Roby Rakhit

Nitric oxide: an emerging role in cardioprotection?

Over a decade of research has shown nitric oxide (NO) to be a ubiquitous modulator of biological phenomena from cell signal to effector and from physiology to pathophysiology. The involvement of NO in cardiovascular biology has contributed significantly to our understanding of complex disease states including atherosclerosis, systemic and pulmonary hypertension, endotoxic shock, pre-eclampsia,1cardiomyopathy,2 and cardiac allograft rejection.3 However, the emerging role of NO in the maintenance of cell physiology from immunomodulation to calcium signalling has highlighted the importance of this fascinating molecule in cytostasis. This dichotomy of effector function is the “double edged sword” of NO in biological systems. However, the balance between cytostatic and cytotoxic effects of NO may lie in the tissue concentration of NO produced, the particular NO synthase (NOS) isoform activated (that is, “high output” or “low output”), and the complex interaction with other free radicals such as superoxide. However, a much greater understanding of the molecular and cellular actions of NO as a physiological regulator has resulted in a body of recent research increasing our understanding of NO, and thus NO releasing agents, in cytoprotection. Current evidence is outlined below. NO is produced by the catalytic action of NOS on the substrateL-arginine. The reaction involves the oxidation of one of the guanidinonitrogens of arginine and the process involves the oxidation of NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) and the reduction of molecular oxygen. Three NOS enzymes have been characterised: type I (ncNOS), type II (iNOS), and type III (ecNOS). ncNOS and ecNOS are calcium dependent and low output enzymes associated with NO production in the picomolar range, whereas iNOS is a calcium independent and high output enzyme associated with NO production in the nanomolar (nmol) range. All three NOS isoforms have been shown to be present in …

Nitric oxide, nitrates and ischaemic preconditioning

Time for primary review 24 days. In 1986 Furchgott first suggested that endothelial-derived relaxing factor might be nitric oxide (NO) [1]. Since then the remarkable role of nitric oxide (NO) as a modulator of biological phenomena has led to the question of its involvement within the spectrum of cardiovascular disease. The resulting research has implicated NO in atherosclerosis, hypertension, cardiomyopathy, pre-eclampsia, endotoxaemia [2] and cardiac allograft rejection [3] providing important additional insights into the pathogenesis of vascular and heart muscle disease. Although initially characterised in the vasculature NO is present in heart muscle [4] whilst the relative expression of the three isoforms (ncNOS, iNOS, ecNOS) responsible for its synthesis may have important implications in disease pathology. Apart from a cytotoxic role, NO has a role in cytostasis both regulating normal homeostasis and protecting against cell injury [5]. This, has led to the hypothesis that NO is cardioprotective in ischaemic heart disease. In testing this hypothesis very recent research has implicated NO in the phenomenon of ischaemic preconditioning. The current evidence suggesting its involvement in this exciting field is the focus of this review. Ischaemic preconditioning (PC) describes the profound myocardial protection that follows a short period of sublethal ischaemia and was recently considered by a NHBLI workshop to be the most powerful intervention to reduce myocardial infarct size other than reperfusion [6]. Initially described by Murray et al. in 1986 [7], in trying to understand the metabolic consequences of ischaemia, they found that brief periods of repetitive ischaemia in a canine model produced significant protection against myocardial cell death. There appears to be a bimodal distribution of protection with an initial more powerful but short-lived phase existing between 1 and 3 h (‘Early Preconditioning’) and a delayed less powerful phase occurring between 12 and 72 hours … * Corresponding author. Tel.: +44-171-922-8191; fax: +44-171-960-5659 m.marber{at}umds.ac.uk

A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: the REGENERATE-AMI clinical trial

Abstract Aims Clinical trials suggest that intracoronary delivery of autologous bone marrow-derived cells (BMCs) 1–7 days post-acute myocardial infarction (AMI) may improve left ventricular (LV) function. Earlier time points have not been evaluated. We sought to determine the effect of intracoronary autologous BMC on LV function when delivered within 24 h of successful reperfusion therapy. Methods and results A multi-centre phase II randomized, double-blind, and placebo-controlled trial. One hundred patients with anterior AMI and significant regional wall motion abnormality were randomized to receive either intracoronary infusion of BMC or placebo (1:1) within 24 h of successful primary percutaneous intervention (PPCI). The primary endpoint was the change in left ventricular ejection fraction (LVEF) between baseline and 1 year as determined by advanced cardiac imaging. At 1 year, although LVEF increased compared with baseline in both groups, the between-group difference favouring BMC was small (2.2%; 95% confidence interval, CI: −0.5 to 5.0; P = 0.10). However, there was a significantly greater myocardial salvage index in the BMC-treated group compared with placebo (0.1%; 95% CI: 0.0–0.20; P = 0.048). Major adverse events were rare in both treatment groups. Conclusion The early infusion of intracoronary BMC following PPCI for patients with AMI and regional wall motion abnormality leads to a small non-significant improvement in LVEF when compared with placebo; however, it may play an important role in infarct remodelling and myocardial salvage. Clinical trial registration Clinicaltrials.gov NCT00765453 and EudraCT 2007-002144-16.

