Pier A. Gioffrè

Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker.

BackgroundBrief episodes of ischemia render the heart more resistant to subsequent ischemia; this phenomenon has been called ischemic preconditioning. In some animal species, myocardial preconditioning appears to be due to activation of ATP-sensitive K+ (KATP) channels. The role played by KATP channels in preconditioning in humans remains unknown. The aim of this study was to establish whether glibenclamide, a selective KATP channel blocker, abolishes the ischemic preconditioning observed in humans during coronary angioplasty following repeated balloon inflations. Methods and ResultsTwenty consecutive patients undergoing one-vessel coronary angioplasty were randomized to receive 10 mg oral glibenclamide or placebo. Sixty minutes after glibenclamide or placebo administration, patients were given an infusion of 10% dextrose (8 mL/min) to correct glucose plasma levels or, respectively, an infusion of saline at the same infusion rate. Thirty minutes after the beginning of the infusion, both patient groups underwent coronary angioplasty. The mean values (± 1 SD) of ST-segment shifts on the surface 12-lead ECG and the intracoronary ECG were measured at the end of the first and second balloon inflations, both 2 minutes long. In glibenclamide-treated patients, the mean ST-segment shift during the second balloon inflation was similar to that observed during the first inflation (23± 13 versus 20±8 mm, P=NS), and the severity of cardiac pain was greater (55±21 versus 43±23 mm on a scale of 0 to 100, P<.05). Conversely, in placebo-treated patients the mean ST-segment shift during the second inflation was less than that during the first inflation (9±5 versus 23±13 mm, P<.001), as was the severity of cardiac pain (15±15 versus 42±19 mm, P<.01). Blood glucose levels were significantly reduced 60 minutes after glibenclamide compared with those at baseline (53±9 versus 102±10 mg/100 mL, P<.001) in the glibenclamide group; however, before coronary angioplasty, blood glucose levels increased to 95±19 mg/100 mL, a value similar to that found in placebo group (96±11 mg/100 mL, P=NS). ConclusionsIn humans, ischemic preconditioning during brief repeated coronary occlusions is completely abolished by pretreatment with glibenclamide, thus suggesting that it is mainly mediated by KATP channels.

A Comparison of Coronary-Artery Stenting with Angioplasty for Isolated Stenosis of the Proximal Left Anterior Descending Coronary Artery

BACKGROUND Randomized studies have shown that the use of coronary-artery stenting as the initial treatment for coronary stenosis is associated with a lower risk of restenosis than is standard coronary angioplasty. We prospectively investigated the efficacy of these two approaches in selected patients with isolated stenosis of the proximal left anterior descending coronary artery. METHODS A total of 120 patients with isolated stenosis of the proximal left anterior descending coronary artery were randomly assigned to stent implantation or standard coronary angioplasty. The primary clinical end points were the rate of procedural success (defined as residual stenosis of less than 50 percent and the absence of death, myocardial infarction, and the need for coronary-artery bypass surgery during the hospital stay) and the rate of event-free survival (defined as freedom from death, myocardial infarction, and the recurrence of angina) at 12 months. The angiographic end point was the rate of restenosis 12 months after the procedure. RESULTS The two treatment groups did not differ significantly with respect to demographic, clinical, or angiographic characteristics. The rates of procedural success were similar in the two groups of patients (95 percent in the stenting group vs. 93 percent in the angioplasty group, P = 0.98). The 12-month rates of event-free survival were 87 percent after stenting and 70 percent after angioplasty (P = 0.04). The rates of restenosis were 19 percent after stent implantation and 40 percent after angioplasty (P = 0.02). CONCLUSIONS In patients with symptomatic isolated stenosis of the proximal left anterior descending coronary artery, stenting had advantages over standard coronary angioplasty in that it was associated with both a lower rate of restenosis and a better clinical outcome.

Ischemic Preconditioning in Humans Models, Mediators, and Clinical Relevance

Ischemic preconditioning, a powerful form of endogenous protection against myocardial infarction, has been demonstrated in several animal species and, recently, in isolated human cardiomyocytes. For both logistic and ethical reasons, no clinical study can meet the strict conditions of experimental studies on preconditioning with infarct size as the end-point. Nevertheless, the demonstration of adaptation to ischemia observed during in vitro studies on human atrial trabeculae, in patients in the setting of coronary bypass surgery, and in the setting of coronary angioplasty in the absence of collateral vessel recruitment strongly suggests that ischemic preconditioning occurs in humans. This notion is further supported by the observation that in these human models, the adaptation to ischemia is influenced by drugs acting on K(ATP) channels and on purinergic and alpha-adrenergic receptors, similar to what is observed in accepted experimental models of ischemic preconditioning. This important form of myocardial endogenous protection may also play a role in the warm-up phenomenon and in mediating the beneficial effects of preinfarction angina. The demonstration of ischemic preconditioning in humans and the identification of some of its mediators suggests that in patients at high risk for myocardial infarction, drugs known to block this endogenous form of protection should be used with caution, whereas drugs known to elicit preconditioning might have a relevant therapeutic role.

