Rethinking the pathophysiology of stable coronary artery disease

Cardiothoracic Department
Division of Cardiology
Azienda Ospedaliero
Universitaria Pisana

Rethinking the pathophysiology of stable coronary artery disease

by A. Huqi and M. Marzilli , Italy

Current guidelines consider obstructive atherosclerotic coronary artery disease to be the most common cause of chronic stable angina, to the point that the terms obstructive coronary artery disease and ischemic heart disease are interchangeably used. However, a large body of accumulating evidence challenges this view: for example, (i) coronary atherosclerotic obstructions are not consistently present in angina patients; (ii) coronary stenosis does not have a predictable impact on myocardial perfusion; and (iii) stenosis removal is not consistently effective in curing angina pectoris and does not have an impact on prognosis in patients with chronic ischemic heart disease. Altogether, these data strongly support the hypothesis that ischemic heart disease is a multifactorial syndrome, with coronary stenosis being just one of the many mechanisms that can precipitate myocardial ischemia in man. A better understanding of the nature and prevalence of these mechanisms could provide the basis for a tailored approach to therapy in patients with stable angina/chronic ischemic heart disease.

Medicographia. 2014;36:31-36 (see French abstract on page 36)

Ischemic heart disease (IHD) is a leading cause of mortality and, among others, stable angina represents the most frequent clinical presentation.1,2 The annual incidence of uncomplicated angina pectoris is estimated at around 0.5%, with a prevalence ranging from 20 000 to 50 000 per 1 million in Western general populations aged over 40.1

According to major guidelines, obstructive atherosclerotic coronary artery disease (CAD) is regarded as the most common cause of chronic stable angina, with nonobstructive CADs (ie, vasospastic angina and X syndrome) being considered only rare conditions that do not deserve particular attention.1 Current understanding of the pathophysiological basis of myocardial ischemia is derived from experimental observations that coronary artery narrowing limits resting and hyperemic coronary blood flow.3 These concepts have been further extended, with the current paradigm delineating the atherosclerotic plaque as the target of both diagnostic protocols and therapeutic strategies. As a consequence, “the search for and treatment of obstructive CAD” is viewed as the crucial aspect in the management of patients with suspected IHD,4 with cardiologists, as pointed out in a recent paper by Rothberg, being viewed more or less as “pipe” specialists.5 Nonetheless, overt clinical inconsistencies and the prohibitive costs associated with the current approach, together with the disappointing results with regard to hard events (mortality, myocardial infarction), suggest the need for reconsidering longstanding views. Indeed, while in everyday practice CAD is regarded as synonymous and equivalent to IHD, a growing body of evidence strongly challenges this concept, supporting the need for an innovative approach to IHD, focused on myocardial ischemia more than on coronary atherosclerotic plaques. In this review, we will report on recent evidence suggesting that the link between coronary atherosclerotic obstructions and IHD is much more elusive than we have believed so far.

Are coronary atheromatous obstructions consistently present in angina patients?

In a recent study involving 397 954 subjects referred for cardiac catheterization, Patel et al tested the effectiveness of current criteria in predicting obstructive CAD and compared the prevalence of coronary stenosis ≥50% with the result of provocative tests. A positive test result was recorded in 68.6% of all the patients in the cohort. At angiography, a much smaller fraction, 37.6%, was found to have coronary obstructive lesions. Even more surprisingly, the prevalence of coronary stenosis ≥50% was similar in all groups, including patients with a positive test result, patients with an equivocal result, patients with a negative result, and in patients that had not undergone the test, suggesting the absence of any consistent association between prevalence of CAD stenosis ≥50% and inducible myocardial ischemia. Interestingly enough, a linear relation was observed between the Framingham Risk Score (FRS) and the prevalence of coronary stenosis, with patients with higher scores more likely to have obstructive CAD.6 Based on this data, the question arises whether established coronary risk factors are indeed predictive of coronary atherosclerosis more than of IHD.