Antiarrhythmic and anti-ischaemic effects of angina in patients with and without coronary collaterals

Objective: To determine whether the changes in the manifestations of myocardial ischaemia during sequential angina episodes caused by exercise or coronary artery occlusion are collateral dependent. Methods: 40 patients awaiting percutaneous transluminal coronary angioplasty for an isolated left anterior descending artery stenosis underwent three sequential treadmill exercise tests, with the second exertion separated from the first by 15 minutes, and from the third by 90 minutes; 28 patients subsequently completed two (> 180 s) sequential intracoronary balloon inflations with measurement of collateral flow index from mean coronary artery wedge, aortic, and coronary sinus pressures. Results: On second compared with first exercise, time to 0.1 mV ST depression (mean (SD): 340 (27) v 266 (25) s) and rate–pressure product at 0.1 mV ST depression (22 068 (725) v 19 586 (584) beats/min/mm Hg) were increased (all p < 0.005), while angina and ventricular ectopic beat frequency were diminished (p < 0.05). This advantage, which had waned by the third effort, was independent of collateral flow index. Similarly, at the end of the second compared with the first coronary occlusion, ventricular tachycardia (21% v 0%, p < 0.05), ST elevation (0.47 (0.07) v 0.33 (0.05) mV, p < 0.005), and angina severity (6.1 (0.7) v 4.6 (0.7) units, p < 0.005) were reduced despite similar collateral flow indices. Conclusions: In patients with coronary artery disease, ventricular arrhythmias, ST deviation, and angina are reduced during a second exertion or during a second coronary occlusion. This protective effect can occur independently of collateral recruitment. These characteristics, together with the breadth and temporal pattern of protection, are consistent with ischaemic preconditioning.

Culprit Vessel Versus Multivessel Intervention at the Time of Primary Percutaneous Coronary Intervention in Patients With ST-Segment–Elevation Myocardial Infarction and Multivessel Disease: Real-World Analysis of 3984 Patients in London

Background—It is estimated that up to two thirds of patients presenting with ST-segment–elevation myocardial infarction have multivessel disease. The optimal strategy for treating nonculprit disease is currently under debate. This study provides a real-world analysis comparing a strategy of culprit-vessel intervention (CVI) versus multivessel intervention at the time of primary percutaneous coronary intervention in patients with ST-segment–elevation myocardial infarction. Methods and Results—We compared CVI versus multivessel intervention in 3984 patients with multivessel disease undergoing primary percutaneous coronary intervention between 2004 and 2011 at all 8 tertiary cardiac centers in London. Multivariable-adjusted models were built to determine independent predictors for in-hospital major adverse cardiovascular events (MACEs) and all-cause mortality at 1 year. To reduce confounding and bias, propensity score methods were used. CVI was associated with reduced in-hospital MACE (4.6% versus 7.2%; P=0.010) and mortality at 1 year (7.4% versus 10.1%; P=0.031). CVI was an independent predictor for reduced in-hospital MACE (odds ratio, 0.49; 95% confidence interval [CI], 0.32–0.75; P<0.001) and survival at 1 year (hazard ratio, 0.65; 95% CI, 0.47–0.91; P=0.011) in the complete cohort; and in 2821 patients in propensity-matched cohort (in-hospital MACE: odds ratio, 0.49; 95% CI, 0.32–0.76; P=0.002; and 1-year survival: hazard ratio, 0.64; 95% CI, 0.45–0.90; P=0.010). Inverse probability treatment weighted analyses also confirmed CVI as an independent predictor for reduced in-hospital MACE (odds ratio, 0.38; 95% CI, 0.15–0.96; P=0.040) and survival at 1 year (hazard ratio, 0.44; 95% CI, 0.21–0.93; P=0.033). Conclusions—In this observational analysis of patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, CVI was associated with increased survival at 1 year. Acknowledging the limitations with observational analyses, our findings support current recommended practice guidelines.

Radial versus femoral access is associated with reduced complications and mortality in patients with non-ST-segment-elevation myocardial infarction: an observational cohort study of 10,095 patients.

Background—Compared with transfemoral access, transradial access (TRA) for percutaneous coronary intervention is associated with reduced risk of bleeding and vascular complications. Studies suggest that TRA may reduce mortality in patients with ST-segment–elevation myocardial infarction. However, there are few data on the effect of TRA on mortality, specifically, in patients with non–ST-segment–elevation myocardial infarction. Methods and Results—We analyzed 10 095 consecutive patients with non–ST-segment–elevation myocardial infarction treated with percutaneous coronary intervention between 2005 and 2011 in all 8 tertiary cardiac centers in London, United Kingdom. TRA was a predictor for reduced bleeding (odds ratio=0.21; 95% confidence interval [CI]: 0.08–0.57; P=0.002), access-site complications (odds ratio=0.47; 95% CI: 0.23–0.95; P=0.034), and 1-year mortality (hazard ratio [HR]=0.72; 95% CI: 0.54–0.94; P=0.017). Between 2005 and 2007, TRA did not appear to reduce mortality at 1 year (HR=0.81; 95% CI: 0.51–1.28; P=0.376), whereas between 2008 and 2011, TRA conferred survival benefit at 1 year (HR=0.65; 95% CI: 0.46–0.92; P=0.015). The mortality benefit with TRA at 1 year was not seen at the low-volume centers (HR=0.80; 95% CI: 0.47–1.38; P=0.428) but specifically seen in the high volume radial centers (HR=0.70; 95% CI: 0.51–0.97; P=0.031). In propensity-matched analyses, TRA remained a predictor for survival at 1 year (HR=0.60; 95% CI: 0.42–0.85; P=0.005). Instrumental variable analysis demonstrated that TRA conferred mortality benefit at 1-year with an absolute mortality reduction of 5.8% (P=0.039). Conclusions—In this analysis of patients with non–ST-segment–elevation myocardial infarction, TRA appears to be a predictor for survival. Furthermore, the evolving learning curve, experience, and expertise may be important factors contributing to the prognostic benefit conferred with TRA.

Long-term Survival in Patients Undergoing Percutaneous Interventions With or Without Intracoronary Pressure Wire Guidance or Intracoronary Ultrasonographic Imaging: A Large Cohort Study

IMPORTANCE Intracoronary pressure wire-derived measurements of fractional flow reserve (FFR) and intravascular ultrasonography (IVUS) provide functional and anatomical information that can be used to guide coronary stent implantation. Although these devices are widely used and recommended by guidelines, limited data exist about their effect on clinical end points. OBJECTIVE To determine the effect on long-term survival of using FFR and IVUS during percutaneous coronary intervention (PCI). DESIGN AND SETTING Cohort study based on the pan-London (United Kingdom) PCI registry. In total, 64,232 patients are included in this registry covering the London, England, area. PARTICIPANTS All patients (n = 41,688) who underwent elective or urgent PCI in National Health Service hospitals in London between January 1, 2004, and July 31, 2011, were included. Patients with ST-segment elevation myocardial infarction (n = 11,370) were excluded. INTERVENTIONS Patients underwent PCI guided by angiography (visual lesion assessment) alone, PCI guided by FFR, or IVUS-guided PCI. MAIN OUTCOMES AND MEASURES The primary end point was all-cause mortality at a median of 3.3 years. RESULTS Fractional flow reserve was used in 2767 patients (6.6%) and IVUS was used in 1831 patients (4.4%). No difference in mortality was observed between patients who underwent angiography-guided PCI compared with patients who underwent FFR-guided PCI (hazard ratio, 0.88; 95% CI, 0.67-1.16; P = .37). Patients who underwent IVUS had a slightly higher adjusted mortality (hazard ratio, 1.39; 95% CI, 1.09-1.78; P = .009) compared with patients who underwent angiography-guided PCI. However, this difference was no longer statistically significant in a propensity score-based analysis (hazard ratio, 1.33; 95% CI, 0.85-2.09; P = .25). The mean (SD) number of implanted stents was lower in the FFR group (1.1 [1.2] stents) compared with the IVUS group (1.6 [1.3]) and the angiography-guided group (1.7 [1.1]) (P < .001). CONCLUSIONS AND RELEVANCE In this large observational study, FFR-guided PCI and IVUS-guided PCI were not associated with improved long-term survival compared with standard angiography-guided PCI. The use of FFR was associated with the implantation of fewer stents.