Immunosuppressive therapy for the prevention of restenosis after coronary artery stent implantation (IMPRESS study)

OBJECTIVES This study tested the effect of oral prednisone on clinical and angiographic restenosis rate after successful stent implantation in patients with persistent elevation of systemic markers of inflammation after the procedure. BACKGROUND Experimental studies have shown that corticosteroids have the potential to reduce the inflammatory response associated with stent implantation. METHODS Eighty-three patients undergoing successful stenting with C-reactive protein (CRP) levels >0.5 mg/dl 72 h after the procedure were randomized to receive oral prednisone or placebo for 45 days. The primary clinical end point was 12-month event-free survival rate (defined as freedom from death, from myocardial infarction, and from recurrence of symptoms requiring additional revascularization). The angiographic end points were restenosis rate and late loss at six months. RESULTS Twelve-month event-free survival rates were 93% and 65% in patients treated with prednisone and placebo, respectively (relative risk [RR] 0.18, 95% confidence intervals [CI], 0.05 to 0.61, p = 0.0063). Six-month restenosis rate and late loss were lower in prednisone-treated than in placebo-treated patients (7% vs. 33%, p = 0.001, and 0.39 +/- 0.6 mm vs. 0.85 +/- 0.6 mm, p = 0.001, respectively). CONCLUSIONS In patients with persistently high CRP levels after successful coronary artery stent implantation, oral immunosuppressive therapy with prednisone results in a striking reduction of clinical events and angiographic restenosis rate.

Predictive value of C-reactive protein in patients with unstable angina pectoris undergoing coronary artery stent implantation.

This study was aimed at establishing the relation between baseline C-reactive protein levels and 12-month outcome in patients with unstable angina successfully treated with coronary artery stent implantation. Our results suggest that in patients with unstable angina and 1-vessel coronary disease successfully treated with coronary artery stent implantation, normal baseline serum levels of C-reactive protein identify a subgroup of patients at low risk of cardiac events during follow-up.

Effects of Naloxone on Myocardial Ischemic Preconditioning in Humans

OBJECTIVES We attempted to establish whether naloxone, an opioid receptor antagonist, abolishes the adaptation to ischemia observed in humans during coronary angioplasty after repeated balloon inflations. BACKGROUND Experimental studies indicate that myocardial opioid receptors are involved in ischemic preconditioning. METHODS Twenty patients undergoing angioplasty for an isolated stenosis of a major epicardial coronary artery were randomized to receive intravenous infusion of naloxone or placebo during the procedure. Intracoronary electrocardiogram and cardiac pain (using a 100-mm visual analog scale) were determined at the end of the first two balloon inflations. Average peak velocity in the contralateral coronary artery during balloon occlusion, an index of collateral recruitment, was also assessed by using a Doppler guide wire in the six patients of each group with a stenosis on the left anterior descending coronary artery. RESULTS In naloxone-treated patients, ST-segment changes and cardiac pain severity during the second inflation were similar to those observed during the first inflation (12+/-6 vs. 11+/-7 mm, p = 0.3, and 58+/-13 vs. 56+/-12 mm, p = 0.3, respectively), whereas in placebo-treated patients, they were significantly less (6+/-3 vs. 13+/-6 mm, p = 0.002 and 31+/-21 vs. 55+/-22 mm, p = 0.008, respectively). In both naloxone- and placebo-treated patients, average peak velocity significantly increased from baseline to the end of the first inflation (p = 0.04 and p = 0.02, respectively), but it did not show any further increase during the second inflation. CONCLUSIONS The adaptation to ischemia observed in humans after two sequential coronary balloon inflations is abolished by naloxone and is independent of collateral recruitment. Thus, it is due to ischemic preconditioning and is, at least partially, mediated by opioid receptors, suggesting their presence in the human heart.

Coronary artery stent placement in patients with variant angina refractory to medical treatment

We performed a prospective study to establish the efficacy of coronary stent placement in a highly selected group of patients with focal coronary artery spasm in whom anginal attacks could not be prevented by full medical therapy. The results of this study indicate that intracoronary stent placement may represent an alternative and feasible treatment for patients with vasospastic angina refractory to aggressive medical therapy.

