The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension.

In a retrospective study, we tested the hypothesis that anticoagulant therapy with warfarin sodium (Coumadin) has a beneficial influence on the long-term prognosis in patients with primary pulmonary hypertension (PPH) and aminorex-induced plexogenic pulmonary hypertension. The study included a total of 173 patients from two European cities. One hundred four of these patients took the anorectic drug aminorex (Menocil), which was available in some European countries almost 30 years ago; 69 patients had pulmonary hypertension of unexplained etiology, ie, PPH. Fifty-six of the 104 aminorex-treated patients and 24 patients in the PPH group received warfarin after diagnosis was established. For analysis, patients were divided into four groups according to their history of aminorex intake and anticoagulant therapy. Survival time, changes in hemodynamics (pulmonary arterial pressure), and improvement in quality of life (scored by the New York Heart Association [NYHA] classification) were compared and analyzed. We found that aminorex-treated patients had a better long-term prognosis than those with PPH (7.5 vs 3.9 years; p < or = 0.001). The best mean survival time of 8.3 years was found in anticoagulated aminorex-treated patients, compared to 6.1 years in nonanticoagulated aminorex-treated patients. Moreover, aminorex-treated patients who received anticoagulant therapy soon after the onset of symptoms showed significantly better prognosis (10.9 years) than those who commenced treatment 2 years thereafter (5.9 years) (p < or = 0.05). In patients with PPH, systolic pulmonary pressure was shown to influence survival time significantly (p < or = 0.0005); however, this correlation was not found in aminorex-treated patients. An improvement of symptoms like dyspnea on exertion was seen in 44.8% of the anticoagulated aminorex-treated patients, while deterioration was evident in 72.2% of the nonanticoagulated aminorex-treated patients. In conclusion, our study has shown that anticoagulant therapy had a positive influence on long-term survival and a significant improvement in quality of life in patients with PPH, in particular in patients with a history of anorectic drug intake.

[Aminorex-induced, plexogenic pulmonary arteriopathy: 25 years later!]. / Aminorex-induzierte, plexogene pulmonale Arteriopathie: 25 Jahre danach!

The purpose of this study was to examine the influence of treatment on long-term prognosis of patients with aminorex-induced plexogenic pulmonary hypertension. The study included 104 patients (13 males, 91 females) with an aminorex (menocil) intake between 1966 and 1968. All patients were treated with digitalis and diuretics, 52% received an anticoagulant medication with warfarin after pulmonary hypertension was diagnosed. During follow-up, a second right-heart catheterization was performed in 37 patients with a mean interval of 5 years. The longest mean survival time, 8.3 years, was found in patients treated with anticoagulant medication, compared to the 6.1 years found in the non-anticoagulated aminorex patients. Also, in the 5- and 10-years survival rate, patients with an anticoagulant therapy have shown better results (62.9 vs. 38% and 39 vs. 20%, respectively). Patients who received anticoagulant therapy soon after the onset of symptoms showed a better mean survival (10.9 years) than those who commenced treatment more than 1 year thereafter (mean survival 5.9 years). In 57% of the patients who had a second right-heart catheterization a decrease of pulmonary pressures could be diagnosed. Two-thirds of these patients with pulmonary pressure decrease were under anticoagulant therapy. An improvement in the NYHA-classification was seen in 44.8% of the patients treated with warfarin, in comparison to 22.2% of those who did not receive anticoagulant therapy. Although this study is retrospective, it shows a positive influence of anticoagulant therapy on survival in patients with a history of anorectic drug intake.

Limitations to VO2max in humans after blood retransfusion.

Seven young, healthy male subjects performed maximal exercise on a cycloergometer with central venous and arterial catheters, before and after autologous retransfusion of red blood cells. Maximal oxygen consumption (VO2max), blood gas composition and haemodynamic variables were measured, in order to test the hypothesis of monofactorial vs. polyfactorial VO2max limitation. Autologous blood retransfusion led to significant increases in haemoglobin concentration and consequently arterial oxygen concentration during maximal exercise, while maximal cardiac output, heart rate and stroke volume were not significantly changed. The relationship between maximal oxygen delivery (cardiac output.arterial oxygen concentration; (Q.CaO2)max and maximal oxygen consumption in this study was VO2max (L.min-1) = 0.02 + 0.64.(Q.CaO2)max (L.min-1), the slope being significantly less than unity. These results suggest that (Q.CaO2)max plays but a fractional role in limiting VO2max, in agreement with recent models concerning the resistance to oxygen flow in the respiratory system (di Prampero and Ferretti, Respir. Physiol. 80: 113-128, 1990). The relative increase in VO2max after blood retransfusion matched the relative increase in 'aerobic performance', measured as the maximal power output that could be maintained aerobically for 30 min. Furthermore, the increase in maximal power output (15 +/- 3 watts) could account for almost all of the extra oxygen consumption. This match suggests that there is an inability to fully utilize muscle oxidative capacity in the normocythaemic state.

