N. van Royen

Stimulation of collateral artery growth: travelling further down the road to clinical application

Collateral artery growth is a potent natural defence mechanism to prevent death and myocardial infarction in occlusive artery disease. Given the high prevalence of arterial obstructive disease, a therapeutic compound stimulating collateral vessel growth could have a major impact on morbidity and mortality world wide. Although experimental studies on the stimulation of arteriogenesis have been promising, not a single drug has been proved to be applicable in clinical practice, either because of lack of efficacy or because of undesired side effects. This review summarises current knowledge on the mechanisms of collateral artery growth and examines problems that arise from the clinical implementation of pro-arteriogenic treatments to date. Future directions in the translation from bench to bedside and potential new approaches to the stimulation of vascular growth are discussed.

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.

Comparison of a new slender 6 Fr sheath with a standard 5 Fr sheath for transradial coronary angiography and intervention: RAP and BEAT (Radial Artery Patency and Bleeding, Efficacy, Adverse evenT), a randomised multicentre trial

AIMSnThe 6 Fr Glidesheath Slender (GSS6Fr) is a recently developed thin-walled radial sheath with an outer diameter (OD) that is smaller than the OD of standard 6 Fr sheaths. The purpose of this trial was to clarify whether the use of this new slender sheath would result in similar rates of RAO to a standard 5 Fr sheath in unselected patients undergoing transradial (TR) coronary angiography and/or intervention, and to assess the relative importance of sheath size and haemostasis protocol on the rate of RAO.nnnMETHODS AND RESULTSnWe conducted a randomised, multicentre, non-inferiority trial comparing the GSS6Fr against the standard GS5Fr in patients undergoing TR coronary angiography and/or intervention. Patients in each group were subsequently randomised to undergo patent haemostasis or the institutional haemostasis protocol. The primary endpoint was the occurrence of RAO at discharge. A total of 1,926 patients were randomised in 12 centres. The incidence of RAO was 3.47% with GSS6Fr compared with 1.74% with GS5Fr (risk difference 1.73%, 95% CI: 0.51-2.95%; pnon-inferiority=0.150). Patients randomised to patent haemostasis had a similar rate of RAO compared with institutional haemostasis (2.61% vs. 2.61%, p=1). There was no difference with regard to all secondary endpoints, including vascular access-site complications, local bleeding and spasm.nnnCONCLUSIONSnIn this large multicentre randomised trial, the GSS6Fr was associated with a low event rate for the primary endpoint (RAO), although non-inferiority to the GS5Fr was not met, due to a lower than expected rate of RAO in the GS5Fr group. As compared to institutional haemostasis, the use of patent haemostasis was not associated with a reduced rate of RAO.

Changes in remote myocardial tissue after acute myocardial infarction and its relation to cardiac remodeling: A CMR T1 mapping study

Objectives To characterize the temporal alterations in native T1 and extracellular volume (ECV) of remote myocardium after acute myocardial infarction (AMI), and to explore their relation to left ventricular (LV) remodeling. Methods Forty-two patients with AMI successfully treated with primary PCI underwent cardiovascular magnetic resonance after 4–6 days and 3 months. Cine imaging, late gadolinium enhancement, and T1-mapping (MOLLI) was performed at 1.5T. T1 values were measured in the myocardial tissue opposite of the infarct area. Myocardial ECV was calculated from native- and post-contrast T1 values in 35 patients, using a correction for synthetic hematocrit. Results Native T1 of remote myocardium significantly decreased between baseline and follow-up (1002 ± 39 to 985 ± 30ms, p<0.01). High remote native T1 at baseline was independently associated with a high C-reactive protein level (standardized Beta 0.32, p = 0.04) and the presence of microvascular injury (standardized Beta 0.34, p = 0.03). ECV of remote myocardium significantly decreased over time in patients with no LV dilatation (29 ± 3.8 to 27 ± 2.3%, p<0.01). In patients with LV dilatation, remote ECV remained similar over time, and was significantly higher at follow-up compared to patients without LV dilatation (30 ± 2.0 versus 27 ± 2.3%, p = 0.03). Conclusions In reperfused first-time AMI patients, native T1 of remote myocardium decreased from baseline to follow-up. ECV of remote myocardium decreased over time in patients with no LV dilatation, but remained elevated at follow-up in those who developed LV dilatation. Findings from this study may add to an increased understanding of the pathophysiological mechanisms of cardiac remodeling after AMI.

Non-invasive assessment of the collateral circulation in the hand: validation of the Nexfin system and relation to clinical outcome after transradial catheterisation

AIMSnThis study aims primarily to assess the extent of the collateral circulation of the hand in a combined population of healthy individuals and patients who underwent transradial catheterisation, using both the Nexfin system and laser Doppler perfusion imaging.nnnMETHODS AND RESULTSnIn total, 85 adults were included in the study (18 healthy volunteers; 67 patients who underwent transradial catheterisation). The perfusion of the thumb was assessed prior to and during complete radial artery compression using laser Doppler perfusion imaging (LDPI) and the Nexfin system. The palmar collateral flow index (PCFI) was compared between both devices and PCFINEXFIN was related to hand angiography and the upper limb function, using the QuickDASH questionnaire. Mean PCFILDPI was 0.77±0.15 and mean PCFINEXFIN was 0.88±0.08. Both were significantly related (Pearson correlation=0.49, 95% CI: 0.31-0.64, p<0.001, agreement -0.11±0.13). PCFINEXFIN correlated with the maximal diameter of the superficial palmar arch (R=0.49, p=0.04) and total minimal arch diameter (R=0.51, p<0.02). High PCFINEXFIN, measured at baseline, was correlated with a lower QuickDASH score for pain, activity and total at one month post transradial catheterisation (p=0.02, p<0.01, p<0.01), but not with discomfort or disability.nnnCONCLUSIONSnThe Nexfin monitoring system is comparable with laser Doppler perfusion imaging in the quantification of the collateral perfusion in the hand. In patients, the Nexfin-derived collateral flow index measured at baseline is associated with clinical outcome at 30 days post transradial catheterisation.

