Acute coronary occlusion: prolonged increase in collateral flow following brief administration of nitroglycerin and methoxamine.

Regional coronary blood flow was determined with the radioactive microsphere technique 10 an 70 minutes and 2 1/2 and 5 hours after abrupt occlusion of the left anterior descending coronary artery in 12 closed chest sedated dogs. In six dogs, nitroglycerin, 200 to 400 microng/min, was infused intravenously 10 to 70 minutes after occlusion. Methoxamine was administered to return blood pressure and heart rate to prenitroglycerin levels. Ten minutes after occlusion (before treatment) collateral flow values and ischemic zone endocardial/epicardial flow ratios were equivalent in untreated (0.11+/-0.03 ml/min per g; 0.31+/-0.05) and treated dogs (0.14+/-0.02 ml/min per g; 0.29+/-0.03). In untreated dogs, collateral flow did not change over 5 hours; the endocardial/epicardial flow ratio was decreased at 5 hours (0.21+/-0.05, P less than 0.05). In contrast, in treated dogs, collateral flow and the endocardial/epicardial flow ratio were increased at 70 minutes (0.27+/-0.04 ml/min per g, P less than 0.05; 0.53+/-0.10, P less than 0.05). Most importantly, collateral flow remained elevated 5 hours after occlusion (0.26+/-0.03 ml/min per g, P less than 0.05) although treatment was discontinued 70 minutes after occlusion. Hence, collateral flow was unchanged over 5 hours of occlusion in untreated dogs, but short-term treatment with nitroglycerin and methoxamine resulted in a sustained increase in collateral flow. These findings may be a result of stimulation by nitroglycerin and methoxamine of the spontaneous rate at which intrinsic collateral function increases after ischemia. Alternatively, nitroglycerin and methoxamine may maintain cell viability until collateral vessels develop spontaneously.     

Recent studies on the chemistry of human, bovine and porcine parathyroid hormones

The amino acid sequence of the NH₂-terminal 34 residues of human parathyroid hormone (PTH) has been determined and duplicated synthetically to produce a peptide that is biologically active. In the amino acid sequences of the bovine and porcine hormones, the glutamic acid function at position 22 has been revised to glutamine. Among these initial 34 residues, human PTH differs from bovine PTH by 5 residues and from porcine PTH by 4 residues. Native human PTH and the synthetic human PTH (1–34) peptide are not rigid structures, and significant changes in conformation were observed during pH titration. In addition, at physiologic pH, native human PTH appeared to differ in structure from human PTH (1–34) in the region of the tryptophan residue (residue 23). The fluorescence spectrum of human PTH revealed a maximum at 344 nm, but the spectrum of human PTH (1–34) had a peak at 343 nm; the spectrum of human PTH (1–34) was normalized to 346 nm in 6 M guanidine hydrochloride, but there was no shift with the intact hormone. Fluorescence titration of human PTH in the alkaline region revealed no loss of tryptophanyl fluorescence in aqueous solution or in 6 M guanidine hydrochloride. The synthetic human PTH (1–34) peptide, however, showed an approximately 25 per cent loss of indole fluorescence during alkaline titration which could be normalized with denaturing reagents. These studies suggest that synthetic fragments of the native hormone may not have the same tertiary conformation as the same sequence in the intact hormone. These findings may be of major significance with regard to the biologic activity and immunologic cross reactivity of synthetic fragments and the native hormone.     

Topographic changes in the left ventricle after experimentally induced myocardial infarction in the rat