Left ventricular structure and determinants in normotensive offspring of essential hypertensive parents.

OBJECTIVE: To assess whether currently normotensive offspring of essential hypertensive parents may have alterations in left ventricular mass (LVM) and function, and how these relate to some potential determinants. DESIGN AND METHODS: Echocardiographical indices of LVM (assessed by two-dimensional guided M-mode echocardiogram), 'clinic' blood pressure and daytime ambulatory blood pressure profiles, blood pressure responses to dynamic and isometric exercise testing, haematocrit, plasma and 24-h urinary electrolytes and catecholamines, and plasma angiotensin II were assessed on a defined Na+ intake in 31 normotensive lean sons of essential hypertensive parents (OHYP group) and 30 body mass index- and age-matched sons of normotensive parents (ONORM group). RESULTS: Clinic supine systolic blood pressure was higher in the OHYP than the ONORM group, but clinic diastolic and daytime ambulatory mean blood pressures, blood pressure loads and blood pressure during dynamic or isometric exercise did not differ significantly. LVM index (LVMI), interventricular septum thickness (IVST), posterior wall thickness (PWT), the IVST:PWT ratio, ejection fraction, fractional shortening, cardiac index and measured biochemical variables also did not differ significantly between groups. In the whole study population the LVMI correlated positively with the body mass index and negatively with plasma noradrenaline. CONCLUSIONS: In young lean men with one essential hypertensive parent and blood pressure still in the normal range, left ventricular structure and systolic function, as assessed by echocardiography, seem to be often unaltered and appropriate relative to the existing body habitus and blood pressure. Moreover, an early tendency for increasing resting blood pressure in genetically hypertension-prone humans may be more apparent under clinic than usual ambulatory conditions, whereas the blood pressure reactivity to physical stress seems to be largely normal at this stage.

[Cardiac complications of American trypanosomiasis (Chagas disease). Various case reports and general observations]. / Kardiale Komplikationen der amerikanischen Trypanosomiasis (Chagas-Krankheit). Eigene Fälle und allgemeine Bemerkungen.

Three young female patients with heart problems and positive serologic tests or characteristic histologic lesions for Chagas' disease (American trypanosomiasis) are reported, one of them having presented with acute anterior myocardial infarction with only minor coronary lesions. The most prominent features of the disease are discussed with emphasis on late cardiac complications. Chagas' cardiomyopathy is the leading cause of sudden death in Latin America, where an estimated 10 to 12 million people are infected in endemic areas from southern Mexico to southern Argentina. It has also been termed "emboligenic cardiomyopathy" since arterial embolism is a very frequent complication. Embolic obstruction of a coronary artery may therefore well be the most probable cause of myocardial infarction in young people with Chagas' disease, although other mechanisms cannot be excluded.

Conversion of induced ventricular tachycardia by single and serial chest thumps: a study in domestic pigs 1 week after experimental myocardial infarction.

A single chest thump (CT) is widely accepted in the emergency treatment of ventricular asystole, whereas there exists controversy about this method for the interruption of ventricular tachycardia (VT). Hitherto, delivering serial chest thumps (SCTs) has been described only once for the treatment of VT. A systematic analysis for interruption of VT by CT or SCTs (or both) is lacking. We have therefore investigated this subject in five domestic pigs after experimental myocardial infarction. Manual conversion was attempted in 20 induced VTs. Six VTs were converted by CT, seven VTs were converted by the first SCTs, and six VTs were converted by the last of multiple (two to seven) SCTs. The overall success was 95%. There were no serious complications. The rate of successful SCTs exceeded the rate of VT by 10% to 126%. The technique of SCTs, the mechanisms of manual conversion, and the controversial opinions regarding the value of precordial thumping in asystole, VT, and ventricular fibrillation are discussed. SCTs should be practiced only very cautiously in patients until further experience is available.

Increased peripheral vasoconstrictor reaction upon local cold in patients with coronary heart disease.

