M. Böhm

Isolated presynaptic inotropic beta-adrenergic supersensitivity of the transplanted denervated human heart in vivo.

BackgroundThe regulation of contractility of the transplanted heart depends on circulating catecholamines resulting from cardiac denervation. Supersensitivity to circulating catecholamines may result from loss of presynaptic neuronal uptake or upregulation of postsynaptic β-adrenergic receptors. Methods and ResultsDose-response curves using the β-adrenergic receptor agonists isoprenaline (no neuronal uptake) and epinephrine (neuronal uptake) were performed in vivo. The inotropic response was measured echocardiographically as the increase of fractional shortening (ΔFS) and the increase of the systolic pressure/dimension ratio (ΔP/D). The inotropic response to increasing doses of isoprenaline (5–20 ng/kg· min) was identical in 36 heart transplant recipients compared with 13 control subjects: AFS during 20 ng/kg · min isoprenaline amounted to 18.2±6.2% versus 17.4±4.0% (NS) and ΔP/D to 2.3±1.2 mm Hg/mm versus 2.2±0.5 mm Hg/mm (NS), respectively. A vagally mediated indirect negative inotropic effect in the innervated hearts was excluded by identical inotropic responses to isoprenaline in control subjects without and after atropine pretreatment. The inotropic response to increasing doses of epinephrine (10–40 ng/kg · min) was significantly augmented in 13 heart transplant recipients compared with 11 control subjects: ΔFS during 40 ng/kg · min epinephrine amounted to 19.9±2.6% versus 8.6±2.0% (p<0.001) and ΔP/D to 2.3±0.9 mm Hg/mm versus 0.6±0.3 mm Hg/mm (p<0.001), respectively. Pretreatment with desipramine (blockade of neuronal uptake) in control subjects resulted in a significantly increased inotropic response: ΔFS during 40 ng/kg · min epinephrine amounted to 17.6±3.6% (p<0.001 versus untreated controls, NS versus heart transplant recipients) and ΔP/D to 1.7±0.8 mm Hg/mm (p<0.001 versus untreated controls, NS versus heart transplant recipients). ConclusionsThese findings provide evidence against a postsynaptic inotropic supersensitivity or subsensitivity of the β-adrenergic receptor-effector system of the transplanted denervated human heart in vivo. However, a marked presynaptic inotropic supersensitivity is present because of denervation-associated loss of neuronal catecholamine uptake.

Different β-adrenoceptor-effector coupling in human ventricular and atrial myocardium

Abstract. To examine whether the downregulation of β‐adrenoceptors is accompanied by reduced β‐adrenoceptor‐mediated effects in atrial as well as in ventricular myocardium, we investigated the β‐adrenoceptor‐effector coupling in atrial and papillary muscle strips from patients with terminal heart failure (heart transplantation because of dilated cardiomyopathy; New York Heart Association Class IV, NYHA IV) and moderate heart failure (mitral valve replacement, NYHA II‐III) and in tissue from non‐failing hearts. The isometric force of contraction induced by isoprenaline (0·001‐1 μmoll‐1) or Ca2+ 1·8–15 mmoll‐1) in atrial muscle strips and papillary muscle strips has been measured. We also examined the number of β‐adrenoceptors in both tissues by radioligand binding.

Kommentar zu den Leitlinien der Europäischen Gesellschaft für Kardiologie (ESC) zur Diagnostik und Behandlung der akuten und chronischen Herzinsuffizienz

ZusammenfassungZiel dieses Kommentars ist es, auf neue wichtige Aspekte der Leitlinien besonders einzugehen, kontroverse Empfehlungen zu diskutieren und auf Punkte einzugehen, die zwar in der Vollversion der Leitlinien, aber nicht in der Pocket-Leitlinie Erwähnung finden. Wesentliche Neuerungen sind der Einsatz von Aldosteron-Antagonisten und der kardialen Resynchronisationstherapie bereits bei mild symptomatischer Herzinsuffizienz, der Einsatz des Sinusknoteninhibitors Ivabradin, einer Eisensubstitutionstherapie zur symptomatischen Verbesserung der Herzinsuffizienz und die Empfehlung eines strukturierten Trainingsprogramms bei Patienten mit Herzinsuffizienz. Außerdem werden Revaskularisationsstrategien, die interventionelle Klappentherapie sowie der frühe Einsatz von Unterstützungssystemen bei fortgeschrittener Herzinsuffizienz diskutiert.AbstractIt is a goal of this commentary to address 1) most important aspects of the new guidelines, 2) to discuss controversial recommendations and 3) to focus on relevant aspects which are only addressed in the long version of the guidelines, but not in the pocket guidelines. Important new topics are the administration of mineralocorticoid receptor antagonists (aldosterone antagonists) and the indication for cardiac resynchronization therapy (CRT) already in patients with mild heart failure symptoms, the application of the sinus node inhibitor ivabradine, the substitution of iron to improve symptoms in heart failure and recommendation of a structured training program in patients with heart failure. In addition, revascularization strategies in heart failure will be discussed as well as interventional approaches for aortic stenosis and mitral regurgitation and finally early implantation of cardiac assist devices in patients with terminal heart failure.