Consistent observations have been reported in the CONFIRM study (COronary computed tomography angiography evaluatioN For clinical outcomes: an InteRnational Multicenter study).7 The investigators compared the pretest probability of angiographically significant CAD as estimated by current guidelines with the prevalence observed at coronary computed tomography (CT) angiography. The study included 12797 patients. There were 7113 men and 5684 women analyzed on the basis of clinical symptoms of myocardial ischemia: patients with typical angina, patients with atypical angina, patients with nonanginal chest pain, and asymptomatic patients.

In all patient groups of both sexes, the prevalence of coronary stenosis was linearly related to age (Figure 1).7 Unexpected findings included (i) a much lower prevalence of obstructive CAD in patients with typical angina than predicted by guidelines, ranging from 25%-45% in men and 10%-25% in women (Figure 1) and (ii) a prevalence of obstructive CAD at CT angio that was similar in all patient groups, from totally asymptomatic patients to typical angina patients (Figure 1). Based on these observations, 2 conclusions can be drawn. Firstly, most patients with angiographically significant coronary stenosis do not have angina. Secondly, less than 50% of older men with typical angina and less than 30% of older women with typical angina have an angiographically significant coronary stenosis. Obviously, one has to ask why so many patients with a significant coronary stenosis do not have symptoms or other evidence of IHD and what causes angina in patients free from obstructive CAD. Certainly, these data strongly challenge the popular concept that angina is consistently associated with a significant coronary stenosis. Actually, these observations are not entirely new: inducible ischemia in the absence of obstructive CAD has long been documented.8,9 Conversely, patients with normal stress single-photon emission CT (SPECT) images have been reported to have obstructive CAD detected by CT coronary angiography (CTA).10 However, these contradictory observations have been traditionally attributed to a low predictive value of noninvasive imaging techniques.6 Given the consistency of these observations, the evidence has been accepted with time: angina can frequently occur in the absence of significant coronary stenosis, and most subjects with obstructive CAD simply do not suffer from myocardial ischemia.

Does coronary stenosis have a predictable impact on myocardial perfusion?

In contrast with the linear model originally proposed by Gould et al,3 the relationship between stenosis severity and coronary myocardial blood flow is characterized by wide scatter on scatterplot analysis, and direct transfer to the clinical setting appears overly simplistic.11,12 Naya et al13 sought to determine the effects of coronary atherosclerosis morphology and extent, assessed by CTA, on myocardial flow reserve (MFR), evaluated by positron emission tomography. The authors found that severity of stenosis by CTA had only a modest effect on downstream MFR. Indeed, stenosis severity did not reliably predict physiological myocardial blood flow effects. More specifically, they found that patients with 0% stenosis diameter or 0 summed stenosis score by CTA could present with a MFR ranging from 1 to 5, and, on the other hand, that patients with ≥70% stenosis diameter or higher summed stenosis score could have a normal MFR.

Figure 1
Figure 1. Prevalence of coronary stenosis predicted by current guidelines (dark bars) and observed at computed tomography angiography
(light bars) in asymptomatic, nonanginal chest pain, atypical angina, and typical angina patients.

Abbreviations: CAD50, coronary artery disease with ≥50% diameter stenosis.
Based on data from reference 7: Cheng et al. Circulation. 2011;124:2423-2432.

Kang et al assessed the accuracy of intravascular ultrasound (IVUS) in predicting the functional significance of intermediate coronary lesions.14 In this study, 201 patients, with a total of 236 coronary lesions, underwent IVUS and invasive physiological assessment with fractional flow reserve (FFR) before intervention. The authors identified an IVUS minimal lumen area (MLA) of ≥2.4 mm2 as a cutoff with high predictive value for an FFR ≥0.80. However, 63% of lesions with an MLA <2.4 mm2 had an FFR ≥0.80, and the results were similar when other IVUS-measured parameters were related to FFR. These observations imply that, in the individual patient, it is impossible to estimate the physiological impact of a coronary stenosis from its cross-sectional area, however accurately it is measured. In other words, stenosis anatomy is not a reliable predictor of stenosis physiology. Similarly, FIRST (Fractional flow reserve and Intravascular ultrasound RelationShip sTudy) investigators sought to determine the optimal MLA correlating with FFR and correlation between virtual histology IVUS and FFR for intermediate coronary lesions. This was a multicenter, prospective, international registry involving 350 patients with intermediate coronary lesions at angiography. An MLA <3.07 mm2 was identified as the best threshold value for identifying FFR <0.8. However, this finding was shown to be dependent on vessel diameter. On the other hand, FFR correlated with plaque burden, but not with other plaque parameters, thus questioning the clinical utility of IVUS MLA, hence of coronary anatomy, in predicting myocardial perfusion.15

Figure 2
Figure 2. Prevalence of angina following “successful”
coronary revascularization.

Based on BARI, CABRI, RITA, and EAST studies.
Abbreviations: BARI, Bypass Angioplasty Revascularization Investigation;
CABG, coronary artery bypass grafting; CABRI, Coronary Angioplasty
versus Bypass Revascularization Investigation; EAST, Emory Angioplasty versus
Surgery Trial; PTCA, percutaneous transluminal coronary angioplasty;
RITA, Randomized Intervention Treatment of Angina.

Is stenosis removal consistently effective in curing angina pectoris?

Large clinical trials have reported that following coronary revascularization, many patients present with persistent symptoms (Figure 2, page 33).16-22 In a recent comparison of medical therapy and medical therapy plus percutaneous coronary intervention (PCI) in the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation), about one-third of patients still complained with angina at the 1- year follow-up, with a minor difference between those whose stenosis had been removed (PCI branch) and those whose stenosis had not been removed (medical therapy branch) (Figure 3).21

We conducted a single center, prospective, observational study on a highly selected, chronic angina patient population undergoing successful and complete PCI with a preprocedural positive exercise stress test. We made an effort to avoid all confounding factors (ie, patients with valvular dysfunction, primary cardiomyopathy, etc).23 Of the 220 patients included in the study, nearly 50% still had positive exercise stress test results at 1 month after the index PCI (Figure 4).23 A similar rate for positive stress test results were found at 6- and 12-month follow-up visits. Most importantly, one-third of the total population also had effort angina with impaired quality of life as assessed by the Seattle Angina Questionnaire (SAQ). As the stenosis had been removed, what was the cause of persisting symptoms/ischemia in these patients?

Does stenosis removal have an impact on prognosis?

When compared with medical therapy, neither the advent of PCI itself16,17,21 nor the progressive sophistication of percutaneous techniques24 have changed the mortality and morbidity of patients with chronic IHD. Recently, De Bruyne et al25 reported on the efficacy of FFR-guided PCI versus medical therapy in 1220 patients with stable CAD. Among patients deemed in stable condition and considered appropriate candidates for PCI, about one-third was found not to have a significant coronary stenosis. The patients found to have a significant coronary stenosis, based on a FFR below 0.80, were randomized to PCI plus medical therapy or medical therapy alone. Similar to what was observed in the COURAGE trial,21 PCI had no impact on mortality and morbidity, and the rate of revascularization was the only outcome that significantly differed between treatment groups. Patients in the PCI group underwent 14 additional procedures during the follow-up; patients initially treated medically underwent 86 procedures. Half of the procedures at follow-up were rated as urgent in both groups. According to these results, following stenosis assessment with FFR, 12 patients with significant obstructions need to be treated in order to prevent 1 unplanned revascularization procedure. In this way, one would unnecessarily and prematurely expose 11 patients to revascularization-related adverse effects (ie, early and late stent thrombosis), an aspect that could not be assessed in the present work due to the short follow-up period. Considering that an initially invasive strategy does not change patient outcome in terms of death and myocardial infarction, wouldn’t it be more prudent and cost-effective to manage patients medically until “unplanned revascularization” is needed, if ever?

