Nico H. J. Pijls

Because current reperfusion strategies in acute myocardial infarction (AMI) seem to be exhausted in terms of additional mortality benefit, there remains a need for new methods to attenuate reperfusion injury and, thereby, further reduce myocardial infarct size and improve long-term survival. Therapeutic hypothermia (32–35°C) diminishes reperfusion injury and reduces infarct size in a variety of animal models of AMI if provided before reperfusion. In human studies this reduction has not been confirmed so far, most likely because systemic cooling acts slowly, and therefore, the target temperature is not reached in time or at all in a substantial number of patients. Furthermore, systemic cooling can cause adverse effects such as severe shivering, volume overload, and an enhanced adrenergic state. In most randomized clinical trials, however, subgroups of patients with anterior myocardial infarction that reached the target temperature before reperfusion did show a reduction in infarct size. To transform therapeutic hypothermia into a clinically feasible treatment for AMI, its method must be modified. An ideal technique should be quick enough to achieve sufficient myocardial hypothermia before reperfusion, without significant delay and without the adverse effects of systemic cooling. In this review, we propose a novel, potentially feasible method of selective intracoronary hypothermia to overcome the problems encountered with prior techniques.

Fractional flow reserve (FFR) has proven to its prognostic and therapeutic value. However, the additive prognostic value of coronary flow reserve (CFR) remains unclear. This study sought to investigate the clinical utility of combined FFR and CFR measurements to predict outcomes. Using the prospective, multicentre Interventional Cardiology Research Incooperation Society–FFR registry, a total of 2088 lesions from 1837 patients were included in this substudy. Based on baseline and hyperaemic pressure gradients, we computed physiologic limits of CFR [the so called pressure-bounded (pb) CFR] and classified lesions as low (0.80 [adjusted hazard ratio (aHR): 2.15, 95% confidence interval (CI): 1.19–3.89; P = 0.011. In contrast, the incidence of MACE did not differ between patients with pb-CFR < 2 vs. pb-CFR ≥ 2 (4.2% vs. 4.2%; aHR: 0.98, CI: 0.60 to 1.58; P = 0.92). Incorporation of FFR significantly improved model prediction of MACE (global χ² 38.8–48.1, P = 0.002). However, pb-CFR demonstrated no incremental utility to classify outcomes (global χ² 48.1–48.2, P > 0.99). In this large, prospective registry of over 2000 coronary lesions, FFR was strongly associated with clinical outcomes. In contrast, a significant association between pb-CFR and clinical events could not be determined and adding knowledge of pb-CFR did not improve prognostication over FFR alone.

Hypothermia may attenuate reperfusion injury and thereby improve acute myocardial infarction therapy. Systemic cooling trials failed to reduce infarct size, perhaps because the target temperature was not reached fast enough. The use of selective intracoronary hypothermia combined with intracoronary temperature monitoring allows for titrating to target temperature and optimizing the cooling rate. We aimed to the test the feasibility of intracoronary cooling for controlled, selective myocardial hypothermia in an isolated beating pig heart. In five porcine hearts the left anterior descending artery (LAD) was occluded by an over-the-wire balloon (OTWB). After occlusion, saline at 22 degrees C was infused through the OTWB lumen for 5 minutes into the infarct area at a rate of 30 ml/min. Thereafter the balloon was deflated but infusion continued with saline at 4 degrees C for 5 minutes. Distal coronary temperature was continuously monitored by a pressure/temperature guidewire. Myocardial temperature at several locations in the infarct and control areas was recorded using needle thermistors. In the occlusion phase, coronary temperature decreased by 11.4 degrees C (range 9.4-12.5 degrees C). Myocardial temperature throughout the infarct area decreased by 5.1 degrees C (range 1.8-8.1 degrees C) within three minutes. During the reperfusion phase, coronary temperature decreased by 6.2 degrees C (range 4.1-10.3 degrees C) and myocardial temperature decreased by 4.5 degrees C (range 1.5-7.4 degrees C). Myocardial temperature outside the infarct area was not affected. In the isolated beating pig heart with acute occlusion of the LAD, we were able to rapidly "induce, maintain, and control" a stable intracoronary and myocardial target temperature of at least 4 degrees C below body temperature without side effects and using standard PCI equipment, justifying further studies of this technique in humans.