The factors that determine the thickness of transmural myocardial infarcts are unknown. Therefore, the relation between the size and thickness of transmural infarcts in 67 rats 21 days after occlusion of the left main coronary artery was studied. On examination of histologic sections, infarct size was determined by planimetry and expressed as a percentage of the left ventricular (LV) area, and thickness was expressed as a percentage of noninfarcted ventricular septal wall thickness. The circumferential length of the infarcted ventricle was measured in millimeters, as well as the circumferential length of the noninfarcted ventricular septum. Septal wall thickness was similar in rats with transmural infarcts and in sham-operated rats. No significant correlation was observed between infarct size and thickness (r = 0.10) or between circumferential length of the infarct and infarct thickness (r = 0.17). However, large (greater than or equal to 20% of the left ventricle, n = 37) and small (less than 20% of the left ventricle, n = 30) infarcts which were similarly thin (37 +/- 1% and 34 +/- 2% of septal wall thickness, respectively) affected LV topography differently. Large infarcts resulted in a 23% greater loss of myocardium (p less than 0.001), greater expansion of the LV cavity (18 +/- 9 mm2 compared with 14 +/- 1 mm2 in small infarcts, p less than 0.005), and lengthening of the septal wall (7.2 +/- 1.1 mm and 6.7 +/- 1.0 mm in large and small infarcts, respectively [p less than 0.05], and 6.3 +/- 0.1 mm in shams). Increase in cavity area and septal length in infarcted ventricles suggested a volume overload hypertrophy, which at 3 weeks was nonetheless inadequate to provide as much normal muscle as was present in sham-operated rats. In an additional 9 rats with subendocardial infarctions (involving less than 75% of the LV wall from endocardium to epicardium), the LV walls were thicker (94 +/- 5% of septal wall thickness, compared with 35 +/- 1% for transmural infarcts, p less than 0.001) and an inverse correlation was observed between infarct size and thickness. In conclusion, neither the size of a transmural infarct in rat nor the circumferential length of infarction determines the thickness of the infarct; however, infarct size does affect LV topography by increasing LV cavity area and the length of the noninfarcted septal wall. Subendocardial infarcts result in less myocardial thinning than do transmural infarcts.     

Sequential chemotherapy and late intensification for malignant lymphomas of aggressive histologic type

Fifty-six patients with malignant lymphoma of aggressive histologic type (51 large cell, three diffuse undifferentiated, and two nodular mixed) were treated with three non-cross-resistant combination chemotherapy regimens that were introduced sequentially according to the response to therapy. The objective was to increase the complete remission rate by changing the chemotherapy regimen early if the patient did not attain a complete remission after three courses of treatment. Late intensification was also used with the aim of prolonging the duration of complete remission. The overall complete remission rate obtained with this approach was 82 percent (100 percent in stages I to III and 66 percent in stage IV). The projected survival at four years is 71 percent (93 percent for stages I to III and 55 percent for stage IV). Eighty percent of patients with complete remission are projected to have continued remission at four years. Compared with previous experience with Adriamycin-based combination regimens, these results represent an improvement in remission and survival parameters. The most significant gains occurred in the prolongation of survival of patients with stages I to III disease and in the improved duration of complete remission of patients with stage IV disease. Toxicity included 15 documented infections among 320 courses of therapy, four cases of congestive heart failure, one case of bleomycin lung toxicity, and two cases of liver dysfunction. This multiple combination regimen represents an improvement over previous results utilizing Adriamycin-based combination chemotherapy.     

Symptomatic, electrocardiographic, metabolic, and hemodynamic alterations during pacing-induced myocardial ischemia

Atrial pacing has been used to assess the physiologic impact of coronary artery disease (CAD). Several variables have served as markers of pacing-induced myocardial ischemia, but their specificities and sensitivities are unknown. Accordingly, in 28 patients, incremental atrial pacing was performed. Of the 28, 10 had no CAD. The left ventricular ejection fraction (LVEF) (by gated equilibrium blood pool scintigraphy) increased in this group (0.60 ± 0.11 [mean ± standard deviation] before pacing to 0.67 ± 0.13 at peak-pacing, p = 0.002). In no patient did left ventricular end-diastolic pressure increase by > 5 mm Hg. No patient had lactate production, and 2 (20%) had electrocardiographic S-T segment depression ≥0.1 mV. Four (40%) had chest pain with atrial pacing. In the remaining 18 patients with CAD, atrial pacing caused a decrease in LVEF ≥0.05 (0.46 ± 0.10 to 0.33 ± 0.09, p < 0.001) and new segmental wall motion abnormalities in all, indicating pacing-induced myocardial ischemia. Only 8 (44%) had an increase in left ventricular end-diastolic pressure of > 5 mm Hg, and only 9 (50%) had lactate production. Ten (56%) had ischemic electrocardiographic changes, and 12 (67%) had chest pain. Thus, the electrocardiographic, metabolic, and hemodynamic alterations that may accompany pacing-induced ischemia are specific but relatively insensitive markers of ischemia. In contrast, chest pain during atrial pacing is a nonspecific occurrence, appearing with similar frequency in normal subjects and patients with CAD and pacing-induced ischemia.     

