Peripheral endothelial function after st-segment elevation myocardial infarction
Cardiovascular disease is the number two cause of death in the Netherlands, and ischemic heart disease and stroke are responsible for approximately half of all cardiovascular deaths. Due to improvements in medical therapy and cardiovascular prevention, mortality rates of ischemic heart disease in general, and myocardial infarction in particular, have been reduced. Nevertheless, in the aging population of our country, the absolute number of patients with ischemic heart disease is expected to further increase.
A good function of the endothelium, a key regulator of blood flow, is important for arterial health. Endothelial dysfunction, on the other hand, plays a central role in the development of atherosclerosis and in the disease progression to the formation of advanced atheromas. These lesions may cause stable chest pain during physical exertion or they can lead to acute coronary syndromes. The most serious type of acute syndrome is the ST-segment elevation myocardial infarction (STEMI), which is generally treated by a primary percutaneous coronary intervention (PPCI) and associated with the highest adverse event risk in the long-term. The early identification of patients with endothelial dysfunction may help reduce the incidence of major complications of atherosclerosis, such as a STEMI, for instance by treating cardiovascular risk factors in a more aggressive way. As the peripheral and coronary arterial endothelial function correlate well, non-invasive detection of peripheral endothelial dysfunction is used as surrogate marker of coronary endothelial dysfunction. In patients with known cardiovascular risk factors or mild atherosclerotic disease, the relevance of detecting endothelial dysfunction for risk assessment has been shown.
However, it was unclear whether knowledge about the endothelial function is useful in patients who already experienced a STEMI. Several research questions arose in this context, as in patients with a recent STEMI there was a lack of data on both, the course of endothelial function and the relation between endothelial function and long-term clinical outcome. These research questions were related to the assessment of: (1) a potential relation between the patency of the culprit vessel at initial coronary angiography in patients with an acute STEMI and endothelial function; (2) a potential relation between high levels of laboratory markers of (vascular) inflammation and endothelial function; (3) a potential improvement of endothelial function after STEMI as a result of lifestyle modifications and medical therapy; and (4) a potential relation between endothelial function after a STEMI and long-term cardiovascular outcome. This thesis reports the result of our attempt to answer these research questions.
In Chapter 2 we reviewed the function of the endothelium and the consequences of endothelial dysfunction. In addition, we briefly reviewed several methods for the detection of endothelial dysfunction, in particular the non-invasive assessment of peripheral endothelial function that correlates well with coronary endothelial function. Many previous studies used ultrasound to assess the hyperemia-induced flow-mediated dilatation (FMD) of the brachial artery, which requires training and experience of the operators. An operator-independent alternative is the reactive hyperemia peripheral artery tonometry (RH-PAT) method. We reported the technical background (a lower RH-PAT index indicates worse endothelial function) and previous validation studies of the RH-PAT method, which was used in this thesis.
In Chapter 3 we assessed to what extent the injection of dye during coronary angiography elevates intracoronary pressure, which may accelerate coronary blood flow velocity – a research question that was highly relevant for Chapter 4. There was a minor increase in intracoronary pressure, which may be neglected, as it did not increase coronary blood flow to such an extent that the estimation of flow velocity was affected. The limited impact of dye injection on intracoronary blood pressure confirms the value of coronary angiography for estimation of coronary blood flow velocity.
In Chapter 4 we evaluated the coronary blood flow velocity at the initial coronary angiography of 71 patients with an acute STEMI (prior to any mechanical intervention) in order to investigate whether patients who presented with patent culprit coronary arteries had a better endothelial function than patients who had occluded culprit vessels. Patients with an open culprit vessel and either slow or normal coronary blood flow before PPCI had a significantly better endothelial function than patients with occluded culprit vessels (RH-PAT index 2.08±0.34 vs. 1.75±0.35, p=0.007). A better endothelial function was strongly and independently associated with initial culprit vessel patency; even when adjusting for age, gender, and various other cardiovascular risk factors, this relation remained strong. Logistic regression analysis demonstrated that the time interval between symptom onset and PPCI did not disturb the relationship between endothelial function and patency of the culprit artery, a relationship that so far had not been demonstrated yet.