Different negative inotropic activity of Ca2+-antagonists in human myocardial tissue

SummaryTo evaluate the negative inotropic effect of various Ca2+-antagonists in human myocardium without additional influences of preload, afterload, or frequency, we examined their effects on isometric force of contraction in isolated human papillary muscle strips and in auricular trabeculae. The 1,4-dihydropyridines isradipine, nitrendipine, and nifedipine, the phenylalkylamine verapamil, and the benzothiazepine diltiazem exerted concentration-dependent negative inotropic effects. The potency of the investigated Ca2+-antagonists was identical in papillary muscle strips of patients with only moderate clinical signs of heart failure undergoing mitral valve replacement-operation (NYHA II–III) and in terminally failing (heart transplantation, NYHA IV) human hearts. The IC50 values were lower in auricular trabeculae than in papillary muscle strips. The difference was significant for nifedipine, nitrendipine, and verapamil. The restorative effects of external Ca2+ after pretreatment with Ca2+-antagonists were significantly less strong after pretreatment with 1,4-dihydropyridine than with non-dihydropyridines in papillary muscle strips. It is concluded that 1,4-dihydropyridines and verapamil and diltiazem did differently influence Ca2+-mediated increase in force of contraction. Moreover, a relation between the therapeutically active free plasma concentration in vivo and the negative inotropic potency in vitro can be found. This relation follows a rank order of potency for negative inotropism (isradipine≤nitrendipine

[Alterations of the cAMP-adenylate cyclase system in the failing human heart. Consequences for the therapy with inotropic drugs].

In heart failure, an increase in the activity of the sympathetic nervous system takes place to maintain perfusion pressure to vital organs, resulting in increased levels of noradrenaline in the blood of these patients. This permanent stimulation produces a down-regulation of cardiac beta-adrenoceptors. Since noradrenaline acts primarily on the cardiac beta 1-adrenoceptor subtype, beta 1-adrenoceptors decrease in number, whereas the beta 2-adrenoceptor subpopulation remains unchanged in most instances. Consequently, the positive inotropic response to beta-adrenoceptor agonists is diminished. However, there is also a decrease in the positive inotropic effect of beta 2-adrenoceptor agonists, histamine and cAMP-phosphodiesterase inhibitors such as milrinone, whereas the positive inotropic effect of cAMP-independent Na(+)-channel activators such as DPI 206-106 and the effects of cardiac glycosides are not diminished. These observations suggest a more generalised alteration of the cAMP-adenylate cyclase system in the failing heart. Stimulatory guanine nucleotide-binding protein (Gs) couples receptors to adenylate cyclase that stimulate cAMP formation, such as beta-adrenoceptors, histamine receptors and glucagon receptors. In the failing human heart, Gs content has been reported to remain unchanged as compared with that in non-failing myocardium. However, there is a 35%-40% increase in inhibitory guanine nucleotide-binding proteins (Gi), which are involved in the receptor-mediated inhibition of adenylate cyclase. Taken together, two defects of the cAMP-adenylate cyclase system have been identified: an increase in Gi content and a decrease in the number of beta-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)SummaryIn heart failure, an increase in the activity of the sympathetic nervous system takes place to maintain perfusion pressure to vital organs, resulting in increased levels of noradrenaline in the blood of these patients. This permanent stimulation produces a down-regulation of cardiacβ-adrenoceptors. Since noradrenaline acts primarily on the cardiacβ1-adrenoceptor subtype,β1-adrenoceptors decrease in number, whereas theβ2-adrenoceptor subpopulation remains unchanged in most instances. Consequently, the positive inotropic response toβ-adrenoceptor agonists is diminished. However, there is also a decrease in the positive inotropic effect ofβ2-adrenoceptor agonists, histamine and cAMP-phosphodiesterase inhibitors such as milrinone, whereas the positive inotropic effect of cAMP-independent Na+ -channel activators such as DPI 206-106 and the effects of cardiac glycosides are not diminished. These observations suggest a more generalised alteration of the cAMP-adenylate cyclase system in the failing heart. Stimulatory guanine nucleotide-binding protein (Gs) couples receptors to adenylate cyclase that stimulate cAMP formation, such asβ-adrenoceptors, histamine receptors and glucagon receptors. In the failing human heart, Gs content has been reported to remain unchanged as compared with that in nonfailing myocardium. However, there is a 35%–40% increase in inhibitory guanine nucleotide-binding proteins (Gi), which are involved in the receptor-mediated inhibition of adenylate cyclase. Taken together, two defects of the cAMP-adenylate cyclase system have been identified: an increase in Gi content and a decrease in the number ofβ-adrenoceptors. Both alterations might contribute to the reduced effectiveness of cAMP-dependent positive inotropic agents. cAMP-independent agents might be more efficacious in mobilizing the contractile reserve of the failing myocardium. Reduction of the permanentβ-adrenergic stimulation of the failing heart, e.g. byβ-blockers, might be a promising approach for reversing these alterations of the cAMP-adenylate cyclase system.ZusammenfassungAufgrund experimenteller Untersuchungen an explantierten menschlichen Herzen lassen sich zwei biochemische Veränderungen charakterisieren: In Abhängigkeit vom Schweregrad der Herzinsuffizienz entsteht eine Abnahme von kardialenβ1-Adrenozeptoren, wohingegen dieβ2-Adrenozeptordichte unbeeinflußt bleibt. Zusätzlich kommt es bei der dilatativen Kardiomyopathie zu einer Zunahme von Gi. Diese Veränderungen imβ-Adrenozeptor-cAMP-Adenylatcyclasesystem führen zu einer Verminderung der Wirkung cAMP-abhängig positiv inotrop wirksamer Substanzen wieβ-Adrenozeptor-Agonisten und Phosphodiesterasehemmstoffen. Der positive inotrope Effekt von cAMP-unabhängig wirksamen positiv inotropen Maßnahmen wie die Erhöhung der extrazellulären Calciumkonzentration, Aktivierung des Natriumeinwärtsstromes und Hemmung der Natrium-Kalium-ATPase durch Herzglykoside ist bei der Herzinsuffizienz unvermindert. Das bedeutet, daß am insuffizienten menschlichen Herzen die kontraktile Reserve des Myokards im wesentlichen erhalten bleibt, aber ihre Ausschöpfung durch endogene Katecholamine und exogene, cAMP-abhängige positiv inotrop wirkende Pharmaka vermindert ist. Die Konsequenz aus diesen Beobachtungen ist, daß eine pharmakologische Erhöhung der zellulären cAMP-Spiegel durchβ-Adrenozeptoragonisten oder Phosphodiesterasehemmstoffe bei Herzinsuffizienz nicht sinnvoll erscheint. Eine Kontraktionskraftsteigerung kann am besten durch cAMP-unabhängig wirksame positiv inotrope Substanzen erreicht werden.

