Wolfram Terres

Cardioprotective Effects of the Na+/H+ Exchange Inhibitor Cariporide in Patients With Acute Anterior Myocardial Infarction Undergoing Direct PTCA

BACKGROUNDnActivation of Na(+)/H(+) exchange in myocardial ischemia and/or reperfusion leads to calcium overload and myocardial injury. Experimental studies have shown that Na(+)/H(+) exchange inhibitors can attenuate Ca(2+) influx into cardiomyocytes. We therefore performed a multicenter, randomized, placebo-controlled clinical trial to test the hypothesis that inhibition of Na(+)/H(+) exchange limits infarct size and improves myocardial function in patients with acute anterior myocardial infarction (MI) treated with direct PTCA.nnnMETHODS AND RESULTSnOne hundred patients were randomized to receive placebo (n=51) or a 40-mg intravenous bolus of the Na(+)/H(+) exchange inhibitor cariporide (HOE 642) (n=49) before reperfusion. Global and regional left ventricular functions were analyzed by use of paired contrast left ventriculograms performed before and 21 days after PTCA and myocardial enzymes (ie, creatine kinase ¿CK, CK-MB, and LDH) as markers for myocardial tissue injury were evaluated. At follow-up, the ejection fraction was higher (50% versus 40%; P<0.05) and the end-systolic volume was lower (69.0 versus 97.0 mL; P<0.05) in the cariporide group. Significant improvements in some indices of regional wall motion abnormalities were observed, such as the percentage of chords with hypokinesis < -2 SD (P=0.045) and the severity of hypokinesis in the border zone of the infarct region (P=0.052). In addition, CK, CK-MB, or LDH release was significantly reduced in the cariporide patients.nnnCONCLUSIONSnOur findings suggest that inhibition of Na(+)/H(+) exchange by cariporide may attenuate reperfusion injury and thereby improve the recovery from left ventricular dysfunction after MI.

Rapid Angiographic Progression of Coronary Artery Disease in Patients With Elevated Lipoprotein(a)

BACKGROUNDnThe mechanisms underlying rapid angiographic progression of coronary artery disease are still unknown. Intravascular thrombosis with or without plaque rupture may be involved.nnnMETHODS AND RESULTSnIn a prospective study in 79 patients with coronary artery disease and at least one coronary diameter stenosis > or = 50%, possible risk factors for rapid progression were investigated. Quantitative coronary angiography was performed twice at a mean time interval of 66 +/- 25 days. Rapid progression of coronary disease defined as (1) an increase > 10% in stenosis severity in at least one stenosis > or = 50%, (2) occurrence of a new stenosis > or = 50%, or (3) occlusion of a formerly patent vessel was found in 21 patients (27%). Between patients with rapid progression and those without, there were no significant differences in sex distribution, age, smoking history, frequency of hypertension or diabetes mellitus, and serum LDL cholesterol, HDL cholesterol, and apolipoprotein B concentrations. In contrast, serum lipoprotein(a) [Lp(a)] concentrations > or = 25 mg/dL were found in 14 of 21 patients (67%) with rapid progression of coronary artery disease but in only 19 of 58 (33%) in the group without progression (P = .007). The respective median Lp(a) concentrations were 66 mg/dL (range, 2 to 139) and 13 mg/dL (range, 2 to 211; P = .01).nnnCONCLUSIONSnLp(a) appears to be a risk factor for the rapid angiographic progression of coronary artery disease. The pathophysiological link between Lp(a) and rapid progression may be an interference with thrombolysis through the partial structural homology of Lp(a) with plasminogen.

Intravascular Therapeutic Ultrasound Thrombolysis in Acute Myocardial Infarctions

Catheter-delivered, therapeutic ultrasound was shown to effectively dissolve thrombus in vitro and in vivo. This first study in 14 patients with acute myocardial infarctions demonstrates that it is a safe and effective treatment alternative that deserves further clinical evaluation.

Six-month clinical and angiographic outcome after successful excimer laser angioplasty for in-stent restenosis

OBJECTIVESnThis study evaluated the clinical and angiographic six-month follow-up after excimer laser coronary angioplasty (ELCA) for restenosed coronary stents.nnnBACKGROUNDnExcimer laser coronary angioplasty has recently been shown to be safe and efficient for the treatment of in-stent restenosis.nnnMETHODSnNinety-six consecutive patients successfully treated with ELCA within 141 stents were included in a six-month clinical and angiographic follow-up.nnnRESULTSnDuring follow-up there was one sudden death and one patient with documented myocardial infarction. Angina pectoris classified as > or = Canadian Cardiovascular Society II reoccurred in 49 patients. Follow-up angiography was obtained in 89 patients (93%) with 133 stents. Quantitative coronary angiography revealed a mean diameter stenosis of 77 +/- 10% before intervention, 41 +/- 12% after laser treatment and 11% +/- 12% after adjunctive percutaneous transluminal coronary angioplasty (p < 0.001). Six months after ELCA the mean diameter stenosis had increased to 60 +/- 26% (p < 0.001). A > or =50% diameter stenosis was present in 48 patients (54%); in 24 of these patients diameter stenosis was > or =70%. Total occlusions occurred in an additional 10 patients (11%). There was a trend toward an increased recurrent restenosis rate in patients with diabetes mellitus and long lesions or total occlusions (p = 0.059). Forty-eight patients (50%) received medical treatment after six months. Reinterventions were necessary in 30 patients (31%), and coronary artery bypass surgery was performed in 17 patients (18%). Event-free survival was 50%.nnnCONCLUSIONSnExcimer laser angioplasty for in-stent restenosis was associated with a high incidence of recurrent restenosis in this group of patients, suggesting that this technique is unlikely to reduce recurrent in-stent restenosis and that other approaches are necessary.

