Earl C. Harrison

Efficacy and safety of medium- and high-dose diltiazem alone and in combination with digoxin for control of heart rate at rest and during exercise in patients with chronic atrial fibrillation.

We evaluated the efficacy and the safety of medium-(240 mn/day) and high-dose (360 mg/day) diltiazem alone and in combination with digoxin when used for control of heart rate in 12 patients with chronic atrial fibrillation. Medium-dose diltiazem was comparable to therapeutic dose of digoxin at rest (88 +/- 19 vs 86 +/- 12 beats/min) but superior during peak exercise (154 +/- 23 vs 170 +/- 20 beats/min; p less than .05). High-dose diltiazem resulted in better control of heart rate than digoxin both at rest (79 +/- 17 beats/min; p less than .05) and exercise (136 +/- 25 beats/min; p less than .05) but was associated with side effects in 75% of the patients. Combined therapy of digoxin and diltiazem enhanced the effect of digoxin alone and resulted in significantly better control of heart rate at rest (67 +/- beats/min with medium-dose and 65 +/- beats/min with high-dose diltiazem) and during peak exercise (132 +/- 32 and 121 +/- 24 beats/min, respectively). However, the difference in heart rate between these two doses was not significant. Reduction of heart rate combined with concomitant effect on blood pressure resulted in a significant fall in pressure-rate product at rest from 10,077 +/- 1708 mm Hg/min on digoxin alone to 7877 +/- 1818 mm Hg/min after the addition of medium-dose diltiazem (p less than .05) and during exercise form 25,670 +/- 3606 to 18,439 +/- 4115 mm Hg/min (p less than .05). Continued therapy with digoxin combined with diltiazem 240 mg/day for 21 +/- 8 days in nine patients showed persistent effect on heart rate and blood pressure without any toxic manifestations or change in serum digoxin (1.5 +/- 0.4 vs 1.3 +/- 0.4 ng/ml) or plasma diltiazem concentrations (204 +/- 72 vs 232 +/- 129 ng/ml). In conclusion, medium-dose diltiazem when combined with digoxin is an effective and safe regimen for the treatment of patients with chronic atrial fibrillation and enhances digoxin-mediated control of heart rate both at rest and during exercise.

Pressure drops across prosthetic aortic heart valves under steady and pulsatile flow—In vitro measurements

Abstract Pressure drops across ten prosthetic aortic heart valves have been measured under both steady and pulsatile flow using two different Newtonian liquids having viscosities of 0.01 and 0.035 dyn sec/cm 2 , respectively. The difference in viscosities of the test fluids seemed to have negligible effect within experimental error on the pressure drops over a range of flow rates from 83 to 500 cm 3 /sec. The correlation coefficients between the pressure drop experiments conducted with the two liquids were at least 0.99. The experimental results and the theory developed (equations 12 and 14) indicate that for a given aortic valve it is possible to predict peak systolic and mean systolic pressure drops from experimental pressure drop data for steady flow in the same channel. Correlation coefficients of at least 0.98 were obtained between the experimental and predicted values.

In vitro velocity measurements in the vicinity of aortic prostheses

Abstract A laser-Doppler anemometer was used for in vitro measurements of velocity profiles in the vicinity of aortic prostheses at steady flow rates of 167 cm 3 /sec to 417 cm 3 /sec. Results showed that at these high flow rates the wall shear stresses were about 1 × 10 3 dyn/cm 2 in the near vicinity of the aortic prostheses studied. Also maximum turbulence-intensity levels of 25–50% were measured, and they decayed to about 15–20% at 120 mm downstream from the valves. The experimentally observed wall-shear stresses were of a magnitude that could damage the endothelial lining of the ascending aorta and the formed elements of blood, at least when they adhere to the wall of the aorta. In the near vicinity of the aortic prostheses, maximum values of bulk-turbulent-shear stresses estimated from turbulence-intensity measurements and simple flow models were in the range of 10 2 –10 3 dyn/cm 2 . Turbulent shears in that range could damage red-blood cells and platelets and lead to thrombus formation. With pulsatile flow, where there is an acceleration phase, the shear stresses would even be larger.

Flow characteristics of four commonly used mechanical heart valves

The in vivo and in vitro fluid dynamic performance of 4 mechanical heart valves was reviewed: Starr-Edwards silicon-rubber ball valves (models 1200/1260 aortic and 6120 mitral valves), Björk-Shiley tilting disc valves (standard spherical model, modified and unmodified convexo-concave [60 degrees and 70 degrees C-C] models), the Medtronic-Hall (Hall-Kaster) tilting disc valve and the St. Jude Medical bileaflet valve. These valves were chosen because of their past or present popularity in clinical use and because they encompass most of the basic mechanical valve designs used during the past 2 decades. The flow measurements reported include in vivo and in vitro mean pressure drop, cardiac output or cardiac index, regurgitant volume, effective orifice area and performance index.

The Pharmacokinetics of Antiarrhythmic Agents in Pregnancy and Lactation

SummaryThe pharmacokinetics of various drugs may be profoundly altered during different stages of pregnancy, parturition, and lactation. Gastrointestinal absorption or bioavailability of drugs may vary due to changes in gastric secretion and motility. Various haemodynamic changes such as an increase in cardiac output, blood volume, and renal plasma flow may affect drug disposition and elimination. The increase in blood volume and total body water which occurs during pregnancy can alter the volume of distribution for various drugs. Although exact quantifications are not easy, these changes in pharmacokinetic parameters should be considered when dosing antiarrhythmic agents in pregnant women.Plasma protein concentrations and drug binding capacity are altered in the mother and fetus as pregnancy advances. With highly protein bound drugs, these changes may be clinically significant, as the pharmacological efficacy and toxicity are presumed to be related to the concentration of free drug in both the mother and fetus. In some instances, the fetus may be susceptible to greater drug toxicity as free drug concentrations may be underestimated by measurement of total drug concentrations.Changes in maternal drug metabolism and metabolism by the fetoplacental unit also contribute to alterations in the pharmacokinetics of drugs. As the placenta contains many metabolising enzymes, biotransformation of drugs at this site could potentially convert a drug into an active metabolite, or prevent fetal exposure to a toxic drug.Placental transfer of drugs, leading to toxicity in the fetus, is a major concern in the pharmacological management of the pregnant patient. The passage of individual drugs will vary depending on their apparent volumes of distribution, degree of protein binding, the rates of metabolic conversion and excretion within the placenta and fetus, the pH difference between the maternal and fetal fluids, and maternal haemodynamic changes. Drug properties such as lipid solubility, protein binding characteristics, and ionisation constant (pKa) also influence the placental passage of drugs. For weakly basic antiarrhythmic agents, the fetal drug concentration may potentially exceed the maternal plasma concentration when the fetal pH is lowered as in the case of fetal acidosis; this is due to ‘ion trapping’. Additionally, higher free drug concentrations of these basic drugs may exist, due to decreased α1acid glycoprotein concentration and binding affinity in the fetus.Lignocaine(lidocaine) has been shown to enter fetal plasma rapidly with fetal-maternal concentration ratios in the range of 0.52 to 0.66. The metabolites, monoethylglycinexylidide and glycinexylidide have been detected in the maternal plasma within 10 minutes and 40 minutes, respectively, after epidural administration. Fetal-maternal concentration ratios for these metabolites range between 0.55 to 1.0. Alterations in protein binding and pH differences between the mother and fetus may thus be clinically important considerations with lignocaine.Increased dose requirements and reduced plasma phenytoin (diphenylhydantoin) concentrations have been reported during the administration of phenytoin. Impaired drug absorption has also been reported, although the data are conflicting. Phenytoin appears to readily cross the placenta, with fetal cord concentrations ranging from 65 to 100% of the maternal concentrations. Decreases in the maternal albumin concentration with advancing pregnancy have been correlated with a progressive increase in the phenytoin free fraction. However, both total and free drug concentrations were found to be lower during late pregnancy than in the non-pregnant state. Increases in phenytoin plasma clearance have also been reported.Quinidine appears to readily cross the placenta with fetal cord-maternal concentration ratios ranging from 0.24 to 1.4. High concentrations of quinidine have also been detected in the amniotic fluid. Procainamide appears to be transferred across the placenta with fetal-maternal concentration ratios reported as high as 1.32. The N-acetyl procainamide metabolite has been detected in the fetal cord with fetal-maternal concentration ratio of 123.Reports of isolated experiences with disopyramide and mexiletine reveal fetal-maternal concentration ratios of 0.39 and 1.0, respectively. Both digitoxin and digoxin appear to be rapidly transferred into the fetus after maternal administration, with fetal-maternal concentration ratios ranging from 0.38 to 1.0.Both amiodarone and desethylamiodarone have been detected in fetal cord blood. Fetal-maternal drug concentration ratios for amiodarone range from 0.095 to 0.145, while one neonatal-maternal concentration ratio was 0.26. The fetal-maternal concentration ratios for desethylamiodarone ranged from 0.17 to 0.285. Both amiodarone and desethylamiodarone were detected in the amniotic fluid, and high concentrations of desethylamiodarone were detected in the amniotic fluid, and high concentrations of desethylamiodarone were found in the placental tissue.Experience with verapamil in pregnancy is quite limited, but the drug appears to cross the placental membrane with fetal-maternal concentration ratios of 0.17 and 0.26 at 49 minutes and 109 minutes, respectively, after a single oral dose.The β-adrenoceptor blockers reviewed, propranolol, metoprolol, atenolol, and acebutolol all appear to transfer across the placenta, showing fetal-maternal concentration ratios in the range of 0.88 to 1.27. The protein binding of propranolol and alprenolol, but not metoprolol, were reduced during pregnancy. Increased plasma clearance, decreased bioavailability, and an increase in total urinary metabolites are reported with metoprolol during pregnancy.Protein binding, lipid solubility, and ionisation characteristics of the antiarrhythmic agents similarly influence partitioning of these drugs into breast milk during lactation. The pH difference between the maternal plasma and milk may also allow for accumulation of weakly basic agents into breast milk. Although data are limited, attempts have been made to estimate breast milk-maternal plasma concentration ratios with equations that include these physiochemical properties. However, better clinical data supporting the use of the equations to predict milk-maternal concentration ratios are still needed. Several of the antiarrhythmic agents reviewed show that many of these agents show wide variation in the milk-plasma concentration ratios.The clinical impact of antiarrhythmic drug partitioning to the fetus and into breast milk remains to be established. More rigorous studies with appropriate body fluid sampling and pharmacokinetic modelling would provide necessary data to help clinicians establish safe and effective antiarrhythmic dosage regimens in the pregnant and lactating patient.

