Jan G. Grandjean

Verapamil Reduces Tachycardia-Induced Electrical Remodeling of the Atria

BACKGROUND Prolonged periods of atrial fibrillation or rapid atrial pacing induce shortening of the atrial effective refractory period (AERP), which is thought to be related to the lower success rates of various antifibrillatory treatments when the arrhythmia has lasted for a longer period of time. METHODS AND RESULTS To investigate whether an increase in intracellular calcium could be the stimulus for electrical remodeling, the effects of verapamil on shortening of the AERP in response to 24 hours of rapid atrial pacing (300 bpm) were studied in five chronically instrumented conscious goats during infusion of saline or verapamil. During rapid atrial pacing, the ventricular rate was kept constant by ventricular pacing (150 bpm). The AERP was measured by programmed electrical stimulation at basic cycle lengths of 430, 300, and 200 ms. Verapamil had no effects on the AERP before rapid atrial pacing. However, in the course of 24 hours of rapid atrial pacing, the AERP shortened significantly less (27% to 58%) in the presence of verapamil compared with control (at 430, 300, and 200 ms, P < .001, P < .01, and P < .01, respectively). Also, after cessation of pacing, complete recovery of the AERP during verapamil infusion occurred much sooner than in the control experiments. Despite a significant reduction in electrical remodeling, there was only a minimal reduction in inducibility of atrial fibrillation by verapamil (34% versus 39% in the control experiments, P = .03). CONCLUSIONS Electrical remodeling of the atrium during rapid atrial pacing was significantly attenuated by verapamil. This suggests that electrical remodeling of the atrium is triggered by the high calcium influx during rapid atrial pacing rates.

Ion Channel Remodeling Is Related to Intraoperative Atrial Effective Refractory Periods in Patients With Paroxysmal and Persistent Atrial Fibrillation

Background —Sustained shortening of the atrial effective refractory period (AERP), probably due to reduction in the L-type calcium current, is a major factor in the initiation and maintenance of atrial fibrillation (AF). We investigated underlying molecular changes by studying the relation between gene expression of the L-type calcium channel and potassium channels and AERP in patients with AF. Methods and Results —mRNA and protein expression were determined in the left and right atrial appendages of patients with paroxysmal (n=13) or persistent (n=16) AF and of 13 controls in sinus rhythm using reverse transcription polymerase chain reaction and slot-blot, respectively. The mRNA content of almost all investigated ion channel genes was reduced in persistent but not in paroxysmal AF. Protein levels for the L-type Ca2+ channel and 5 potassium channels (Kv4.3, Kv1.5, HERG, minK, and Kir3.1) were significantly reduced in both persistent and paroxysmal AF. Furthermore, AERPs were determined intraoperatively at 5 basic cycle lengths between 250 and 600 ms. Patients with persistent and paroxysmal AF displayed significant shorter AERPs. Protein levels of all ion channels investigated correlated positively with the AERP and with the rate adaptation of AERP. Patients with reduced ion channel protein expression had a shorter AERP duration and poorer rate adaptation. Conclusions —AF is predominantly accompanied by decreased protein contents of the L-type Ca2+ channel and several potassium channels. Reductions in L-type Ca2+ channel correlated with AERP and rate adaptation, and they represent a probable explanation for the electrophysiological changes during AF.

Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: Differential regulation of protein and mRNA levels for K+ channels

OBJECTIVES Our purpose was to determine whether patients with persistent atrial fibrillation (AF) and patients with paroxysmal AF show alterations in potassium channel expression. BACKGROUND Persistent AF is associated with a sustained shortening of the atrial action potential duration and atrial refractory period. Underlying molecular changes have not been studied in humans. We investigated whether a changed gene expression of specific potassium channels is associated with these changes in patients with persistent AF and in patients with paroxysmal AF. METHODS Right atrial appendages were obtained from 8 patients with paroxysmal AF, 10 with persistent AF and 18 matched controls in sinus rhythm. All controls underwent coronary artery bypass surgery, whereas most AF patients underwent Coxs MAZE surgery (atrial arrhythmia surgery to cure AF) (n = 12). All patients had normal left ventricular function. mRNA (ribonucleic acid) levels were measured by semiquantitative polymerase chain reaction and protein content by Western blotting. RESULTS mRNA levels of transient outward channel (Kv4.3), acetylcholine-dependent potassium channel (Kir3.4) and ATP-dependent potassium channel (Kir6.2) were reduced in patients with persistent AF (-35%, -47% and -36%, respectively, p < 0.05), whereas only Kv4.3 mRNA level was reduced in patients with paroxysmal AF (-29%, p = 0.03). No changes were found for Kv1.5 and HERG mRNA levels in either group. Protein levels of Kv4.3, Kv1.5 and Kir3.1 were reduced both in patients with persistent AF (-39%, -84% and -47%, respectively, p < 0.05) and in those with paroxysmal AF (-57%, -64%, and -40%, respectively, p < 0.05). CONCLUSIONS Persistent AF is accompanied by reductions in mRNA and protein levels of several potassium channels. In patients with paroxysmal AF these reductions were observed predominantly at the protein level and not at the mRNA level, suggesting a post-transcriptional regulation.

Procoagulant activity after off-pump coronary operation: is the current anticoagulation adequate?

BACKGROUND Hemostasis is preserved after off-pump coronary operations compared with conventional coronary procedures. However, this preserved hemostasis may result in a procoagulant activity. METHODS We prospectively studied coagulation in 22 patients who underwent off-pump coronary operation either through a midline sternotomy (n = 14) or with minimally invasive anterolateral thoracotomy (n = 8). RESULTS Procoagulant activity, represented by prothrombin factor 1 and 2, remained at baseline levels during operation but increased significantly on postoperative day 1. Factor VII remained at baseline levels during the operation but decreased significantly on postoperative day 1. Fibrinolysis was increased as indicated by the fibrin degradation products on postoperative day 1. A promoted hemostasis attributable to endothelial activation was indicated by the increase in von Willebrand factor on postoperative day 1. Platelets counts and platelet activation (beta-thromboglobulin) remained at baseline levels after the operation. No adverse clinical events occurred. CONCLUSIONS Patients undergoing off-pump coronary operation show an increased procoagulant activity in the first postoperative 24 hours regardless of the surgical approach (midline sternotomy or anterolateral thoracotomy). This procoagulant activity is not mediated by platelet-related factors. Therefore, a specific perioperative prophylactic pharmacologic regimen is advisable.

Reduction of the inflammatory response in patients undergoing minimally invasive coronary artery bypass grafting

BACKGROUND The aim of this prospective study was to determine whether the inflammation-associated clinical morbidity as well as the subclinical markers of the inflammatory response are reduced in patients who undergo minimally invasive coronary artery bypass grafting without cardiopulmonary bypass. METHODS From June 1995 to June 1996, 62 consecutive patients with isolated stenosis of the left anterior descending coronary artery were assigned randomly to two groups: 31 patients underwent minimally invasive coronary artery bypass grafting and 31 patients underwent conventional coronary artery bypass grafting with cardiopulmonary bypass. In a subgroup of 10 patients in each group, subclinical markers were measured to determine the level of the inflammatory response generated during the operation. RESULTS In the group that underwent minimally invasive coronary artery bypass grafting, leukocyte elastase, platelet beta-thromboglobulin, and complement C3a were unchanged at the end of the procedure compared with their baseline concentrations, whereas these inflammatory markers were increased significantly in the group that underwent conventional coronary artery bypass grafting with cardiopulmonary bypass. The patients who underwent minimally invasive coronary artery bypass grafting had a shorter duration of operation (104 +/- 28 versus 140 +/- 28 minutes; p < 0.01), less blood loss (312 +/- 167 versus 788 +/- 365 mL; p < 0.01), shorter ventilatory support (7.7 +/- 4.1 versus 12.9 +/- 3.4 hours; p < 0.01), and a shorter postoperative hospital stay (4.4 +/- 1.7 versus 7.7 +/- 2.6 days; p < 0.01) than the patients who underwent the conventional procedure. CONCLUSIONS These data suggest that patients who undergo minimally invasive coronary artery bypass grafting have a significant reduction in the systemic inflammatory response, postoperative morbidity, and hospital stay compared with patients who undergo conventional coronary artery bypass grafting with cardiopulmonary bypass.

Effects of Quinapril on Clinical Outcome After Coronary Artery Bypass Grafting (The QUO VADIS Study)

The QUO VADIS study was designed to explore whether 1 year of angiotensin-converting enzyme inhibition with quinapril (40 mg/day) would decrease ischemia in patients who underwent coronary artery bypass grafting (CABG). Patients (n = 149) scheduled for CABG were randomized 4 weeks before surgery. Study medication was used from randomization up to 1 year after CABG. Exercise testing was performed at randomization; the exercise test was repeated 1 year after CABG and patients underwent 48-hour Holter monitoring. Clinical ischemic events were recorded and defined as death, revascularization, myocardial infarction, recurrence of angina pectoris, ischemic stroke, or transient ischemic attack. Baseline characteristics were similar between groups. Total exercise time increased overall by 75 +/- 76 seconds 1 year after CABG (placebo +79 +/- 75 seconds, quinapril +72 +/- 79 seconds, p = 0.6). All patients had ischemic ST-segment changes at randomization; 33% of patients had ischemic ST-segment changes 1 year after CABG (placebo 29%, quinapril 37%, p = 0.4). On Holter monitoring, the number of patients experiencing > or = 1 episodes of ischemia was equal in both groups. Treatment with quinapril significantly reduced clinical ischemic events after CABG: 15% in patients on placebo versus 4% of patients on quinapril (hazard ratio 0.23, 95% confidence interval 0.06 to 0.87, p = 0.02). Long-term quinapril treatment significantly reduced clinical ischemic events within 1 year after CABG, although ischemia at exercise testing and Holter monitoring was unchanged.

A prospective randomized trial comparing stenting with off-pump coronary surgery for high-grade stenosis in the proximal left anterior descending coronary artery: three-year follow-up

OBJECTIVES This study was done to identify the best treatment for an isolated high-grade stenosis of the proximal left anterior descending coronary artery (LAD). BACKGROUND Percutaneous transluminal coronary angioplasty with stenting (PCI) and off-pump coronary artery bypass grafting (surgery) are used to treat single-vessel disease of a high-grade stenosis of the proximal LAD. Midterm results of both treatments are compared in this prospective randomized study. METHODS In a single-center prospective trial, we randomly assigned 102 patients with a high-grade stenosis of the proximal LAD (American College of Cardiology/American Heart Association classification type B2 or C) to PCI (n = 51) or surgery (n = 51). Primary composite end point was freedom from Major Adverse Cardiac and Cerebrovascular Events (MACCE) at follow-up, including death, myocardial infarction, cerebrovascular accident, and repeat target vessel revascularization (TVR). Secondary end points were angina pectoris class and need for antianginal medication at follow-up. Analysis was by intention-to-treat (ITT) and received treatment (RT). RESULTS Mean follow-up time was three years (90% midrange, two to four years). Incidence of MACCE was 23.5% after PCI and 9.8% after surgery; p = 0.07 ITT (24.1% vs. 8.3%; p = 0.04 RT). After surgery a significantly lower angina pectoris class (p = 0.02) and need for antianginal medication (p = 0.01) was found compared to PCI. Target vessel revascularization was 15.7% after PCI and 4.1% after surgery (p = 0.09). CONCLUSIONS At three-year follow-up (range, two to four years), a trend in favor of surgery is observed in regard to MACCE-free survival with a significantly lower angina pectoris status and significantly lower need for antianginal medication.

Video-assisted minimally invasive coronary operations without cardiopulmonary bypass: A multicenter study

OBJECTIVE The need to avoid the risks associated with cardiopulmonary bypass has led to the interest in coronary operations without cardiopulmonary bypass. PATIENTS AND METHODS From April 1994 to September 1995, 44 patients (mean age 63.3 +/- 10.0 years, range 43 to 83 years) were selected for video-assisted coronary artery bypass grafting without cardiopulmonary bypass through a small anterior thoracotomy. Mean preoperative ejection fraction was 50.7% +/- 13.4% (range 20% to 65%). Four patients had left ventricular dysfunction (ejection fraction below 35%). Thirty patients had stable angina (26 with class 3 angina) and 14 had unstable angina. One had recurrent angina (redo). In all cases a small (3.5 to 11 cm) anterior thoracotomy (43 left and one right) was performed and the harvesting of the left internal thoracic artery was video-assisted by thoracoscopy. RESULTS The left internal thoracic artery was used in 43 cases to graft the left anterior descending coronary artery; the right thoracic mammary was used in one case to graft the right coronary artery; the radial artery was used in one case to perform a T-graft to the first diagonal and first marginal branches. We recorded one death (2.3%) and one case of postoperative low cardiac output syndrome (2.3%). Perioperative myocardial infarction occurred in two cases (4.5%). We did not record noncardiac complications (cerebrovascular complications, kidney failure, prolonged ventilatory support, or wound complications). Supraventricular and ventricular arrhythmias were never detected. CONCLUSION According to our experience, video-assisted coronary bypass through a small anterior thoracotomy is a new promising technique that can be considered an alternative in most cases to angioplasty and complementary to conventional coronary operations.

Dual pathway for angiotensin II formation in human internal mammary arteries

1 Angiotensin converting enzyme (ACE) is thought to be the main enzyme to convert antiotensin I to the vasoactive angiotensin II. Recently, in the human heart, it was found that the majority of angiotensin II formation was due to another enzyme, identified as human heart chymase. In the human vasculature however, the predominance of either ACE or non‐ACE conversion of angiotensin I remains unclear. 2 To study the effects of ACE‐ and chymase‐inhibition on angiotensin II formation in human arteries, segments of internal mammary arteries were obtained from 37 patients who underwent coronary bypass surgery. 3 Organ bath experiments showed that 100 μM captopril inhibited slightly the response to angiotensin I (pD2 from 7.09±0.11–6.79±0.10, P<0.001), while 100 μM captopril nearly abolished the response to [pro10] angiotensin I, a selective substrate for ACE, and the maximum contraction was reduced from 83±19%–23±17% of the control response (P=0.01). A significant decrease of the pD2 of angiotensin I similar to captopril was observed in the presence of 50 μM chymostatin (pD2 from 7.36±0.13–6.99±0.15, P<0.039), without influencing the maximum response. In the presence of both inhibitors, effects were much more pronounced than either inhibitor alone, and a 300 times higher dose was needed to yield a significant contraction response to angiotensin I. 4 These results indicate the presence of an ACE and a non‐ACE angiontensin II forming pathway in human internal mammary arteries.

Improved method for direct coronary grafting without CPB via anterolateral small thoracotomy

We describe an improved method of minimally invasive coronary artery bypass grafting that facilitates the anastomosis on the beating heart by means of a rigid and simple coronary stabilizer. This technique permits anastomosis of the left internal mammary artery to the left anterior descending coronary artery through a small (8 to 10 cm) left anterolateral thoracotomy without cardiopulmonary bypass. We successfully used this technique in 20 primary coronary artery bypass grafting operations, without in-hospital mortality or any other cardiac complication.