The effect of nifedipine on left ventricular isovolumic relaxation and diastolic filling properties and systemic and left ventricular hemodynamics was studied in 15 patients with hypertrophic cardiomyopathy. After nidefipine (10 mg sublingually), the prolonged left ventricular isovolumic relaxation time assessed by echocardiography decreased from 112 +/- 26 to 83 +/- 23 msec (p less than 0.0001), and the left ventricular pressure decay as measured by time constant T improved from 63 +/- 20 to 49 +/- 11 msec (p less than 0.05). Left ventricular filling dynamics also improved as assessed by a return toward normal in the depressed peak rate of left ventricular diastolic filling (dimension change 72 +/- 37 to 101 +/- 39 mm/sec, p less than 0.01) and the peak rate of posterior wall thinning (47 +/- 31 to 68 +/- 36 mm/sec, p less than 0.001). These changes were accompanied by hemodynamic evidence of improved diastolic function shown as a decrease in left ventricular end-diastolic pressure and a downward shift in the left ventricular diastolic pressure-dimension relationship, suggesting improved left ventricular distensibility. After nifedipine, there was a slight increase in heart rate and a decrease in systemic ventricular distensibility. After nifedipine, there was a slight increase in heart rate and a decrease in systemic arterial blood pressure, and no depression of the left ventricular percent fractional shortening or cardiac index. These data indicate that abnormal left ventricular relaxation and diastolic filling rates in hypertrophic cardiomyopathy are dynamic and favorably modified by nifedipine, and that this effect is not related to a depression of left ventricular systolic function.

Modification of abnormal left ventricular diastolic properties by nifedipine in patients with hypertrophic cardiomyopathy.

Treadmill exercise capacity and symptomatic status were evaluated in 19 patients with hypertrophic cardiomyopathy while on placebo, low and high dosages of propranolol and low and high dosages of verapamil. Exercise duration on placebo was 6.1 ± 0.8 minutes. Verapamil administration improved exercise capacity by 26 ± 8% (1.6 ± 0.5 minutes; p < 0.005); propranolol improved exercise capacity by 21 ± 8% (1.3 ± 0.5 minutes; p < 0.025). Twelve patients on verapamil and 11 on propranolol improved their exercise duration by at least 15% compared with placebo. No patient on verapamil but three on propranolol had more than 15% deterioration in exercise capacity. Seven patients considered their symptomatic status \"best\" while

Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. II. Effects on exercise capacity and symptomatic status.

The hemodynamic effects of intravenous verapamil administration were examined in 27 patients with hypertrophic cardiomyopathy. Increasing doses of verapamil produced small increases in heart rate and cardiac output and a significant decrease in systolic blood pressure, but had no significance effect on mean pulmonary artery wedge pressure or left ventricular end-diastolic pressure. The highest dose of verapamil increased heart rate from 72 +/- 3 to 81 +/- 6 beats/min and reduced systolic blood pressure from 118 +/- 8 to 99 +/- 5 mm Hg (p less than 0.005). This dose decreased the basal left ventricular outflow tract gradient from 94 +/- 14 to 49 +/- 14 mm Hg and the average left ventricular outflow tract gradient during the Valsalva maneuver from 76 +/- 5 to 63 +/- 13 mm Hg, during amyl nitrite inhalation from 69 +/- 15 to 39 +/- 13 mm Hg, and during isoproterenol infusion from 108 +/- 29 to 70 +/- 21 mm Hg (p less than 0.01). These results indicate that verapamil can significantly decrease left ventricular outflow obstruction in patients with hypertrophic cardiomyopathy and thus may provide an important new therapeutic agent in the treatment of this disorder.

Verapamil therapy: a new approach to the pharmacologic treatment of hypertrophic cardiomyopathy. I. Hemodynamic effects.

Calcium out of control.

Various stressful stimuli are known to activate the sympathetic nervous system to release catecholamines and the hypothalamic–pituitary–adrenal axis to release glucocorticoids in the circulation. Although initial actions of both catecholamines and glucocorticoids are beneficial for the function of the cardiovascular system, their delayed effects on the heart are deleterious. Glucocorticoids not only increase plasma levels of catecholamines by inhibiting their extraneuronal uptake, but they have also been shown to induce supersensitivity to catecholamines in the heart by upregulating different components of the β-adrenoceptor signal transduction system. Low concentrations of catecholamines stimulate the heart by promoting Ca2+ movements, whereas excessive amounts of catecholamines produce cardiac dysfunction by inducing intracellular Ca2+ overload in cardiomyocytes. Several studies have shown, however, that under stressful conditions high concentrations of catecholamines become oxidized to form aminolutins...

Role of the excessive amounts of circulating catecholamines and glucocorticoids in stress-induced heart disease.

In the BIO 8262 inbred strain of cardiomyopathic Syrian hamsters, a latent disturbance of their myocardial calcium metabolism could be evidenced. Whereas the myocardial calcium content of untreated young cardiomyopathic hamsters with prenecrotic hearts did not differ from that of healthy control animals, it was distinctly elevated 6 hours after injection of isoproterenol (1 mg/kg body weight s.c.) in cardiomyopathic animals remaining unchanged in healthy controls. However, the same dose of isoproterenol induced elevated myocardial 45Ca uptake in both strains, although that of the cardiomyopathic hearts was distinctly greater. Later, during the stage of spontaneous progressive necrotization of the hearts, a spontaneously increased myocardial uptake of 45Ca and calcium content became manifest. By combined treatment with isoproterenol and verapamil, a substance which is known to decrease the calcium conductivity of myocardial cell membranes without blocking beta-adrenergic receptors, the isoproterenol-stimulated 45Ca uptake by prenecrotic cardiomyopathic hearts as well as the increase of their calcium content could be inhibited. Long-term treatment with verapamil alone beginning during the prenecrotic phase of the cardiac condition, was fully effective in preventing myocardial overload as well as necrotization. These findings demonstrate that overload with calcium of cardiomyopathic cells of the hamsters can be influenced beneficially. Therefore, the disturbed myocardial calcium metabolism in the hereditary cardiomyopathy of the Syrian hamster is considered a decisive pathogenetic factor.

Disturbed myocardial calcium metabolism: a possible pathogenetic factor in the hereditary cardiomyopathy of the Syrian hamster.

The crucial point in the pathogenesis of isoproterenol-induced myocardial necrotization is an abundant intracellular Ca accumulation leading to high energy phosphate exhaustion. Accordingly, in the early stage of the isoproterenol-induced necrotization process, the onset of ATP and creatine phosphate breakdown strictly parallels the acute Ca gain. In this type of necrosis, the Mg losses from the myocardium appear as a concomitant phenomenon. The hearts can be protected against the deleterious Ca overload and necrotization by increasing the plasma concentration of Mg, K, or H ions in order to counterbalance Ca according to the ration (see article). On the other hand, if Mg, K, or H ion concentrations are too low, isoproterenol-induced Ca uptake and myocardial lesions are potentiated.

Prevention of myocardial Ca overload and necrotization by Mg and K salts or acidosis.

Uberdosierung von Vitamin D oder Dihydrotachysterol (DHT) fuhrt insbesondere bei kombinierter Verabreichung mit NaH2PO4 bei Ratten nicht nur zu Myokard-Lasionen, sondern auch zu arteriosklerotischen Gefasprozessen (1). Nach unseren vorausgegangenen Studien mit markiertem 45Ca ist die Nekrotisierung durch eine Ca++-Uberladung der Myokardfasern bedingt und dahernach Schwere und Ausdehnung mit der 45Ca-Inkorporation quantitativ korreliert (2,3). Organische Ca++-Antagonisten wie Verapamil, Substanz D 600 oder Prenylamin, die den transmembranaren Ca++-Influx in die Myokardfasern reduzieren, konnten daher die Nekrosebildung verhuten. Ahnlich wirkten K+- und Mg++-Salze als naturliche Ca++-Antagonisten. Ganz analoge Verhaltnisse wurden nunmehr an den Gefasen gefunden: Ratten wurden 10 Tage lang peroral taglich mit 2 mal 10 mM/kg NaH2PO4 und 7 Tage lang peroral taglich mit 1 mal 0, 5 mg/kg DHT vorbehandelt. Am elften Tag wurde intraperitoneal 45Ca (10 /uC/kg) injiziert und die 45Ca-Inkorporation in Aorta und Arteria mesenterica sup. gemessen. Bei den unbehandelten Kontrollratten erreichte der 45Ca-Gehalt in der Aortenwand innerhalb von 6 Stunden nach der 45Ca-Injektion 70% und in der Mesenterial-Arterie etwa 100% (bezogen auf die Plasma-Aktivitat = 100%), wahrend bei den vorbehandelten Tieren der 45Ca-Gehalt der Aorta innerhalb der gleichen Beobachtungszeit auf 5000–8000%y d.h. auf das 70–120-fache und der Mesenterial-Arterie auf 4000–5000%, d.h. auf das 40-50-fache der Norm anstieg.

Hemmung arteriosklerotischer Gefäßprozesse durch prophylaktische Behandlung mit MgCl2, KCl und organischen Ca++-Antagonisten (Quantitative Studien mit Ca45 bei Ratten)

1. 2,4,7-Triamino-6-phenyl-pteridine (triamterene) protects the rat heart against isoproterenol-induced myocardial lesions: Whilst cardiotoxic doses of isoproterenol produce deleterious myocardial Ca overload, simultaneous admistration of triamterene diminishes myocardial Ca incorporation considerably. 2. As to the mechanism of action, triamterene increases the plasma contents of K and Mg by inhibiting renal excretion. Accordingly, oral administration of K and Mg salts, leading to a similar rise in the K and Mg concentrations of the plasma, also prevents abundant myocardial Ca incorporation. 3. Cardioprotection by triamterene can, in fact, be simply explained by its action on the plasma K and (particularly) Mg levels. This conclusion is drawn from a quantitative comparison of the inhibitory effects of triamterene (40 mg/kg s.c.) with those of KCl or MgCl2 (10 mMol/kg p.o.) on the isoproterenol-induced increase in myocardial 45Ca uptake and absolute Ca concentration. 4. Isoproterenol induced cardiomyopathy of the rat, an experimental model of non-coronarogenic myocardial lesions, has hitherto been successfully prevented with the use of Ca-antagonists (verapamil, D 600, prenylamine, fendiline). These compounds reduce Ca influx by restricting the Ca conductivity of the myocardial sarcolemma membrane ("slow channel"). The action of triamterene, on the other hand, is based on a totally different cardioprotective principle, namely competitive inhibition of intracellular myocardial Ca accumulation via an increase in K and Mg supply. In the future treatment of cardiomyopathy it seems rather promising to try a combination of both a Ca-antagonist and triamterene, thus applying two different therapeutic principles simultaneously.

[Mechanism of the cardioprotective effect of triamterene in the rat heart. Myocardial protection via elevation of extracellular K+ and Mg++ concentrations].

In fruheren tier-experimentellen Studien von Fleckenstein, D00f6ring und Kammer,eier (1966, 1967, 1968) wurden 2 Typen von kontraktiler Herz-In-suffizienz herausgearbeitet: 

1.

Das Herzversagen infolge Mangels an energiereichem phosphat nach Hypoxie, Ischamie oder Hemmung des oxydativen Stoffwechsels;




2.

das Herzversagen infolge einer ungen00fcgenden Utilisation von energie-reichem Phosphat. Eine solche Utilisations-Insuffizienz tritt z. B. bei Ca++- Mangel ein, weil dann die Ca++-abhangige Myofibrillen–ATPase in den erregten Myokardfasern nicth mehr gen00fcgend ATP zur Gewinnung der Kontraktionsenergie spalten kann.

Einschränkung der Isoproterenol-induzierten 45Ca++-Netto-Aufnahme und der Utilisation von energiereichem Phosphat im hypertrophierten Rattenmyokard

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