Mechanisms of cardiac pain during coronary angioplasty

OBJECTIVES This study was conducted to establish whether the cardiac pain patients experience during coronary angioplasty is modulated by 1) the stretching of the coronary artery wall, and 2) the mechanisms responsible for the ischemic preconditioning. BACKGROUND Anecdotal experimental observations indicate that stretching of the coronary artery wall is a stimulus adequate to cause cardiac pain. Furthermore, recent experimental studies indicate that adenosine, a mediator of the anginal pain, appears to play an important role in the genesis of ischemic preconditioning. METHODS We randomly allocated 48 consecutive patients undergoing coronary angioplasty into two groups. In Group A the second balloon inflation was performed at a higher level than the first; in Group B the first two inflations were performed at the same level of balloon pressure. The mean values (+/- 1 SD) of ST segment shift on the surface 12-lead electrocardiogram (ECG) and the intracoronary ECG were measured at the end of each inflation period. Severity of cardiac pain was also obtained at the same time by using a visual analog scale. RESULTS The mean ST segment shift during the second balloon inflation was significantly less than that during the first inflation in both groups of patients (12.8 +/- 9.3 vs. 18.5 +/- 11.9 mm, p < 0.001 and 13.7 +/- 10.1 vs. 21.3 +/- 13.9 mm, p < 0.001, respectively, in Groups A and B). Yet, the severity of cardiac pain during the second inflation was greater than that during the first inflation in Group A (40.8 +/- 32.7 vs. 26.9 +/- 27.2 mm, p < 0.01), whereas it was lesser in Group B (23.1 +/- 20.7 vs. 32.9 +/- 29.6 mm, p < 0.05). However, in the latter group, pain severity after normalization for the mean ST segment shift was similar during the first and second inflations (2.1 +/- 2.4 vs. 2.7 +/- 3.6, p = NS). CONCLUSIONS During coronary angioplasty, the cardiac pain experienced by patients is caused in part by stretching of the coronary artery wall. If the stretching is maintained at a constant level during repeated coronary occlusions, the cardiac pain is entirely predicted by the severity of myocardial ischemia and therefore does not appear to be directly modulated by the mechanisms responsible for the ischemic preconditioning.

Hypertriglyceridemia and the apolipoprotein CIII gene locus: lack of association with the variant insulin response element in Italian school children

Hypertriglyceridemia is a common metabolic disorder with a major inherited component. In some individuals the condition is suspected to occur as a result of overproduction of apolipoprotein (apo)CIII, a major constituent of triglyceride-rich lipoproteins. Population studies have established an association with the apoCIII gene but the identity of the causal mutation remains unknown. In the present study we have examined a series of six 5′ polymorphic nucleotides (G–935 to A, C–641 to A, G–630 to A, deletion of T–625, C–482 to T, and T–455 to C) that lie within the promoter region of the apoCIII gene for evidence of possible involvement in disease susceptibility. The polymorphic nucleotides at positions –455 and –482 reside within a negative insulin-response element. We show, in a community-based sample of 503 school children, that a DNA polymorphism (S2 allele) within the 3′-noncoding region of the apoCIII gene was associated with elevated apoCIII and triglyceride levels, but that the polymorphic nucleotides of the promoter were not. In addition, no obvious effect of any extended apoCIII promoter haplotype on plasma apoCIII or triglyceride levels, over and above that conferred by the presence of the S2 polymorphic nucleotide, was detected. These results demonstrate that none of the 5′ apoCIII polymorphisms can account for the association of the apoCIII gene locus with hypertriglyceridemia and, moreover, owing to linkage disequilibrium, raise the possibility that the region conferring susceptibility maps downstream, rather than upstream, of the apoCIII gene promoter sequences.

Muscular and cardiac adenosine-induced pain is mediated by A1receptors

OBJECTIVES This study attempted to establish whether bamiphylline, a selective antagonist of A1 adenosine receptors, prevents the algogenic effects of adenosine in humans. BACKGROUND Experimental findings indicate that the sympathoexcitatory response elicited by adenosine is mediated by A1 receptors. METHODS An intrailiac infusion of increasing doses (from 125 to 2,000 micrograms/min) of adenosine was given to 20 patients. Adenosine infusion was then repeated after intrailiac infusion of either bamiphylline or saline solution. In 14 other patients with angina, increasing doses of adenosine (from 108 to 1,728 micrograms/min) were infused into the left coronary artery. Adenosine infusion was then repeated after the intravenous infusion of either bamiphylline or placebo. Coronary blood flow velocity was monitored by a Doppler catheter. Data relative to pain severity are expressed as median and all other data as mean value +/- 1 SD. RESULTS Bamiphylline prolonged the time to pain onset caused by the intrailiac adenosine infusion from 444 +/- 96 to 749 +/- 120 s (p < 0.001) and reduced pain severity from 45 to 24 mm (p < 0.01). After placebo infusion, the time to pain onset and pain severity were similar to that of baseline (428 +/- 112 vs. 430 +/- 104 s, p = 0.87 and 44 vs. 43 mm, p = 0.67, respectively). Bamiphylline prolonged the time to pain onset caused by intracoronary adenosine infusion from 519 +/- 128 to 603 +/- 146 s (p < 0.01) and reduced pain severity from 58 to 28 mm (p < 0.02). After placebo infusion, the time to pain onset and pain severity were similar to that at baseline (542 +/- 87 vs. 551 +/- 79 s, p = 0.14 and 55 vs. 50 mm, p = 0.61). Maximal coronary blood flow velocities before and after bamiphylline administration were similar (47 +/- 22 vs. 49 +/- 24 cm/s, p = 0.36) as well as before and after placebo administrtion (40 +/- 20 vs. 41 +/- 20 cm/s, p = 0.07). CONCLUSIONS Bamiphylline reduces adenosine-induced muscular and cardiac pain but does not affect adenosine-induced coronary vasodilation. These findings indicate that at the dose used in this study, bamiphylline does not detectably block vascular A2-receptor-mediated adenosine effects in humans, which suggests that the muscular and cardiac algogenic effects of adenosine are mediated mainly by A1 receptors.