N.W. Van Der Hoeven

Clinical parameters associated with collateral development in patients with chronic total coronary occlusion

Objective Well-developed collaterals provide survival benefit in patients with obstructive coronary artery disease (CAD). Therefore, in this study we sought to determine which clinical variables are associated with arteriogenesis. Design Clinical and laboratory variables were collected before percutaneous coronary intervention. Multivariate analysis was performed to determine which variables are associated with the collateral flow index (CFI). Patients Data from 295 chronic total occlusion (CTO) patients (Bern, Switzerland, Amsterdam, the Netherlands and Jena, Germany) were pooled. In earlier studies, patients had varying degrees of stenosis. Therefore, different stages of development of the collaterals were used. In our study, a unique group of patients with CTO was analysed. Interventions Instead of angiography used earlier, we used a more accurate method to determine CFI using intracoronary pressure measurements. CFI was calculated from the occlusive pressure distal of the coronary lesion, the aortic pressure and central venous pressure. Results The mean CFI was 0.39±0.14. After multivariate analysis, β blockers, hypertension and angina pectoris duration were positively associated with CFI (B: correlation coefficient β=0.07, SE=0.03, p=0.02, B=0.040, SE=0.02, p=0.042 and B=0.001, SE=0.000, p=0.02). Furthermore also after multivariate analysis, high serum leucocytes, prior myocardial infarction and high diastolic blood pressure were negatively associated with CFI (B=−0.01, SE=0.005, p=0.03, B=−0.04, SE=0.02, p=0.03 and B=−0.002, SE=0.001, p=0.011). Conclusions In this unique cohort, high serum leucocytes and high diastolic blood pressure are associated with poorly developed collaterals. Interestingly, the use of β blockers is associated with well-developed collaterals, shedding new light on the potential action mode of this drug in patients with CAD.

Coronary angiography and percutaneous coronary intervention after out-of-hospital cardiac arrest: major leaps towards improved survival?

Out-of-hospital cardiac arrest (OHCA) is a leading cause of death in developed countries. Both resuscitation care and intensive care management for patients after OHCA has notably improved over the years.

Pressure- and flow-derived indices of coronary stenosis severity: old rivals, new allies

Although the presence of epicardial stenosis has constituted largely the focus of diagnosis and treatment in patients with coronary artery disease (CAD), myocardial ischemia in ischemic heart disease (IHD) is caused by both obstructive and nonobstructive coronary involvement. Awareness of this fact has generated a growing interest in the diagnosis of microvascular disease (MVD), which has been found to be associated with poor clinical outcomes in both unobstructed [1] and obstructed CAD [2,3] and other cardiac diseases [4–6]. This renewed interest in coronary domains beyond the epicardial vessel occurs at a time in which fractional flow reserve (FFR) has almost completely replaced coronary flow reserve (CFR) as a method of assessing stenosis severity, despite the fact that CFR was the first tool postulated for this purpose [7]. FFR is a pressure-derived estimate of maximum achievable myocardial blood flow in the presence of an epicardial stenosis, as a fraction of the maximal achievable blood flow to the distal myocardium in the absence of a stenosis [8]. FFR is based on the supposition that pressure and flow are linear when coronary resistance is minimal and steady, which justifies the use of hyperemic agents in current clinical practice. While this approach is of great practical value, FFR measurements do not provide insights into the status of non-obstructive IHD or other key contributors to total myocardial flow, such as collateral support or microcirculatory status. On the other hand, CFR infers the hemodynamic relevance of a coronary stenosis from the response of the microcirculation to a hyperemic stimulus [7,9], which will be attenuated if arterioles are already vasodilated as a result of an upstream severe stenosis. This rationale has the obvious caveat that a low CFR also will occur in cases in which the vasodilatory capacity results from microcirculatory dysfunction [10]. CFR can be measured in multiple manners; for instance, noninvasively such as with positron emission tomography and single-photon emission computed tomography. CFR can also be determined with echocardiography using high-frequency fundamental imaging or echo-contrast enhanced harmonic Doppler methods. Obviously, the main advantage of these tools is that they can be measured noninvasively and are quickly available at bedside. This topic, however, reaches beyond the scope of this editorial. For now, we will solely focus on intracoronary measured indices.

The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease, another funny aspect of the funny channel?