Bivalirudin infusion to reduce ventricular infarction: the open-label, randomised Bivalirudin Infusion for Ventricular InfArction Limitation (BIVAL) study

AIMSnThe aim of the study was to investigate whether bivalirudin versus unfractionated heparin (UFH) reduces infarct size (IS) for primary percutaneous coronary intervention (PPCI) in large acute myocardial infarction (AMI).nnnMETHODS AND RESULTSnThis multicentre open-label trial randomised 78 patients undergoing PPCI for large AMI to bivalirudin or UFH. The primary endpoint was IS, assessed by cardiac magnetic resonance (CMR) five days after PPCI. Secondary endpoints included index of microcirculatory resistance (IMR), CMR-assessed microvascular obstruction (MVO) and ejection fraction, and biomarkers for thrombin activity and cell injury. No difference was observed in mean IS at five days (25.0±19.7xa0g for bivalirudin vs. 27.1±20.7xa0g for UFH; p=0.75). Early MVO was numerically lower with bivalirudin (5.3±5.8xa0g vs. 7.7±6.3xa0g; p=0.17), with no significant difference in ejection fraction at 90 days (54.6±12.0% vs. 49.1±12.1%; p=0.11). In the biomarkers, thrombin-antithrombin complexes were reduced by 4.8 ug/L over the first day for bivalirudin versus an increase of 1.9 ug/L in the heparin arm (p=0.0003). Acute IMR was lower (43.5±21.6 vs. 68.7±35.8 mmHg×s, respectively; p=0.014). In a planned interim analysis, an approximate 11% reduction in IS was observed with bivalirudin; the trial was discontinued for futility.nnnCONCLUSIONSnThis study did not achieve its primary endpoint of significant infarct size reduction in PPCI by prolonged bivalirudin infusion compared to UFH, even though complete thrombin inhibition was achieved in the acute phase, with a lower myocardial microcirculation resistance at the end of the procedure.

Effects of successful percutaneous coronary intervention of chronic total occlusions on myocardial perfusion and left ventricular function

AIMSnThe aim of the present study was to investigate the effects of successful PCI CTO on absolute myocardial blood flow (MBF) and functional recovery.nnnMETHODS AND RESULTSnPatients with a documented CTO were prospectively examined for ischaemia and viability with [15O]H2O positron emission tomography (PET) and late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR). Sixty-nine consecutive patients, in whom PCI was successful, underwent follow-up PET and CMR after approximately 12 weeks to evaluate potential improvement of MBF as well as systolic function. After PCI, stress MBF in the CTO area increased from 1.22±0.36 to 2.40±0.90 mL·min-1·g-1 (p<0.001), whilst stress MBF in the remote area also increased significantly between baseline and follow-up PET (2.58±0.68 to 2.77±0.77 mL·min-1·g-1, p=0.01). The ratio of stress MBF between CTO and remote area was 0.49±0.13 at baseline and increased to 0.87±0.24 at follow-up (p<0.001). The MBF defect size of the CTO area decreased from 5.12±1.69 to 1.91±1.75 myocardial segments after PCI (p<0.001). Left ventricular ejection fraction (LVEF) increased significantly (46.4±11.0 vs. 47.5±11.4%, p=0.01) at follow-up.nnnCONCLUSIONSnThe vast majority of CTO patients with documented ischaemia and viability showed significant improvement in stress MBF and a reduction of ischaemic burden after successful percutaneous revascularisation with only minimal effect on LVEF.

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.

The long-term effect of transradial coronary catheterisation on upper limb function

AIMSnAnatomic and physiologic changes that are induced by radial access may lead to a decrease of upper limb function at long-term follow-up; however, this has never been studied. We aimed to study the long-term effect of transradial catheterisation on upper limb function.nnnMETHODS AND RESULTSnBetween January 2013 and April 2014, upper limb function was assessed in a total of 348 patients with complete one-year follow-up after coronary catheterisation. Upper limb function was assessed with the self-reported shortened version of the DASH questionnaire. The presence and severity of upper extremity cold intolerance was assessed with the self-reported CISS questionnaire. Both questionnaires were completed before the catheterisation and at one-year follow-up. Higher scores represent worse upper limb functionality or symptoms. The non-parametric Wilcoxon signed-rank test was used to assess the change of upper limb function and symptoms over time. Extremity complaints were reported at one-month and one-year follow-up. At one-year follow-up, upper limb function did not change over time when catheterisation was performed through the radial artery (p-value 0.20). Upper extremity was also not affected by cold intolerance at one-year follow-up (p-value 0.09). Extremity complaints were reported equally in both access groups and diminished significantly over time (p-value <0.001).nnnCONCLUSIONSnUpper limb function was not affected at long-term follow-up after transradial procedures.

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.