Nitroglycerin-induced improvement in exercise tolerance and hemodynamics in patients with chronic rheumatic heart valve disease.

Nitroglycerin reduces elevated left ventricular filling and pulmonary arterial pressures in resting patients with rheumatic valve disease and reduces symptoms when given over long periods to patients with primary myocardial disease. To determine whether nitroglycerin may prove effective therapeutically in ambulatory patients with heart valve disease, its effects on hemodynamics and exercise capacity were studied in 11 severely symptomatic adults who were already receiving optimal treatment with digitalis and diuretic agents. Seven had predominant mitral valve disease, one had predominant aortic insufficiency and three had equally severe mitral and aortic valve disease. Maximal exercise capacity was assessed with graded treadmill exercise after placebo and after nitroglycerin (0.5 mg sublingually) administered in random sequence to each patient. Exercise capacity (exercise time to limiting fatigue or dyspnea) increased from a mean of 8.3 minutes after placebo to 9.8 minutes after nitroglycerin (P less than 0.005). Eight patients were studied hemodynamically during further intense treadmill exercise. Pulmonary arterial pressure was significantly lower (P less than 0.05) after nitroglycerin than after placebo (mean 44 versus 56 mm Hg), but cardiac output was greater after nitroglycerin (5.0 versus 4.6 liters/min, P less than 0.005). Thus, nitroglycerin appears to increase exericse tolerance and improve the hemodynamic response to exercise in patients with heart valve disease and may be valuable in the long-term pharmacologic therapy of such patients.     

Value of radionuclide ventriculography in the immediate characterization of patients with acute myocardial infarction

The ability of admission radionuclide ventriculography to discriminate among various clinical subsets was evaluated in patients with acute myocardial infarction. One hundred patients with acute myocardial infarction were evaluated within 8 ± 3.1 hours (mean ± standard deviation) after the onset of chest pain. Forty-one patients were in Killip functional class I, 52 in class II and 7 in class III. The mean radionuclide left ventricular ejection fraction was significantly lower in patients with higher Killip classification because of significant elevation of mean left ventricular end-systolic volume rather than significantly altered mean end-diastolic volume. Killip classification frequently failed to correlate with ejection fraction in individual cases. Admission chest X-ray findings were categorized according to the presence of findings suggestive of impaired left ventricular function. Mean left ventricular ejection fraction was significantly lower in patients with abnormal than in patients with normal chest X-ray findings because of significant elevations in both mean end-diastolic and end-systolic volumes. The chest X-ray findings frequently failed to correlate with ejection fraction in individual cases.Stepwise linear regression analysis was employed to analyze the ability of historical, physical, electrocardiographic and chest X-ray findings to predict radionuclide left ventricular ejection fraction. The most predictive variables in order of decreasing significance were anterior myocardial infarction, abnormal chest X-ray findings, rales to two thirds of the posterior thorax, previous myocardial infarction, transmural myocardial infarction and heart rate greater than 100 beats/min. However, even these six optimal predictive variables could explain only 42 percent of the observed variability in left ventricular ejection fraction. Thus, early radionuclide ventriculography adds significantly to the discriminant power of clinical and radiographic characterization of ventricular function in patients with acute myocardial infarction.     

Mortality Probability Model (MPM II0–72) bei Patienten einer kardiologischen Intensivstation