A local cold exposure test of the nailfold capillaries produces a typical flow stop reaction in 88% of patients with Raynaud's phenomenon. We applied this test to 12 patients with variant angina and compared the results with the findings in 2 control groups of 12 patients each, matched for age and sex: One group with chronic stable angina and one without heart disease. We found a flow stop with cold exposure in 9/12 patients with variant angina (mean duration 24 s), in 6/12 patients with chronic angina (mean 11 s), and in 1/12 normal controls without heart disease (mean 1 s). The frequency and duration of the flow stop was significantly higher in patients with variant angina (p = 0.002) and in patients with chronic stable angina (p = 0.02) than in normal controls. Patients with variant angina also tended to have an increased frequency and longer duration of the flow stop than those with chronic stable angina (p = 0.09). Administration of sorbidilate preparations and nifedipine resulted in a decrease of the mean flow stop duration from 23.5 to 10.8 s in patients with variant angina (p = 0.03). The strong association of a vasoconstrictive reaction in finger microcirculation and coronaries in patients with variant angina suggests a vasospastic tendency with manifestation in different vascular regions.

Comparative diagnostic value of a new computerized vectorcardiographic method (cardiogoniometry) and other noninvasive tests in medically treated patients with chest pain.

The diagnostic value of cardiogoniometry (CGM), a new computerized vectorcardiographic method, for the identification of coronary artery disease was compared with other noninvasive tests in 48 medically treated patients with chest pain. Coronary angiography revealed one-vessel disease in 18, two- or three-vessel disease in 21, and normal coronary arteries in 9 patients. Cardiogoniometry was less sensitive (63%) than thallium-201 (201T1) scanning (82%), but slightly more sensitive than the exercise ECG (50%) or a recently proposed parameter of exercise performance (50%). On the other hand, specificity was comparable among these tests (exercise ECG 78%, thallium-201 scanning 72%, CGM 67%, new parameter of exercise performance 66%). Moreover, the false negative rate of noninvasive testing was reduced from 8 to 3% when CGM was added to thallium-201 scanning and exercise ECG. Our findings indicate that in view of the easier feasibility with computerized technology, the future role of vectorcardiographic methods such as CGM in the noninvasive diagnosis of coronary artery disease should be redefined.

Effects of pindolol therapy on the size of experimentally induced myocardial infarction in the pig.

The effect of pindolol on experimental myocardial infarction was studied in a pig model. Intravenous application of 0.05 mg pindolol per kg body weight was initiated one hour after coronary ligation and repeated at 12-hour intervals for five days. No significant difference in infarct size could be found between pindolol-treated animals (20.4 +/- 0.6% SEM of whole ventricular mass, n = 6) and untreated controls (20.5 +/- 1.2% SEM, n = 9). Hemodynamic data did not change significantly throughout the experiment. These results differ in part from those reported by other investigators: The disagreement may be due to the specific pharmacological properties of the applied drug, to variations in the dosages of beta blockers, as well as to differences in the study design.

Polymorphic debrisoquine and mephenytoin hydroxylation in patients with pulmonary hypertension of vascular origin after aminorex fumarate.

During the period 1967 to 1971 an increase in the incidence of pulmonary hypertension of vascular origin (PHVO) was observed in Austria, Federal Republic of Germany, and Switzerland. Most patients had been given aminorex fumarate and a possible link was suspected. We therefore investigated the possibility of genetically-determined drug hydroxylation deficiencies (debrisoquine or mephenytoin type) in these patients as an explanation for the development of PHVO. Seventeen patients took 10 mg debrisoquine and 100 mg mephenytoin orally. Sixteen PHVO patients were classified as extensive metabolizers of debrisoquine with logarithmic metabolic ratios of -0.35 +/- 0.11 (mean +/- SEM), whereas one patient was a poor metabolizer with a logarithmic metabolic ratio of 1.82. For the mephenytoin hydroxylation sixteen patients with PHVO were extensive metabolizers, with logarithmic hydroxylation indices of 0.27 +/- 0.05. One poor metabolizer of mephenytoin had a logarithmic hydroxylation index of 1.59. Deficient hydroxylation of debrisoquine and mephenytoin was found in two different patients. The prevalence of poor metabolizers among patients with PHVO after aminorex fumarate was therefore approximately 9% for both debrisoquine and mephenytoin. This corresponds closely to the data of our reference population study where genetic debrisoquine and mephenytoin hydroxylation deficiencies occurred independently, with a prevalence of 10% and 5% respectively. Thus, the normal prevalence of extensive drug hydroxylation phenotypes in patients with PHVO is not consistent with the hypothesis that the development of PHVO after aminorex fumarate might be related to a pharmacogenetically determined impairment of polymorphic drug oxidation.

