ABSTRACT

For many years, we thought of coronary artery disease (CAD) as a disease of deposition of atherosclerotic plaque in arteries that ultimately became occluded and caused either ischemia or an acute myocardial infarction. Therapy for CAD focused on lipid lowering to reduce atherosclerosis, and initially bypass surgery and then PCI to restore blood flow to arteries occluded by atherosclerotic plaque. Logic dictates that the opened artery would cure CAD if all the occluded arteries were opened. But alternate facts would occasionally appear that did not fit this open artery hypothesis.

The observation that a population of patients exists with ischemic heart disease who show no evidence of proximally occluded arteries has been a focus of interest for over 50 years. These patients showed clear evidence of microvascular narrowing that produced ischemia and infarction. Other clinical studies indicated that patients with inflammatory disorders like rheumatoid arthritis had an increased incidence of CAD — and with these observations the word “inflammation” began to appear in the cardiology literature.

In the early 1970s, investigators were suggesting that an inflammatory component contributed to the atherosclerotic process, and that it may also contribute to angina produced by coronary spasm. In more recent times, we’ve elucidated more of the inflammatory process. We now understand the inflammatory process is an important contributor to the atherosclerotic process and to the development of progressive narrowing of the coronary arteries. The process of inflammatory injury to endothelium that initiates the atherosclerotic process also renders large arteries prone to spasm and infarction without evidence of proximal atherosclerosis. In 2017, we saw some interesting and exciting information about the use of a monoclonal antibody to reduce the incidence of coronary events. The CANTOS trial was an important and novel approach to CAD that did not approach the problem by lipid lowering, but by inhibiting inflammatory markers using a monoclonal antibody that was designed to reduce the inflammatory burden in patients with stable CAD.

The results showed a significant reduction in coronary events in the patients who received a 150 mg dose of canakinumab every three months over a three-year period. This was the first time that a reduction in coronary events was established by reducing the inflammatory burden on the coronary arteries, rather than lowering a lipid level. We saw data from multiple prior observations suggesting there was a beneficial effect of lowering coronary risk with medications that were not related to the lipid-lowering effects of statins. This was called the pleomorphic effect of statin therapy. This nonlipid-lowering effect, although much debated, appears now to be an important component of therapy.

More importantly, CANTOS established a new pathway for reducing coronary disease that appears to be the next step forward in eliminating coronary atherosclerosis. There appears to be a direct relation between the high-sensitivity C-reactive protein (hsCRP) level and inflammation. A low hsCRP level was related to a lower risk for subsequent coronary events.

As we look further into the inflammatory hypothesis, we find a number of causal relations between vascular pathology and inflammation. Studies of coronary spasm have demonstrated important inflammatory components of microvascular angina that are related to specific inflammatory mediators that induce vascular inflammation in distal coronary arteries, not related to proximal arterial disease. Deficiencies in the cytochrome P450 system appear to be one of the culprits in microvascular angina through alterations in inflammatory mediators that affect microvascular function. Here again the classic concepts seem to be crumbling under the scrutiny of the inflammatory system that appears to have direct effects on vascular smooth muscle in the distal coronary arteries. These pathways, recently discovered, appear to be a likely cause of angina in the presence of normal proximal coronary arteries.

It is likely that future evaluation of patients with coronary spasm will rely more on evaluation of inflammatory mediators than on angiographic imaging or provocative testing.

In the future, we will concentrate on finding a cause for microvascular inflammation as well as documenting its presence. We can now find evidence of an inflammatory component to vasospastic angina that occurs after implantation of a drug-eluting stent for occlusive disease. The continuing inflammatory response to the implanted coronary stent is a stimulus for post-stent stenosis, and can be reduced significantly by adding a calcium channel blocker to post-PCI therapy to minimize the risk of restenosis.

Future care for patients with CAD will likely require a team that includes vascular medicine, rheumatology and cardiology to provide patients with optimal therapy for both the treatment and prevention of coronary and peripheral vascular disease. The future of cardiovascular medicine and education of future cardiologists will likely emphasize managing the inflammatory state through specific modulators of inflammation as a new approach to prevention of cardiovascular disease.