Zusammenfassung Fragestellung Die Diskriminierungsf?higkeit bezüglich überleben und Versterben sowie die Kalibrierung der Mortalit?tsprognose durch das Mortality Probability Model (MPM II) sollte in dieser prospektiven Studie bei Patienten einer kardiologischen Intensivstation evaluiert werden. Methode Alle konsekutiven Patienten der kardiologischen Intensivstation mit einer Liegedauer >12 Stunden wurden zwischen 12/97 und 2/98 in diese prospektive Studie eingeschlossen (Ausschluss: Wiederaufnahmen). MPM II wurde bei Aufnahme (MPM II₀), nach 24 (MPM II₂₄), 48 (MPM II₄₈) und 72 Stunden (MPM II₇₂) erhoben. SAPS II wurde nach 24 Stunden bestimmt. Die Wahrscheinlichkeit der Krankenhausmortalit?t (Pr) für die jeweiligen Modelle wurde berechnet. Die Fl?che unter der Receiver Operating Characteristic (AUC) Kurve diente zur Analyse der Diskriminierungsf?higkeit. Die Kalibrierung der Modelle wurden anhand der standardisierten Mortalit?tsratio (SMR) und dem Goodness of fit (GOF) Test untersucht. Ergebnisse 303 Patienten (62,4±12,6 Jahre, 71,3% M?nner) wurden eingeschlossen. Die Intensivmortalit?t betrug 8,3%, die Krankenhausmortalit?t 14,5%. Die mittlere Liegedauer auf der Intensivstation lag bei 3,7 Tage (1–36 Tage), die mittlere Krankenhausliegedauer bei 15,2 Tage (1–79). Pr war in beiden Modellen für nicht überlebende Patienten signifikant h?her. AUC (±SD): SAPS II 0,77±0,05, MPM II₀ 0,77±0,04, MPM II₂₄ 0,72±0,05, MPM II₄₈ 0,85±0,05 und MPM II₇₂ 0,78±0,06. Die SMR für SAPS II betrug 1,25 (0,91–1,69), für MPM II₀ 1,37 (0,99–1,84), MPM II₂₄ 1,32 (0,89–1,87), MPM II₄₈ 1,07 (0,69–1,58) und für MPM II₇₂ 1,19 (0,74–1,82). Der GOF-C-Test zeigte einen signifikanten Unterschied zwischen vorhergesagter und beobachteter Mortalit?t für den MPM II₀ (χ²=39,44 [p<0,001, df=9]), der GOF H Test für den MPM II₇₂ (χ²=15,35 [p=0,01, df=6]). Diagnose- und Alterskategorien sowie Aufnahmemodus wiesen ebenfalls variable SMRs auf. Schlussfolgerung Die Mortalit?tsvorhersage durch das MPM-II-Modell war zufriedenstellend. Die SMR zeigte jedoch eine statistisch nicht signifikante Untersch?tzung der Mortalit?t. Die Abweichung der vorhergesagten von der beobachteten Mortalit?t trat v.a. in den h?heren Risikostrata auf. Eine unterschiedliche Patientenselektion („case mix”) und divergente Vorbehandlungen der Patienten („lead time”) beeinflussen die Performance von MPM II_0–72. Daher scheint eine Anpassung des Vorhersagemodells an die Zielpopulation („customization”) erforderlich zu sein. Eingegangen: 12. M?rz 2001 Akzeptiert: 5. April 2001     

Verapamil therapy: A new approach to the pharmacologic treatment of hypertrophic cardiomyopathy: III. Effects of long-term administration

To determine the efficacy of long-term therapy with verapamil in patients with hypertrophic cardiomyopathy, 78 patients began treatment with the drug in the hospital. Sixty-two patients (79 percent) were in New York Heart Association functional class III or IV despite treatment with beta receptor blocking drugs. Fifty-four percent of all patients evaluated (42 of 78) and 63 percent of those discharged from the hospital (42 of 68) experienced sustained symptomatic improvement 6 to 30 months (median 14 months) after initiation of verapamil therapy. Of these 42 patients in improved condition, 25 had improvement by at least one New York Heart Association functional class, 14 improved by less than one functional class, two felt better taking verapamil than propranolol, and in one patient verapamil controlled asymptomatic ventricular tachycardia. Of the 53 patients who had the obstructive form of the disorder and were considered operative candidates, 25 (47 percent) experienced sufficient improvement so as to forgo operation. In patients remaining on verapamil therapy, the duration of treadmill exercise performed 5 days after the start of verapamil therapy increased by 3.1 ± 0.6 minutes (53 ± 10 percent, p < 0.001) from the value obtained with no medication before verapamil. A further increase of 2.3 ± 0.6 minutes (25 ± 7 percent, p < 0.0025) over the initial value with verapamil was recorded on the patients' last vistt (median 12 months after the start of therapy). Echocardiographic measurements of wall thicknesses and left atrial dimension demonstrated no significant changes during 1 year of verapamil treatment in 31 patients. Administration of verapamil was associated with adverse hemodynamic effects in 9 patients (12 percent) and adverse electrophysiologic effects In 10 (13 percent): Three patients died (with pulmonary edema) and 6 had to have treatment terminated. These results indicate an important role for long-term verapamil therapy in the treatment of hypertrophic cardiomyopathy, but patients must be carefully selected and followed up closely for the development of important adverse hemodynamic or electrophysiologic effects.