Influence of Stent Length and Heparin Coating on Platelet Activation: A Flow Cytometric Analysis in a Pulsed Floating Model

Platelets are involved in acute and subacute thrombotic occlusions of coronary stents and also may play a role in the pathophysiology of in-stent restenosis. This study sought to investigate the expression of activation dependent glycoproteins on platelets by flow cytometry and time until stent thrombosis in an in vitro model of stent thrombosis. Coronary stents were placed in parallel silicon tubings with circulating citrated platelet rich plasma to measure 1) influence of stent length on platelet antigens; 2) influence of heparin coating on platelet antigens; and 3) time until stent thrombosis. After recalcification aliquots of platelet-rich plasma were taken over 10 minutes in 2-minute intervals and immediately fixed and stabilized. For flow cytometric analysis monoclonal antibodies to CD41a (glycoprotein IIb/ IIIa), CD42b (glycoprotein Ib-V-IX), CD62p (P-selectin), and CD63 (glycoprotein 53) were used. Within 2 minutes after start of circulation, the expression of CD62p and CD63 increased. Longer stents resulted in more platelet activation than shorter stents (25 mm vs. 15 mm; p<0.001. Time until stent thrombosis was reduced (25 mm vs. 15 mm; p<0.05). Heparin coating did not significantly influence flow cytometry detectable platelet activation but prolonged time until stent thrombosis (coated vs. uncoated; p<0.005). In control tubing systems without stents platelet activation was less pronounced (p<0.0001). Antibodies to CD41a and CD42b did not show significant changes. In this model platelet activation detected by flow cytometry and time until stent thrombosis were dependent on stent length and coating. In vitro testing could be useful to optimize stent design and material.

Sodium-hydrogen exchange inhibition: novel strategy to prevent myocardial injury following ischemia and reperfusion.

Activation of Na+/H+ exchange and subsequent calcium overload in cardiac myocytes appear to play an important role in myocardial tissue injury following ischemia and reperfusion. Results of several in vitro studies in isolated myocytes and heart preparations and in vivo studies in pigs and rats have suggested that inhibition of Na+/H+ exchange is an effective means to prevent lethal reperfusion injury, arrhythmia, and improve myocardial contractile dysfunction. In patients with acute myocardial infarction (MI), any preventive agent is administered immediately before or shortly after reperfusion, rather than before the occurrence of coronary occlusion. The direct interventional approach to treating acute MI provides the opportunity to see if reperfusion has already occurred; if not, a protective agent prior to mechanical reperfusion by percutaneous transluminal coronary angioplasty (PTCA) can be administered to limit reperfusion injury. In a multicenter, randomized, placebo-controlled clinical trial, we tested the hypothesis that inhibition of Na+/H+ exchange with cariporide (HOE 642) could limit infarct size and improve myocardial function in patients with acute transmural MI treated with direct PTCA. Patients were randomized to receive placebo or cariporide given as a 40-mg intravenous bolus prior to reperfusion. Global and regional left ventricular function were analyzed via paired contrast left ventriculograms performed before direct PTCA and after 21 days. Myocardial enzymes (i.e., creatine kinase [CK], CK-MB, and lactate dehydrogenase) as markers for myocardial tissue injury were evaluated as well. The results of this pilot study suggested that the Na+/H+ exchange inhibition could be of benefit to prevent reperfusion injury in patients with acute anterior MI treated with direct angioplasty.

Enhanced coagulation activation in troponin T-positive unstable angina pectoris.

Intracoronary thrombus formation and systemic activation of coagulation have been demonstrated in unstable angina pectoris. Circulating troponin T as a marker of minor myocardial cell injury is associated with adverse outcome in this condition. Little information exists about the interrelation of coagulation activation and myocardial cell injury in unstable angina. We quantitatively assessed systemic activation of coagulation and myocardial cell injury in serial blood samples obtained up to 10 days from 22 patients with angiographically documented coronary heart disease and unstable angina pectoris at rest. In the nine patients with increased maximal levels of serum troponin T, maximal concentrations of fibrin monomers during the first 48 hours were higher than those in patients with persistently normal troponin T concentrations (6.3+/-4.8 vs. 2.9+/-2.3 mg/L; p = 0.04). The proportion of patients with at least one blood sample showing an increased concentration of plasma fibrin monomer was also higher in the group with increased troponin T (67% vs. 15%; p = 0.04). Plasma prothrombin fragment F1+2 levels showed a nonsignificant trend toward higher values in troponin T-positive patients. Enhanced activation of coagulation in patients with troponin T-positive unstable angina may contribute to the adverse outcome associated with this condition.