Coronary artery disease (CAD) is a well known cause of death and disability in patients worldwide. Although in some countries, mortality rates due to CAD have decreased, CAD is still responsible for one-third of all deaths in patients above the age of 35 years. Thus, many studies aim to search for new anti-ischemic therapy to treat CAD. Collateral arteries provide blood-flow to the myocardium distal to a stenosis in a coronary vessel. Formation of these collateral arteries (arteriogenesis) is related to outcome as well as long-term survival after myocardial infarction. Interestingly, there is a significant variation in the arteriogenic response upon coronary stenosis. This variation is seen between different species and also within the same species, especially in mankind. In about one-third of patients with CAD, a coronary collateral circulation develops that is capable of restoring myocardial blood flow to a level at which complete blockage of antegrade flow by intracoronary balloon inflation does not lead to angina pectoris (AP) or ischaemia, as assessed by intracoronary derived electrocardiography (ECG). Supposedly, these patients will also not encounter exertional angina, at least not from that specific lesion. In two-thirds of patients, however, the development of the coronary circulation lags behind. Hence, this implies that there is a large potential for proarteriogenic therapy in the treatment of CAD. It also stresses the need to search for factors that cause retarded collateral growth in such a large fraction of the CAD patients in order to better understand the heterogeneity in arteriogenesis in response to a coronary artery occlusion. Pharmacological stimulation of collateral growth dates back more than two decades now. Initially, several growth factors were tested for their potential to induce peripheral and coronary collateral growth. Initial promising pilot results were not validated in subsequent larger randomised trials. Growth factors are expensive, degrade easily and seem to work only when given in a localised fashion. Also, the risk of side effects, like atherogenesis, are not negligible. Thus, unfortunately, this approach did not result in a clinically feasible and effective therapy. In the present prospective study, the authors chose another pharmacological approach using ivabradine. Ivabradine, an If-channel blocker, also known as ‘the funny channel’, by contrast with β-blockers, lowers the heart rate by inhibiting a specific sinus node pacemaker current and does not affect the contractility and ventricular afterload of the heart. Lowering of the heart rate leads to an increase in diastolic perfusion time and, hence, an increase in shear stress. Shear stress is required for arteriogenesis, initiating the cascade of endothelial activation, macrophage accumulation and outward vessel remodelling in coronary vessels. Thus, a lower heart rate, theoretically, leads to increased formation of a collateral circulation and some circumstantial evidence is available. 7 This is of course specific to the coronary circulation, but in the peripheral circulation the lower heart rate will lead to a higher pulse pressure, also increasing wall shear stress. Schirmer et al, therefore, investigated whether ivabradine affects arteriogenesis in a murine hindlimb model of arteriogenesis. In atherosclerotic ApoE −/− mice, perfusion of arteries distal to the stenosis indeed increased with ivabradine. They hypothesise improved endothelial function, eNOS activity and modulation of inflammatory cytokine gene expression might cause this increase. Gloekler et al are to be heralded for taking these experimental findings to a clinical study. Patients were randomised in a single-blinded fashion to ivabradine or placebo. The gold standard method to measure the capacity of the collateral circulation, the collateral flow index (CFI), was determined invasively during a 1 min balloon occlusion at baseline and repeated at 6 months follow-up. Furthermore, they assessed intracoronary ECG ST-segment shifts and documented the presence of AP. At follow-up, CFI was significantly increased in the ivabradine group pointing to a proarteriogenic effect of ivabradine also in CAD patients. This is of course accompanied by an expected decrease in heart rate as well as a decrease in ECG segment shifts. However, the occurrence of AP during the 1 min balloon occlusion did not significantly differ in both groups. The endpoint of CFI, instead of angiography, is well chosen for this proof-of-concept study, and the compound is already proven to be safe in thousands of patients, albeit for a different indication. These data provide important insights on the feasibility of therapeutic arteriogenesis, but some remarks need to be made. Probably the most important determinant of the outgrowth of collateral arteries is the degree of the underlying stenosis. The most extensive collateral networks are seen in patients with a chronic total occlusion. In patients without coronary stenosis, the collateral networks are present, but always below the angiographic threshold with a diameter not exceeding 100 mm. Thus, upon gradual occlusion of a coronary artery, the collateral circulation answers with a gradual expansion. In case of removal of the stenosis by placement of a coronary stent after percutaneous coronary intervention (PCI), the collateral circulation regresses. This is something that we need to take into consideration when putting the present study in perspective. At baseline, the percent diameter stenosis was 76±21 in the placebo and 54±30 in the ivabradine group. This was also reflected by the lower FFR values in the placebo group. The fact that baseline FFR was much lower in the control group suggests that in this cohort, more PCIs had to be performed at baseline, or at least the effect of PCI on a decrease in collateral flow was more pronounced which might explain, in part, the outcome of the study. Any future clinical trial on pharmacological stimulation of arteriogenesis should take this into account and exclude the effects of coronary intervention during the course of the study. As an alternative to ivabradine, β-blocking agents could also be tested for their arteriogenic capacity. As mentioned earlier, some studies show that β-blockers are associated with well-developed Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands