Rajesh K. Kharbanda

Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial

BACKGROUND Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty. We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infarction, and done before primary percutaneous coronary intervention, increases myocardial salvage. METHODS 333 consecutive adult patients with a suspected first acute myocardial infarction were randomly assigned in a 1:1 ratio by computerised block randomisation to receive primary percutaneous coronary intervention with (n=166 patients) versus without (n=167) remote conditioning (intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff). Allocation was concealed with opaque sealed envelopes. Patients received remote conditioning during transport to hospital, and primary percutaneous coronary intervention in hospital. The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment; analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00435266. FINDINGS 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index. Median salvage index was 0.75 (IQR 0.50-0.93, n=73) in the remote conditioning group versus 0.55 (0.35-0.88, n=69) in the control group, with median difference of 0.10 (95% CI 0.01-0.22; p=0.0333); mean salvage index was 0.69 (SD 0.27) versus 0.57 (0.26), with mean difference of 0.12 (95% CI 0.01-0.21; p=0.0333). Major adverse coronary events were death (n=3 per group), reinfarction (n=1 per group), and heart failure (n=3 per group). INTERPRETATION Remote ischaemic conditioning before hospital admission increases myocardial salvage, and has a favourable safety profile. Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes. FUNDING Fondation Leducq.

Acute Systemic Inflammation Impairs Endothelium-Dependent Dilatation in Humans

BackgroundWe tested the hypothesis that endothelial dysfunction underlies the association between an acute inflammatory episode and the transiently increased risk of a cardiovascular event by examining the effects of an experimental inflammatory stimulus on endothelium-dependent vasodilation. Methods and ResultsSalmonella typhi vaccine was used to generate a systemic inflammatory response in healthy volunteers. In 12 subjects, dilatation of the brachial artery to flow and to sublingual nitroglycerin (NTG) was recorded (conduit vessel response), and in 6 subjects, venous occlusion plethysmography was used to measure forearm blood flow during intrabrachial infusion of the endothelium-dependent dilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent dilators NTG and verapamil (resistance vessel response). Responses were assessed 16 hours before and 8 and 32 hours after vaccination. Vaccination resulted in elevations in white cell count and serum levels of interleukin-6 and interleukin-1 receptor antagonist. Eight hours after vaccination, resistance vessel responses to BK (P =0.0099) and ACh (P =0.0414) were markedly attenuated, and brachial artery flow-mediated dilatation was depressed. Resistance vessel responses to verapamil and NTG were unchanged, as was the conduit vessel response to NTG. Thirty-two hours after vaccination, resistance vessel responses to BK and ACh had returned to normal. ConclusionsS typhi vaccine generates a mild inflammatory reaction associated with temporary but profound dysfunction of the arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. This finding might explain the association between infection and inflammation and the enhanced risk of an acute cardiovascular event.

Transient Limb Ischemia Induces Remote Ischemic Preconditioning In Vivo

Background—Ischemic preconditioning reduces local tissue injury caused by subsequent ischemia-reperfusion (IR), but may also have a salutary effect on IR injury of tissues remote from those undergoing preconditioning. We tested the hypothesis that limb ischemia induces remote preconditioning, reduces endothelial IR injury in humans, and reduces experimental myocardial infarct size. Methods and Results—Endothelial IR injury of the human forearm was induced by 20 minutes of upper limb ischemia (inflation of a blood pressure cuff to 200 mm Hg) followed by reperfusion. Remote preconditioning was induced by three 5-minute cycles of ischemia of the contralateral limb. Venous occlusion plethysmography was used to assess forearm blood flow in response to acetylcholine at baseline and 15 minutes after reperfusion. Experimental myocardial infarction was achieved by 40 minutes of balloon occlusion of the left anterior descending artery in 15-kg pigs. Remote preconditioning was induced by four 5-minute cycles of lower limb ischemia. Triphenyltetrazolium staining was used to assess the extent of myocardial infarction. In the human study, the response to acetylcholine was significantly attenuated in the control group after 15 minutes’ reperfusion, but remote preconditioning prevented this reduction. Limb ischemia caused a significant reduction in the extent of myocardial infarction relative to the area at risk compared with control (26±9% versus 53±8%, P <0.05). Conclusion—Remote ischemic preconditioning prevents IR-induced endothelial dysfunction in humans and reduces the extent of myocardial infarction in experimental animals. Transient limb ischemia is a simple preconditioning stimulus with important potential clinical applications.

Remote Ischemic Preconditioning Reduces Myocardial and Renal Injury After Elective Abdominal Aortic Aneurysm Repair A Randomized Controlled Trial

Background— Myocardial and renal injury commonly contribute to perioperative morbidity and mortality after abdominal aortic aneurysm repair. Remote ischemic preconditioning (RIPC) is a phenomenon whereby brief periods of ischemia followed by reperfusion in one organ provide systemic protection from prolonged ischemia. To investigate whether remote preconditioning reduces the incidence of myocardial and renal injury in patients undergoing elective open abdominal aortic aneurysm repair, we performed a randomized trial. Method and Results— Eighty-two patients were randomized to abdominal aortic aneurysm repair with RIPC or conventional abdominal aortic aneurysm repair (control). Two cycles of intermittent crossclamping of the common iliac artery with 10 minutes ischemia followed by 10 minutes reperfusion served as the RIPC stimulus. Myocardial injury was assessed by cardiac troponin I (>0.40 ng/mL), myocardial infarction by the American College of Cardiology/American Heart Association definition and renal injury by serum creatinine (>177 &mgr;mol/L) according to American Heart Association guidelines for risk stratification in major vascular surgery. The groups were well matched for baseline characteristics. RIPC reduced the incidence of myocardial injury by 27% (39% versus 12% [95% CI: 8.8% to 45%]; P=0.005), myocardial infarction by 22% (27% versus 5% [95% CI: 7.3% to 38%]; P=0.006), and renal impairment by 23% (30% versus 7%; [95% CI: 6.4 to 39]; P=0.009). Multivariable analysis revealed the protective effect of RIPC on myocardial injury (OR: 0.22, 95% CI: 0.07 to 0.67; P=0.008), myocardial infarction (OR: 0.18, 95% CI: 0.04 to 0.75; P=0.006) and renal impairment were independent of other covariables. Conclusions— In patients undergoing elective open abdominal aortic aneurysm repair, RIPC reduces the incidence of postoperative myocardial injury, myocardial infarction, and renal impairment.

Translation of remote ischaemic preconditioning into clinical practice

Reduction of the burden of ischaemia-reperfusion injury is the aim of most treatments for cardiovascular and cerebrovascular disease. Although many strategies have proven benefit in the experimental arena, few have translated to clinical practice. Scientific and practical reasons might explain this finding, but the unpredictability of acute ischaemic syndromes is one of the biggest obstacles to timely application of novel treatments. Remote ischaemic preconditioning-which is a powerful innate mechanism of multiorgan protection that can be induced by transient occlusion of blood flow to a limb with a blood-pressure cuff-could be close to becoming a clinical technique. Several proof-of-principle and clinical trials have been reported, suggesting that the technique has remarkable promise. We examine the history, development, and present state of remote preconditioning in cardiovascular disease.

Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a katp channel-dependent mechanism

Background. We assess whether remote ischemic preconditioning (rIPC) of the recipient can modify ischemia-reperfusion (IR) injury in the donor heart following orthotopic heart transplantation from brain dead donors and to examine potential mechanisms of protection. Methods. Sixteen pigs weighing from 26 to 34.2 (mean 29.2) kg, randomized to control group (n=5), ischemic preconditioning (rIPC) group (n=6), and to receive rIPC with prior glibenclamide administration (Glib + rIPC) group (n=5) underwent orthotopic heart transplantation with the support of hypothermic (32°C) cardiopulmonary bypass (CPB). The hearts were harvested from donor animal rendered brain dead by balloon compression via a craniotomy. Preconditioning of the recipients was induced by four 5-min cycles of lower limb ischemia. Myocardial infarction (MI) was induced following heart transplantation by 30 min of left anterior descending (LAD) artery occlusion following by 2 hr of regional reperfusion. The extent of myocardial infarction was assessed by triphenyltetrazolium (TTC) staining. Results. Preconditioning of the recipient reduced the mass of MI (6.75±6.3 g in rIPC vs. 18.1±5.8 g in control, P=0.01), MI to area at risk (ARR) mass ratio by 57% (15.6%±15.2% vs. 36.3%±13.4%, P=0.04). The protective effect of preconditioning was abolished by pretreatment with glibenclamide. Conclusions. Remote ischemic preconditioning of the recipient, decreases ischemia-reperfusion injury in the brain dead donor heart following orthotopic heart transplantation via a Katp channel-dependent mechanism. This study suggests that a circulating effector persists after the rIPC stimulus is applied, and excludes an ongoing afferent neurogenic mechanism of cardioprotection.

Cardiovascular magnetic resonance by non contrast T1-mapping allows assessment of severity of injury in acute myocardial infarction

BackgroundCurrent cardiovascular magnetic resonance (CMR) methods, such as late gadolinium enhancement (LGE) and oedema imaging (T2W) used to depict myocardial ischemia, have limitations. Novel quantitative T1-mapping techniques have the potential to further characterize the components of ischemic injury. In patients with myocardial infarction (MI) we sought to investigate whether state-of the art pre-contrast T1-mapping (1) detects acute myocardial injury, (2) allows for quantification of the severity of damage when compared to standard techniques such as LGE and T2W, and (3) has the ability to predict long term functional recovery.Methods3T CMR including T2W, T1-mapping and LGE was performed in 41 patients [of these, 78% were ST elevation MI (STEMI)] with acute MI at 12-48 hour after chest pain onset and at 6 months (6M). Patients with STEMI underwent primary PCI prior to CMR. Assessment of acute regional wall motion abnormalities, acute segmental damaged fraction by T2W and LGE and mean segmental T1 values was performed on matching short axis slices. LGE and improvement in regional wall motion at 6M were also obtained.ResultsWe found that the variability of T1 measurements was significantly lower compared to T2W and that, while the diagnostic performance of acute T1-mapping for detecting myocardial injury was at least as good as that of T2W-CMR in STEMI patients, it was superior to T2W imaging in NSTEMI. There was a significant relationship between the segmental damaged fraction assessed by either by LGE or T2W, and mean segmental T1 values (P < 0.01). The index of salvaged myocardium derived by acute T1-mapping and 6M LGE was not different to the one derived from T2W (P = 0.88). Furthermore, the likelihood of improvement of segmental function at 6M decreased progressively as acute T1 values increased (P < 0.0004).ConclusionsIn acute MI, pre-contrast T1-mapping allows assessment of the extent of myocardial damage. T1-mapping might become an important complementary technique to LGE and T2W for identification of reversible myocardial injury and prediction of functional recovery in acute MI.

Dynamic Changes of Edema and Late Gadolinium Enhancement after Acute Myocardial Infarction and Their Relationship to Functional Recovery and Salvage Index

Background— Changes in the myocardium in acute ischemia are dynamic and complex, and the characteristics of myocardial tissue on cardiovascular magnetic resonance in the acute setting are not fully defined. We investigated changes in edema and late gadolinium enhancement (LGE) with serial imaging early after acute myocardial infarction, relating these to global and segmental myocardial function at 6 months. Methods and Results— Cardiovascular magnetic resonance scans were performed on 30 patients with ST-elevation–myocardial infarction treated by primary percutaneous coronary intervention at each of 4 time points: 12 to 48 hours; 5 to 7 days; 14 to 17 days; and 6 months. All patients showed edema at 24 hours. The mean volume of edema (% left ventricle) was 37±16 at 24 hours and 39±17 at 1 week, with a reduction to 24±13 (P<0.01) by 2 weeks. Myocardial segments with edema also had increased signal on LGE at 24 hours (&kgr;=0.77; P<0.001). The volume of LGE decreased significantly between 24 hours and 6 months (27±15% versus 22±12%; P=0.002). Of segments showing LGE at 24 hours, 50% showed resolution by 6 months. In segments with such a reduction in LGE, 65% also showed improved wall motion (P<0.0001). The area of LGE measured at 6 months correlated more strongly with troponin at 48 hours (r=0.9; P<0.01) than LGE at 24 hours (r=0.7). The difference in LGE between 24 hours and 6 months had profound effects on the calculation of salvage index (26±21% at 24 hours versus 42±23% at 6 months; P=0.02). Conclusions— Myocardial edema is maximal and constant over the first week after myocardial infarction, providing a stable window for the retrospective evaluation of area at risk. By contrast, myocardial areas with high signal intensity in LGE images recede over time with corresponding recovery of function, indicating that acutely detected LGE does not necessarily equate with irreversible injury and may severely underestimate salvaged myocardium.

Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI

Background Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave‐free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. Methods We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR‐guided or FFR‐guided coronary revascularization. The primary end point was the 1‐year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. Results At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, ‐0.2 percentage points; 95% confidence interval [CI], ‐2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). Conclusions Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE‐FLAIR ClinicalTrials.gov number, NCT02053038.)

Prevention of Inflammation-Induced Endothelial Dysfunction A Novel Vasculo-Protective Action of Aspirin

Background—Inflammation and infection may initiate and promote atherosclerosis or its complications by adverse effects on the vascular endothelium. The mechanisms by which aspirin reduces cardiovascular risk might involve anti-inflammatory actions or direct effects on the endothelium in addition to its antiplatelet action. We investigated the role of aspirin in modulating endothelial dysfunction induced by an experimental inflammatory stimulus. Methods and Results—An inflammatory response was generated in healthy volunteers by Salmonella typhi vaccination. Venous occlusion plethysmography was used to assess resistance vessel responses (16 hours before and 8 hours after vaccination) to the endothelium-dependent dilator bradykinin (BK) and the endothelium-independent dilator glyceryl-trinitrate (GTN). Twelve subjects were randomized to receive either aspirin 1.2 g orally or placebo 2 hours before vaccination. After vaccination alone there was suppression of the response to BK in the placebo group (P =0.01), with no change in response to GTN. In the aspirin group there was no change in the response to either BK or GTN after vaccination. Aspirin treatment prevented vaccine-induced elevation of interleukin-1 receptor antagonist but enhanced the generation of tumor necrosis factor-&agr; compared with placebo. In an additional 5 individuals, local intrabrachial aspirin (10 mg/min for 15 minutes) failed to restore responses to BK after vaccination. Conclusions—Experimental inflammation produces endothelial dysfunction, which can be prevented by pretreatment with aspirin. Locally administered aspirin does not reverse vaccine-induced endothelial dysfunction once established. The protective effects of aspirin on inflammation-induced endothelial dysfunction may be through modulation of the cytokine cascade.