Mitral valve aneurysm: Clinical features, echocardiographic-pathologic correlations

Aneurysm of the mitral valve occurs most commonly in association with infective endocarditis of the aortic valve. The probable mechanism of its formation is destruction of the aortic valve which results in a regurgitant jet that strikes the anterior leaflet of the mitral valve, creating a secondary site of infection leading to the development of an aneurysm. Perforation of these aneurysms may occur, resulting in mitral regurgitation and pulmonary edema from a ventricle already volume overloaded from aortic regurgitation. This report describes the clinical and echocardiographic-pathologic findings in five patients with pathologically proven aneurysm of the mitral valve. There are no clinical features that appear specific for this abnormality. The two-dimensional echocardiographic feature that is helpful in the diagnosis is a bulge of the mitral valve leaflet toward the left atrium that persists throughout the cardiac cycle. Preoperative diagnosis is important because a mitral valve aneurysm may produce serious complications and is frequently overlooked during surgery. Repair of the aneurysm may be feasible; otherwise, valve replacement becomes necessary. Careful two-dimensional echocardiographic examination should be done in patients with left-sided infective endocarditis to detect an aneurysm of the mitral valve.

Regurgitation of prosthetic heart valves: Dependence on heart rate and cardiac output

Prosthetic heart valves exhibit closure and leakage backflow; however, no well-controlled study to evaluate the influence of factors such as cardiac output and heart rate on backflow has been reported to date. Four clinically used prosthetic aortic valves (size 27 mm)--St. Jude Medical, Björk-Shiley Spherical Disc, Björk-Shiley Convexo Concave, and Starr-Edwards model 1260--were studied in the aortic chamber of a pulse duplication system at heart rates of 50, 80, 110, and 140 beats/min, cardiac output of 2, 4, 6, and 8 liters/min, and mean aortic pressure of 100 mm Hg. Regurgitation was calculated in percentage and found to vary directly with heart rate and inversely with cardiac output. The range of values obtained were 5.5% for the Starr-Edwards model 1260 valve at 110 beats/min and 8 liters/min, to 37.5% for the Björk-Shiley Convexo Concave valve at 140 beats/min and 2 liters/min. Regurgitation was also calculated in milliliters/stroke and ranged from 3.4 ml/stroke for the Starr-Edwards model 1260 valve at 140 beats/min and 2 liters/min, to 17.3 ml/stroke for the Björk-Shiley spherical disc valve at 50 beats/min and 2 liters/min. Regurgitation associated with prosthetic heart valves may present a problem clinically, particularly under conditions of low cardiac output and tachycardia.

In vitro flow dynamics of four prosthetic aortic valves: a comparative analysis.

The velocity fields downstream of four prosthetic heart valves were mapped in vitro over the entire cross-section of a model aortic root using laser Doppler anemometry. THe Björk-Shiley 60 degrees convexo-concave tilting disc valve, the Smeloff-Cutter caged ball valve, the St. Jude Medical bileaflet valve, and the Ionescu-Shiley standard bioprosthesis were examined under both steady and pulsatile flows. Velocity profiles under steady flow conditions were a good approximation for pulsatile profiles only during midsystole. The pulsatile flow characteristics of the four valves showed variation in large scale flow structures. Comparison of the valves according to pressure drop, shear stress and maximum velocities are also provided.

Sequential left ventricular function studies before and after pericardiectomy for constrictive pericarditis: Delayed resolution of residual restriction

Abstract A patient with constrictive pericarditis was studied 5 days before and 50 days and 13 months after extensive pericardiectomy. Functional data were derived from measurement of intracardiac pressure and left ventricular volume. Before operation the left ventricle was characterized by both systolic and diastolic unloading due to volume restriction. Complete anterior and lateral decortication was accompanied by minimal early clinical improvement. Catheterization studies reflected persistent severe biventricular restriction. A year after operation, marked clinical improvement was accompanied by studies revealing resolution of the restrictive elements.

Cholelithiasis: A frequent complication of artificial heart valve replacement

The results of this investigation reveal that 39 per cent of patients in a study group of 46 patients with heart valve prostheses had gallstones if they survived 18 months or longer following valve replacement. In contrast, the prevalence of gallstones in a general population of autopsied rheumatic heart disease patients, including those who had been operated for severe valvular heart disease and had not survived for more than one month, was only 12 per cent. These findings suggest that gallstones are a frequent late complication of heart valve replacement.