Percutaneous coronary intervention (PCI) of bifurcation lesions can be performed using various techniques. The aim of this study was to analyse the outcome of various techniques of bifurcation stenting in all patients undergoing bifurcation stenting at one large intervention centre in 2013, taking into account that more complex lesions might more often warrant a two-stent technique.

Aims Stenting an angiographically intermediate but functionally non-significant stenosis is controversial. Nevertheless, it has been questioned if deferral of a functionally non-significant lesion on the basis of fractional flow reserve (FFR) measurement, is safe, especially on the long term. Five-year follow-up of the DEFER trial showed that outcome after deferral of percutaneous coronary intervention (PCI) of an intermediate coronary stenosis based on FFR ≥ 0.75 is excellent and was not improved by stenting. The aim of this study was to investigate the validity of this position on the very long term. Methods and results In 325 patients scheduled for PCI of an intermediate stenosis, FFR was measured just before the planned intervention. If FFR was ≥0.75, patients were randomly assigned to deferral (Defer group; n = 91) or performance (Perform group; n = 90) of PCI. If FFR was n = 144). Clinical follow-up was 15 years. There were no differences in baseline clinical characteristics between the randomized groups. Complete 15-year follow-up was obtained in 92% of patients. After 15 years of follow-up, the rate of death was not different between the three groups: 33.0% in the Defer group, 31.1% in the Perform group, and 36.1% in the Reference group (Defer vs. Perform, RR 1.06, 95% CI: 0.69–1.62, P = 0.79). The rate of myocardial infarction was significantly lower in the Defer group (2.2%) compared with the Perform group (10.0%), RR 0.22, 95% CI: 0.05–0.99, P = 0.03. Conclusion Deferral of PCI of a functionally non-significant stenosis is associated with a favourable very long-term follow-up without signs of late ‘catch-up’ phenomenon.

In ST-elevation myocardial infarction (STEMI), reduction in time to reperfusion of the occluded coronary artery reduces infarct size. In animal models, an additional reduction of infarct size was observed when hypothermia was induced before reperfusion, despite a longer ischemic time. However, several human studies did not corroborate this positive effect, which is believed to be in part due to the inability of systemic induced hypothermia to induce sufficient decrease of local myocardial temperature before reperfusion. Providing rapid local myocardial hypothermia by intracoronary infusion of saline before reperfusion in patients with STEMI may overcome this problem. In this study, we evaluate the safety and feasibility of providing rapid intracoronary myocardial hypothermia in patients undergoing intracoronary blood flow measurements based on thermodilution with continuous infusion of saline at room temperature. In 53 patients with stable angina (SA) and 20 patients with STEMI, a total of 215 measurements were performed. The measurements consisted of continuous selective intracoronary infusion of saline at room temperature with rates between 10 ml/min and 30 ml/min. Temperature changes compared to initial blood temperature (T_b) were measured at the tip of the infusion catheter (T_i) and distally in the coronary artery (T_d). In patients with SA, T_i was −5.65 ± 1.41°C (range −9.27 to −2.28) and T_d was −0.78 ± 0.51°C (range −3.27 to −0.23°C). In patients with STEMI, T_i was −7.45 ± 0.51°C (range −8.21 to −6.56) and T_d was −1.37 ± 0.82°C (range −4.62 to −0.74°C). In all patients, steady-state intracoronary hypothermia was achieved within 15 sec and could be maintained without noticeable complications. This study demonstrates the safety and feasibility of inducing intracoronary hypothermia by selective infusion of saline at room temperature in patients with SA and STEMI. Steady-state hypothermia could be achieved and maintained quickly, easily, and safely using common PCI techniques. Therefore, our findings warrant further studies to the use of intracoronary hypothermia to enhance myocardial salvage in acute myocardial infarction.