Figure 3
Figure 3. Prevalence of angina at 1-year follow-up in the COURAGE

Abbreviations: COURAGE, Clinical Outcomes Utilizing Revascularization and
Aggressive druG Evaluation; PCI, percutaneous coronary intervention.
Based on data from reference 21: Boden et al. N Engl J Med. 2007;356:

Figure 4
Figure 4. Prevalence of persistent inducible ischemia after “successful”

Abbreviation: PCI, percutaneous coronary intervention.
Based on data from reference 23: Marzilli et al. Am J Cardiovasc Drugs. 2010;
10(suppl 1):27-32.

What dictates prognosis: coronary atherosclerosis or myocardial ischemia?

Despite scant evidence, patients with chest pain and no obstructive CAD have been traditionally considered at low risk for cardiovascular events. In recent work, Jespersen et al assessed the prognostic implications of angina pectoris in relation to the presence and degree of CAD.26 Major adverse cardiovascular events of 11 223 patients with stable angina pectoris, referred for coronary angiography from 1998 to 2009, were compared with 5705 controls without IHD. In line with previous studies, significantly more women (65%) than men (32%) had nonobstructive CAD on coronary angiography. In addition, the risk of major cardiovascular events increased linearly with increasing CAD burden (hazard ratio, 1.52 for patients with normal coronary arteries and 1.85 for patients with diffuse nonobstructive CAD). However, angina patients with no coronary atherosclerosis had a higher rate of major adverse events when compared with the reference population. Thus, while both CAD burden27 and angina appear to be linear predictors of major cardiovascular events, the most fragile link appears to be the one between obstructive CAD and angina. In line with these considerations, in a recent review paper, Roberts et al pointed out that despite the confusion generated by using CAD and myocardial infarction phenotypes interchangeably, genetic studies show that risk alleles for CAD and myocardial infarction do not display associative properties.28

In conclusion, a large body of evidence conclusively suggests that the close link traditionally assumed between coronary stenosis and myocardial ischemia is no longer tenable.29 It appears that it would be much more realistic to regard IHD as a multifactorial syndrome, considering that several mechanisms can contribute to precipitating myocardial ischemia, including inflammation, coronary spasm, microvascular dysfunction, endothelial dysfunction, platelet activation, and coronary stenosis, etc.30

Myocardial perfusion is modulated by complex regulatory mechanisms adjusting blood flow volume, blood flow velocity, and blood flow pressure.30 Additionally, myocardial ischemia, defined as an imbalance between energy supply and demand, is an even more complicated issue. Delivering an adequate amount of oxygenated blood, at the right pressure and at the right velocity, to cardiomyocytes is just the beginning of the journey. Energy substrates delivered to cardiac cells in adequate amounts must be transferred inside the cells, incorporated by the mitochondria, transformed into high-energy phosphate bonds that in turn must be delivered to the contractile machinery where they are eventually transformed into work and heat. Any dysfunction in this long and complex sequence of events may cause an imbalance in myocardial energy demand and supply, in other words, myocardial ischemia. Indeed, just as a combustion engine with a perfect injection mechanism, the cardiomyocyte may run short on fuel, due to intracellular dyshomeostasis (ie, altered mitochondrial metabolism, dysfunction of extracellular matrix, barriers to oxygen transport, etc).30

With this approach in mind, assuming ischemia to be a problem of “clogged pipes” is clearly an overly simplistic view. A better understanding of the nature and prevalence of the mechanisms underlying IHD may provide the basis for advancement toward tailored therapy in patients with stable angina/chronic ischemic heart disease.

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Keywords: atherosclerosis; ischemic heart disease; multifactorial; stenosis