [fasudil] and nitric oxide donors 14 [molsidomine, pirsidomine, nicorandil, etc.]); adenosine regulating agents (dipyridamole, acadesine, GP531, etc.); metabolic modulation15 (L-carnitine, perhexiline, trimetazidine, etomoxir, etc.); preconditioning via K+ channel activation (nicorandil); inhibition of the If channel (ivabradine and others); and inhibition of the late INa current17 (e.g. amiodarone and derivatives [dronedarone, Multaq, Sanofi Aventis], ranolazine [(Ranexa, CV Therapeutics and derivatives)]); hormone replacement18 (testosterone, estrogen, progestins, tribolone, etc.); and vasculogenesis19 (non-viral DNA plasmid (ilepatril) gene (Ad5FGF-4) and/or cell-based therapies (CD34+) and small molecules). Some devices are also undergoing trial (low intensity extracorporeal shockwave, increased ambient oxygen, spinal cord stimulation, osteopathic manipulation, photopheresis, etc.)

Many of these have the potential to reduce ischemia and angina with minimal or no hemodynamic effects and are potentially complementary to conventional drugs and revascularization. Perhaps some of these emerging approaches will permit the millions of patients with chronic IHD to have a better quality of life.

Carl J. Pepine, MD, MACC, is Eminent Scholar and Professor, Division of Cardiovascular Medicine, University of Florida, Gainesville, and Chief Medical Editor of Cardiology Today.

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