[Chronic pulmonary hypertension of vascular origin, plexogenic pulmonary arteriopathy and the appetite depressant aminorex: addenda to an epidemic]. / Chronische pulmonale Hypertonie vaskulären Ursprungs, plexogene pulmonale Arteriopathie und der Appetitzügler Aminorex: Nachlese zu einer Epidemie.

An epidemic of chronic pulmonary hypertension occurred in Austria, the Federal Republic of Germany, and Switzerland, starting in 1967, peaking in 1968/69, and disappearing after 1972. The mechanism leading to pulmonary hypertension was precapillary vascular obstruction due to plexogenic pulmonary arteriopathy. There was a close geographic and temporal relationship between the epidemic and the marketing and intake of the appetite-depressing drug aminorex fumarate (Menocil). The epidemic was limited to the three above countries where aminorex had been on sale. In the individual patient the symptoms, usually dyspnea, angina pectoris and syncope on exertion, used to follow the beginning of the drug in-take after one year. A similar phase shift could be observed between marketing of the anoretic and the incidence of patients with chronic pulmonary hypertension of vascular origin. The new disease is compared with known forms of pulmonary vascular obstruction. It cannot be distinguished from classical primary pulmonary hypertension or from recurrent silent pulmonary thromboembolism on either clinical or functional grounds; it has plexogenic pulmonary arteriography in common with the former. The prognosis, however, is different: survival is considerably longer in patients with aminorex-associated pulmonary hypertension, and a marked decrease in the pulmonary vascular obstruction after 10 years is no exception. Considering the closeness of the various associations between the event (i.e. the epidemic) and its suspected cause (the anoretic aminorex) from the viewpoint of epidemiological, pharmacological, morphological and prognostic findings and considerations, there is little doubt that aminorex, besides other partly known and partly unknown factors, can in fact favour or cause the development of plexogenic pulmonary arteriography and pulmonary hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminorex and pulmonary hypertension. A review.

There was an epidemic of chronic pulmonary hypertension in Austria, the Federal Republic of Germany and Switzerland, starting in 1967, peaking in 1968/69, and disappearing after 1972. The mechanism leading to pulmonary hypertension was chronic precapillary vascular obstruction due to plexogenic pulmonary arteriopathy. There was a close geographic as well as temporal relation of the epidemic to the marketing and intake of the appetite depressing drug aminorex fumarate (Menocil). 10 years after the epidemic, half of the patients have died, usually of right heart failure. Of those surviving, half present a definite regression of the pulmonary vascular obstruction. Average survival after the initial diagnosis was 3.5 years in those patients who died. Their PA pressure (+22%) and pulmonary arteriolar resistance (+40%) was higher at the onset of the observation period if compared with the corresponding values of the survivors; also the incidence of right heart failure was significantly higher (84 vs. 58%). Among the surviving patients, the only difference between those with an improved and those with a worsened haemodynamic situation was the age at the beginning of the weight-reducing treatment, those with a progression being 10 years older. The probability of survival after 10 years is considerably higher in chronic pulmonary hypertension of vascular origin (CPHVO) after aminorex than in "classical" primary pulmonary hypertension (CPHVO of unknown cause) and in CPHVO due to recurrent silent pulmonary thromboembolism. This difference in prognosis is an argument in favour of the identity of chronic pulmonary hypertension developing after the intake of the appetite depressing drug aminorex.

[Cardiovascular syncope]. / Kardiovaskuläre Synkopen.

The sudden and transient loss of consciousness and muscular tone from which the patient usually recovers spontaneously, i.e. syncope, is a frequent symptom. Diseases of the heart with and without rhythm disturbances together with disorders of the reflex, in particular the orthostatic regulation of the circulation, are among the main causes of syncopal events. The pathophysiological mechanisms of cardiovascular syncopes are manifold, and more than one factor can contribute to a single mechanism. Their aetiological assignment may be straightforward, but sometimes requires laborious and expensive investigational procedures. The treatment of a syncopal attack ranges from simple manipulations to true reanimation, its long-term prevention from antiarrhythmic drugs to major heart surgery, and its prognosis from the bagatelle to sudden death.

[A new model for the quantitative analysis of left ventricular regional function]. / Ein neues Modell für die quantitative Analyse der regionalen Funktion des linken Ventrikels.