Initial experience with a hydrophilic-coated guidewire for recanalization of chronic coronary occlusions.

Chronic coronary occlusions are still a therapeutic challenge to the interventional cardiologist. New techniques such as laser wire have improved recanalization rates, but outcomes are still far from satisfactory. We report the results of a nonrandomized single‐center investigation using a hydrophilic‐coated guidewire (Terumo Crosswire). Between September 1996 and September 1998, 107 chronic occlusions in 106 patients were approached when previous attempts with conventional guidewires failed. Median occlusion duration in these cases was 4 months (range, 0.5–122); mean occlusion length was 19 ± 11 mm (range, 5–60). Forty‐five (42%) of these attempts were successful. Attempts were successful in 42% in the left anterior descending artery, in 30% in the left circumflex artery, in 48% in the right coronary artery, and in 43% in coronary artery bypass grafts. Success rates ranged from 56% for occlusions of less than 4‐month duration to 18% for occlusions of more than 36‐month duration. The success rate in TIMI 1‐flow lesions was significantly higher than in TIMI 0 flow lesions, 85% vs. 36%. In a multivariate regression analysis, TIMI flow grade and occlusion age were independent predictors of success. There were no deaths or Q‐wave myocardial infarctions; two cases of hemopericardium were treated successfully. In five cases, pericardial contrast staining due to vessel perforation occurred. Our results indicate that the Crosswire is an effective tool in the treatment of chronic coronary occlusions, even when recanalization attempts with conventional guidewires fail. Cathet. Cardiovasc. Intervent. 49:45–50, 2000.

Treatment of In-Stent Coronary Restenosis by Excimer Laser Angioplasty

We evaluated the efficacy and safety of excimer laser angioplasty (ELCA) with adjunctive balloon angioplasty in patients with restenotic or occluded coronary stents. ELCA was performed in 70 patients (60 +/- 9 years), who had previously been treated with Micro Stents (n = 65), Palmaz-Schatz (n = 38), Wiktor, NIR, Freedom, and Multi-Link stents (n = 1 each). Restenosis (> or =50% diameter stenosis) was documented in 90 stents, another 17 stents were occluded. Laser energy was delivered to the lesions with catheters 1.4, 1.7 (eccentric), and 2.0 mm in diameter. Procedural success was controlled by intravascular ultrasound in a subgroup. Laser catheters crossed all restenotic or occluded stents and decreased diameter stenosis from 80 +/- 13% to 44 +/- 11% (p <0.001). Adjunctive balloon angioplasty further reduced diameter stenosis to 13 +/- 13% (p <0.001). In 13 patients with 21 stents, serial intravascular ultrasound imaging revealed a reduction of plaque area within the stent by 34 +/- 22% (from 4.2 +/- 1.8 mm2 to 2.7 +/- 1.1 mm2) after ELCA and a reduction by 65 +/- 16% (to 1.5 +/- 0.7 mm2) after balloon angioplasty (p <0.01). There were 4 patients with an increase of creatine kinase levels, 8 patients with major dissections (in 7 patients they were related to adjunctive balloon angioplasty), 1 patient with distal embolization, 2 with minor perforations, and 1 patient with stent dislocation. Reintervention during hospitalization was necessary in 3 patients. ELCA is an efficient and safe technique to debulk tissue in restenotic lesions and total occlusions within stents. The incidence of procedure related complications was low.

Antibodies to Chlamydial Lipopolysaccharides in Unstable Angina Pectoris

Patients with coronary artery disease frequently have elevated antibody titers against Chlamydia pneumoniae, but whether antichlamydial antibody titers are correlated with prognosis in unstable angina remains unclear. We therefore investigated the sera of 1,096 patients with unstable angina regarding immunoglobulin (Ig) IgG, IgA, and IgM antibody titers against chlamydial lipopolysaccharides (LPS) and the concentrations of C-reactive protein (CRP) and troponin T (TnT). Anti-LPS IgG titers were increased in 45% of patients at enrollment and in 48% of patients at discharge (p <0.0001). Anti-LPS IgA titers were increased in 27% of patients at enrollment and in 33% of patients at discharge (p <0.0001). Patients who subsequently died had significantly lower IgM titers at enrollment than patients without events (p = 0.016). IgG, IgA, or IgM titers did not correlate with concentrations of CRP or TnT. In this large-scale study of patients with unstable angina, we frequently found elevated antichlamydial antibody titers. Patients with low IgM anti-LPS titers were at risk for subsequent death. However, there was no correlation between antichlamydial antibody titers and CRP or TnT.