In Chapter 5 we explored in 68 patients with a recent STEMI whether patients with high levels of two markers of (vascular) inflammation, high-sensitivity C-reactive protein (hs-CRP) and lipoprotein-associated phospholipase-A2 (Lp-PLA2), had a worse endothelial function. Of 11 patients with high levels of both laboratory markers, 8 (72.7%) had an endothelial dysfunction (defined by an RH-PAT index <1.67), whereas in all other patients (n=57) endothelial dysfunction was observed in 26 (45.6%) patients (p=0.09). In patients, with high levels of both hs-CRP and Lp-PLA2, endothelial function appeared to be somewhat lower than in all other patients (RH-PAT index 1.68 ± 0.22 vs. 1.95 ± 0.63, p=0.17). Our study showed a significant overlap between the RH-PAT index measurements in patients with versus without high levels of hs-CRP and Lp-PLA2, explaining the absence of a statistically significant difference.
In Chapter 6 we serially assessed endothelial function 1 month (baseline), 6 months, and 12 months after PPCI in 70 STEMI patients, who received adequate or optimal medical therapy. We found that endothelial function decreased over time from an RH-PAT index of 1.90 ±0.58 at baseline, to 1.81±0.57 at 6-month follow-up, and eventually to 1.69±0.49 at 12-month follow-up (p=0.04 in mixed model). A longitudinal mixed model analysis showed that of all cardiovascular risk factors assessed the following worsened significantly over time: HbA1c; diastolic blood pressure; total cholesterol; and low-density lipoprotein cholesterol. However, a multivariate analysis demonstrated that none of these cardiovascular risk factors was found to be responsible for the observed decrease in endothelial function over time. So far, serial endothelial function data from three time points after a recent STEMI was never reported. The highly novel findings of this study suggest that the continuum of endothelial dysfunction can ultimately reach a stage from which restoration is unlikely or impossible, despite adequate or even optimal medical therapy and risk factor control. We hypothesize that at that point other factors such as the total load of atheroma, genetic predisposition, or other unknown risk factors may become increasingly important.
In Chapter 7 we assessed in 70 patients with a recent STEMI whether endothelial function at baseline may predict cardiovascular events during long-term follow-up. A total of 35 (50%) patients had endothelial dysfunction, while in 35 (50%) a normal endothelial function was found. Periprocedural “complications”, such as cardiogenic shock or total atrioventricular block, were more common in patients with endothelial dysfunction than in those without (25.7% vs 2.9%; p<0.01). During four years of follow-up, a total of 20 (28.6%) patients had major adverse cardiovascular events. However, there was no relation between endothelial function at baseline and the occurrence of adverse cardiovascular events during long-term follow-up: Events occurred in 9 (25.7%) patients with endothelial dysfunction and in 11 (31.5%) patients with normal endothelial function (p=0.52). Nevertheless, there was an association between the prevalence of the traditional cardiovascular risk factor diabetes mellitus and the occurrence of adverse events. Thus, in this study, endothelial function at baseline did not predict the risk of major adverse cardiovascular events.
Conclusion
While endothelial dysfunction is a key factor in the development and progression of atherosclerosis, it was unclear whether data on endothelial function are useful in patients who already experienced a STEMI. We found that in patients with an acute STEMI, a better endothelial function is related to higher likelihood of presenting with an initially patent culprit coronary vessel, prior to any mechanical intervention. Cardiovascular risk factors are known to promote both endothelial dysfunction and inflammatory processes that lead to the formation of atherosclerotic lesions. Nevertheless, in patients with a recent STEMI, we did not observe a statistically significant relation between high levels of inflammation markers and endothelial dysfunction. Serial assessment showed in patients with a recent STEMI that endothelial function did not improve from baseline to 12-month follow-up, despite the prescription of guideline-recommended medical therapy in most patients. Our data suggest that the continuum of endothelial dysfunction can ultimately reach a stage from which, despite adequate or even optimal medical therapy and risk factor control, restoration is unlikely. Endothelial function even decreased over time. In addition, endothelial dysfunction at baseline showed a significant relationship with a higher incidence of periprocedural “complications” but did not predict adverse clinical events during a mean follow-up of 4 years. Patients with diabetes mellitus at baseline had a significantly higher adverse event rate during follow-up. These findings imply that in STEMI patients the total extent of vessel wall changes and the number and vulnerability of atherosclerotic lesions, which are known to be increased in patients with diabetes, might be more important for the overall cardiovascular risk than the degree of endothelial dysfunction.