A model of closed chest regional myocardial infarction in the rabbit: a clinically relevant in vivo assay system of post-infarction remodelling.

Abstract. Coronary artery ligation is the standard technique to induce regional myocardial infarction in small animal models. However, opening the chest and incising the pericardium independently influence post-MI remodelling. Our purpose was to develop and characterize a novel closed chest model of regional myocardial infarction (MI) in the rabbit of increased clinical relevance.Coronary angiography was performed percutaneously in New Zealand White Rabbits (NZW) using pre-formed catheters. A 0.36 mm thrombogenic coil was positioned in the circumflex artery to induce closed chest MI. Of rabbits undergoing coil deployment 40 % survived until day 100. Rabbits were classified as small MI (n = 5), moderate MI (n = 6) and large MI (n = 6) < 15 %, 15 – 30 %, > 30 % of LV myocardial volume respectively) or sham controls (n=11). Transthoracic echocardiographic images were obtained 0, 3, 5, 7, 14, 28, 60, 100 days post procedure. At day 100, LVEDP was measured before and after plasma substitute infusion. Hearts were subsequently excised and chamber stiffness (Kc) was derived from the passive pressure-volume relationship. Cardiac weight, dimensions and MI as a percentage of LV volume (MI%) were also recorded.Differences in percentage fractional shortening (%FS) were apparent from day 14. %FS was reduced in rabbits with large and moderate MI compared to controls (day 100, p < 0.005 and p < 0.05, respectively). LVEDP was increased in large and moderate MI compared to small MI and controls (26 mmHg ± 6 and 21 mmHg ± 5 vs. 9 mmHg ± 1 and 7 mmHg ± 3 p < 0.005); these differences were maintained during plasma substitute infusion. Kc in large MI was significantly less than moderate MI, small MI or control (all p < 0.05). Direct morphometric measurements distinguished between all groups.This study provides the first description of post-infarction remodelling after coronary artery occlusion where the pericardium remains intact in a small animal model. We believe it may provide a more physiologically and clinically relevant in vivo assay system of left ventricular dysfunction after myocardial infarction.

Diagnostic role of coronary calcium scoring in the rapid access chest pain clinic: prospective evaluation of NICE guidance

BACKGROUND Coronary artery calcium (CAC) imaging by unenhanced computed X-ray tomography (CT) is recommended as an initial diagnostic test for patients with stable chest pain symptoms but a low likelihood (10-29%) of underlying obstructive coronary artery disease (CAD) after clinical assessment. The recommendation has not previously been tested prospectively in a rapid access chest pain clinic (RACPC). METHODS We recruited 300 consecutive patients presenting with stable chest pain to the RACPC of three hospitals. All patients underwent CAC imaging, followed by invasive coronary angiography (ICA) in patients with CAC ≥ 1000 Agatston units (Au) and CT coronary angiography (CTCA) in those with CAC <1000. Patients with 50-70% stenosis on CTCA underwent myocardial perfusion scintigraphy (MPS) while those with ≥ 70% stenosis underwent ICA. Obstructive CAD was defined as ≥ 70% stenosis on ICA or the presence of inducible ischaemia on MPS. Patients were followed up clinically for a mean of 17 (SD 6) months. RESULTS The mean patient age was 60.6 (SD 9.6) years and 48% were males. Obstructive CAD was found in 56 (19%) patients, of whom 42 (14%) underwent revascularization. CAC was zero in 131 (44%) patients, of whom two (1.5%) had obstructive CAD and one (0.8%) underwent revascularization. The sensitivity, specificity, negative predictive value, and positive predictive value of CAC ≥ 1 for detection of obstructive CAD were 96, 53, 32, and 98%, respectively. None of the 57 patients with low pre-test probability of CAD and zero CAC had obstructive CAD or suffered a cardiovascular event during the follow-up. CONCLUSION Patients with stable chest pain symptoms but a low likelihood of CAD can safely be diagnosed as not having obstructive CAD in the absence of detectable coronary calcification by unenhanced CT. Patients with CAC >400 Au have a high prevalence of obstructive CAD and further investigation with ICA or functional imaging may be warranted rather than CTCA. These findings support NICE guidance for the investigation of stable chest pain. ClinicalTrials gov identifier: NCT01464203.

Improving the UK’s performance on survival after cardiac arrest

The evidence base is strong for changing the way we treat people who have had a cardiac arrest outside hospital