Ignacio Y. Christlieb

Nifedipine: A myocardial protective agent☆

The effectiveness of the calcium antagonist nifedipine in preserving postischemic myocardial function and structural integrity was experimentally demonstrated in isolated rabbit hearts, in conscious dogs subjected to myocardial infarction, in open chest anesthetized dogs with normothermic regional ischemia induced for 1 to 2 hours and in dogs undergoing hypothermic global ischemia for 2 hours followed by 2 hours of reperfusion. Nifedipine had a beneficial effect on postischemic myocardial stiffness and mitochondrial calcium accumulation, which were correlated. Administration of nifedipine at the onset of myocardial infarction increased blood flow to ischemic zones of myocardial infarction and resulted in less loss of creatine kinase. It reduced by two- to three-fold the volume of the ischemia-reperfusion injury induced by left anterior descending coronary arterial occlusion and release and preserved indexes of hemodynamic function. Nifedipine was found effective in protecting myocardial performance and structure after 2 hours of global ischemia during hypothermic cardiopulmonary bypass. It is suggested that this agent may be useful as an adjunct to cold cardioplegia in man for enhanced myocardial protection during cardiac surgery.

Nifedipine Cardioplegia Experience: Results of a 3-Year Cooperative Clinical Study

Previous animal studies and a preliminary clinical trial of the addition of nifedipine to cardioplegic solution demonstrated salutary effects in terms of postischemic performance. This report examines the combined results of extended clinical trials conducted in two centers: Barnes Hospital, St. Louis, and Allegheny General Hospital, Pittsburgh. From an open-heart population of 4,777 patients, 205 highest-risk persons were selected for study. One hundred seventy of them were given nifedipine in cardioplegic solution. The remaining 35 served as controls to compare with 39 treated patients in the randomized subset of 74. Thirty-eight percent were women; the average age was 61 +/- 1 year; and most were in New York Heart Association Class IV. One-third had valve replacement, one-quarter had coronary artery bypass grafting (CABG), and 37% had valve, CABG, and other procedures in combination. Characteristically, these patients had a 50% increase in end-diastolic volumes, low cardiac indexes (1.7 +/- 1 L/min/m2), and low left ventricular stroke work indexes (22 +/- 2 gm-m/m2). Average cross-clamp time was 77 minutes. At Allegheny, an extracellular hyperkalemic solution was used to deliver an average dose of 407 +/- 22 micrograms per patient. At Barnes, a low-sodium hyperkalemic solution was used; the average dose was 476 +/- 22 micrograms. The results of hemodynamic studies in the randomized subset demonstrated approximately a twofold greater improvement in the treated group in cardiac index, stroke volume, left ventricular stroke work index, and pulmonary vascular resistance immediately after bypass. The incidence of acute low cardiac output death was 4% versus 11% in the nontreated group. The hospital survivorship for all treated patients was 84%. It is concluded that the addition of a calcium antagonist, nifedipine, reduced the incidence of acute global cardiac failure in the immediate postoperative interval.

Myocardial Preservation with Nifedipine: A Comparative Study at Normothermia

Sixty-four dogs were placed on normothermic total cardiopulmonary bypass, and global ischemia was induced for 1 hour during which continuous infusions (240 ml per hour) (N = 39) or bolus injections (150 to 200 ml every 30 minutes) (N = 23) into the proximal aortic root were performed. The control groups (N = 26) had infusion or injection of normal saline solution, normal saline solution + 25 mEq/L of potassium chloride, or Normosol-R pH 7.4. The cardioplegic solution (N = 15) contained 25 mEq/L of potassium chloride in Normosol-R pH 7.4, 0.25 mg/ml of lidocaine, 500 mg/dl of glucose, and 1.8 microU/ml of insulin. The nifedipine group (N = 23) had infusion or injection of 0.167 to 0.2 microgram/ml of nifedipine in saline solution, Normosol-R pH 7.4, or the cardioplegic solution. Left ventricular performance was assessed by phasic and mean measurements of left ventricular peak and end-diastolic pressures and its first derivative, left and right atrial pressures, and ascending aortic blood flow. Calculations of stroke work index and total peripheral resistance were performed. Morphological examinations, and light and electron microscopic examinations of heart slices were done. The results demonstrated a consistent superiority of the nifedipine group in terms of performance after bypass compared with the cardioplegic or control group. Normal preischemic stroke work indices and Sarnoff curves were present 2 hours after bypass for the nifedipine-treated groups. The cardioplegic solution was ineffective when given continuously but gave modest protection when given as a bolus injection. It is concluded that the concept of the efficacy of calcium blockade during ischemia and the initial reperfusion period for enhanced myocardial protection is valid.

Laboratory and initial clinical studies of nifedipine, a calcium antagonist for improved myocardial preservation.

This report summarizes five years of laboratory investigations and the initial six-month clinical experience with a calcium antagonist, nifedipine, added to a cold hyperkalcmic cardio-plcgic solution for enhancement of myocardial protection. Regional ischemia was created in 112 dogs and global ischemia in 98 dogs, under normothermic and two hypothermic states. Control solutions, two clinical cardioplegic solutions, and nifedipine solutions were compared. Infusion of nifedipine during regional ischemia and repcrfusion intervals resulted in a two-to-thrccfold reduction in injury volume and maintenance of normal left ventricular function in contrast to infusion of nitroprusside. Nifedipine solutions (0.2 μ/ml) provided superior preservation of left ventricular function in comparison to the two cardioplegic solutions after one hour of global ischemia at 37 C and two hours at 18 C. In a clinical trial of nifedipine in cold potassium cardioplegia, 38 high risk patients with poor ventricular function have been treated; 22 of which were intensively studied serially with radionuclide ventriculography and pyrophosphate scans, myocardial isoenzyme determinations, 24 hour EKG recordings and intra-and postoperative hemodynamic studies. Of the 35 patients admitted to the intensive care unit (ICU), 33 have survived. Stroke work and cardiac indices return promptly to near normal levels after operation. The time-isoenzyme activity curves are low and radionuclide determined ejection fractions show no change for the study group. Death from acute postischemic cardiac failure did not occur in treated patients and the usage of intra-aortic balloon pump (IABP) has decreased threefold in comparison with 40 similar high risk patients treated concurrently with cardioplegic solution alone. It is concluded that nifedipine is a potent adjunct to cold hyper-kalemic cardioplegic solution in high risk patients.

Fatigue resistant muscle with preserved force and mass for cardiac assist.

Sheep under general anesthesia had their left and right latissimus dorsi muscles mobilized for paraneuroelectrode and pulse generator implantation. After a 10‐day recovery period, the left‐side muscles were stimulated with a gradually increasing duration and rate over 3 months. At 4 months after operation, the tendinous end of each latissimus dorsi muscle was freed from its humeral insertion and attached to a strain gauge force transducer. Both left and right latissimus dorsi muscles, from each animal, were stimulated to contract for 2 hours for the fatigue study before being isolated, trimmed, and weighed. Frozen tissue biopsies were used to determine creatine phosphate, adenosine triphosphate, lactate, and glycogen content and muscle myosine ATPase, and succinate dehydrogenase activities. The arterial diameter in the conditioned muscle was 30% larger than that of the control muscle and had a 40% higher blood flow at rest. A three‐ to fivefold increase in blood flow during the fatigue test was observed. The force decreased 47% for the conditioned muscle and 91% for the control muscle. The mass and cross‐sectional area of conditioned and unconditioned muscles were similar. Electric conditionIng increased fatigue resistant fiber content from 33% to 92%, as evidenced by myosine ATPase activity. During the early phase of the fatigue test, higher glucose uptake but significantly lower lactate production were found for the conditioned muscle. This study indicates that it is possible to produce fatigue resistant muscle with preserved force and mass. In addition to skeletal muscle fiber transformation, metabolic adaptations appear to be important factors for fatigue resistance of skeletal muscle.

A standardized nomenclature for latissimus dorsi cardiomyoplasty.

As worldwide clinical and experimental data accumulate, a standardized nomenclature for latissimus dorsi cardiomyoplasty must be accepted and universally applied in order to increase the potential for meaningful and reproducible comparison of results. This article presents a uniform nomenclature for latissimus dorsi cardiomyoplasty that is precise, anatomic and complete.

Use of nifedipine during cardiac surgery for improved myocardial protection

Abstract The combined results of extended clinical trials conducted in two centers following successful laboratory trials are evaluated. From a population of 4,777 patients who underwent open heart surgery, 205 high-risk patients were selected for study. One hundred seventy patients (3.6 percent) were given nifedipine in cardioplegic solution. The remaining 35 patients served as control subjects and were compared with 39 treated patients in the randomized subset of 74. One third of the patients underwent valve replacement, one quarter underwent coronary artery bypass, and 40 percent underwent combinations of valve replacement, coronary artery bypass, and other procedures. Characteristically, the third group had a 50 percent increase in end-diastolic volumes and low cardiac indexes (1.7 ± 0.1 liters/minute/m 2 ). Average cross-clamp time was 77 minutes. At one center, an extracellular hyperkalemic-type solution was used to deliver an average dose of 407 ± 22 μg nifedipine per patient. At the other center, a low-sodium hyperkalemic solution was used, and the average nifedipine dose was 476 ± 22 μg. Hemodynamic studies in the randomized subset demonstrated approximately a twofold improvement in the treated group in cardiac index, stroke volume, stroke work index, and pulmonary vascular resistance following cardiopulmonary bypass. The incidence of acute low cardiac output death was 4 percent versus 11 percent in the control group. Survival for all treated patients was 86 percent. It is concluded that the addition of nifedipine reduced the incidence of acute global cardiac failure in the immediate postoperative interval.