A computer-assisted model for quantitative analysis of left ventricular segmental wall motion is presented. In contrast to standard rectangular and radial chord methods, no coordinate and reference system is used. Normal wall motion of 5 ventricular segments in the RAO projection was evaluated in 20 patients with normal ventriculograms. Segmental wall motion abnormalities after myocardial infarction were then analyzed by the computer-assisted method in 60 patients and the results compared with the visual assessment of an experienced cardiologist as standard reference. 96% of all segments with normal motion, 95% of all hypokinetic segments and 100% of all dyskinetic segments were correctly identified by computer analysis. Akinesia, however, was detected only in 25% of all cases and misinterpreted chiefly as hypokinesia. Further refinement of the software should improve detection of akinesia and classification of hypokinesia.

Influence of sulfinpyrazone on infarct size, hemodynamics, and arrhythmia following coronary occlusion in the pig.

We compared infarct size (nitroblue tetrazolium method), hemodynamic variables, and arrhythmias of a group of seven sulfinpyrazone-treated pigs (30 mg/kg/day for 7 days preoperatively, 30 mg/kg/i.v. 30 min before coronary ligation) with a control group of seven animals. Infarct size after ligation of the left anterior descending coronary artery was 20.3 +/- 1.1% in the sulfinpyrazone group and 20.3 +/- 0.5% in the control group. Heart rate, arterial blood pressure, cardiac output, and stroke volume were comparable in both groups before and for 60 min following ligation. There was no significant difference between the two groups in the number of premature ventricular contractions the PVC grade (Lown) or in the number of episodes of ventricular tachycardia or ventricular fibrillation during the 30-min observation period. We conclude that short-term administration of sulfinpyrazone has no effect on infarct size or arrhythmias in the acutely ischemic myocardium of the pig.

Cardiogoniometry: a new noninvasive method for detection of ischemic heart disease.

Cardiogoniometry is a new vectorcardiographic method. The vector-loops are constructed from three orthogonal ECG leads and registered on-line by a microprocessor. The angle between the maximal QRS and T vectors, as well as the spatial orientation of these vectors are very constant in healthy individuals. Deviations of these vectors and angles are sensitive indicators for changes in repolarization occurring, for instance, during coronary insufficiency. The changes in these variables were evaluated in 50 patients with suspected coronary artery disease and correlated with angiographic findings. Cardiogoniometry showed a sensitivity of 79% and a specificity of 82%, which is comparable to exercise testing. In contrast to the latter cardiogoniometry can be performed at rest, is free of risk, and therefore also suitable for elderly patients.

[Hypertropic obstructive cardiomyopathy. A family study]. / Hypertrophe obstruktive Kardiomyopathie.

Eight patients with HOCM from the same family are presented. The clinical findings and the diagnostic and therapeutic procedures are discussed. Chest pain, palpitations and effort dyspnea were the main clinical symptoms. A characteristic systolic ejection murmur of late onset was present in all the cases. In 6 patients there were electrocardiographic signs of left ventricular hypertrophy and only 4 patients exhibited abnormal septal depolarization. Echocardiography revealed an enhanced diastolic interventricular septal to left ventricular posterior wall ratio (above 1.3), diminished left ventricular septum movement, systolic anterior motion of the mitral valve and mid systolic closure of the aortic valve. Cardiac catheterization showed a left ventricular out-flow gradient which was increased by isoproterenol infusion. In 5 patients the left ventricular angiogram disclosed systolic obliteration of the left ventricle and in 4 cases mitral regurgitation. In the therapy of HOCM, calcium antagonists are now widely used and seem to have replaced betablocking agents.

[Staying at high altitudes and plane travel for heart patients]. / Höhenaufenthalt und Flugreisen bei Herzkranken.

In a normal lung at an altitude of 2000 meters the pO2 in the alveolar air is 77 mm Hg. At 3800 meters it drops to 57 mm Hg. In the healthy individual increasing hypoxia leads to hypoxemia, tachycardia at low levels of exercise, increased sympathetic tone, pulmonary hypertension and, in some instances, retention of water. Under these circumstances acute mountain sickness or high altitude pulmonary edema may occur. In patients with marginal cardiocirculatory function these effects of hypoxia are potentially dangerous and may lead to cardiac decompensation. Patients with coronary artery disease, congestive heart failure, arrhythmias, pulmonary hypertension and valvular heart disease can tolerate altitude and air travel only if, with adequate therapy, they are either asymptomatic or only slightly symptomatic at rest, or if they show some functional reserve during exercise testing.