Zweijährige Interferon-Therapie eines metastasierten Carcinoids

A 39 year old male patient was treated with daily 5 X 10(6) IU interferon alpha 2b s.c. for 22 months because of advanced carcinoid tumor. Objective response was achieved with greater than 50% reduction of 5-HIAA-excretion. Multiple metastases (liver, lung, bones, thyroid gland) were not progressing in size. An unintentional omission of treatment resulted in a rapid biochemical and morphological tumor progression. Reversibility was achieved with reinstitution of effective interferon therapy. Thus, interferon therapy of advanced carcinoid tumor is able to induce a long-term objective response. It seems to be superior to conventional chemotherapy.SummaryA 39 year old male patient was treated with daily 5×106 IU interferonα 2b s.c. for 22 months because of advanced carcinoid tumor. Objective response was achieved with >50% reduction of 5-HIAA-excretion. Multiple metastases (liver, lung, bones, thyroid gland) were not progressing in size. An unintentional omission of treatment resulted in a rapid biochemical and morphological tumor progression. Reversibility was achieved with reinstitution of effective interferon therapy.Thus, interferon therapy of advanced carcinoid tumor is able to induce a long-term objective response. It seems to be superior to conventional chemotherapy.

Klinische Interaktionen zwischen Herz, Kreislauf und Niere

Pathophysiologisch spielen Interaktionen zwischen Herz, Kreislauf und Niere unter anderem eine wesentliche Rolle bei der Herzinsuffizienz, ihrer Therapie und nach Herztransplantation. Die erhohte neuroendokrine Aktivitat aufgrund der Barorezep-tordysfunktion und der verminderten renalen Perfusion ist fur die weitere Prognose der primar kardial erkrankten Patienten entscheidend. Zum einem ist durch die „down-regulation“ der myokardialen Betarezeptoren die physiologische Regulation der Kontraktilitat gestort, zum anderen verstarkt die Vasokonstriktion durch Nachlastzunahme die Auwirkungen der linksventrikularen Dysfunktion. Neben der Entlastung des insuffizienten Herzens mus deshalb eine Zunahme der Nierendurchblutung und eine Empfindlichkeitssteigerung der Barorezeptoren angestrebt werden. Der Erfolg dieser Therapie ist an der Abnahme der vasokonstriktorischen Parameter zu messen, wenn eine Verbesserung der Prognose angestrebt wird.