Negative Chronotropic Properties Research Articles

Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels.

Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a CaV1.2 channel blocker and a KCa1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the CaV1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the CaV1.2 channel blockade and KCa1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy.

Is chronotropic incompetence a limitation in the evaluation of myocardial ischemia and prognosis?

The aim of this study was to evaluate whether chronotropic incompetence (CI), the inability to reach 85% of the maximal predicted heart rate during exercise, affects the assessment of myocardial ischemia and prognosis in patients undergoing myocardial perfusion single-photon emission computed tomography (MPS). Patients undergoing exercise/rest MPS were studied. Those taking drugs with negative chronotropic properties were excluded. Summed stress, rest, and difference scores (SSS, SRS, and SDS, representing, respectively, the extent and severity of the total perfusion defect, fibrosis, or ischemia) were calculated. Patients were followed up for the occurrence of hard events (death or myocardial infarction) or myocardial revascularization for 36±20 months. A total of 391 patients were studied; among them, 11.5% had CI. All perfusion scores were higher in patients with CI. On logistic regression, history of myocardial infarction and SDS were found to be independent predictors of CI. On comparing patients with and without CI, the former more often had hard events (12.5 vs. 0.9%, P=0.007) and revascularization (20.0 vs. 8.1%, P=0.003). CI was associated with myocardial ischemia. Higher rates of hard events and revascularization were observed in patients with CI, in accordance with the larger extent of myocardial ischemia found in these patients. Performing MPS in the setting of CI may maintain the diagnostic and prognostic abilities of the test.

Physiological basis of therapeutic approach to ivabradine use in new acute onset heart failure

Background and Aim: Ivabradine is a selective and specific inhibitor of the sinus node funny current (I f ) channel with negative chronotropic properties while not affecting inotropy. Though the benefit of ivabradine in patients with coronary artery disease and chronic heart failure is well-established, data of its usage in acute heart failure (AHF) is scarce. We investigated the potential role of ivabradine in patients with acute ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention that postprocedurally present in hypoperfusion state without having complete criteria for cardiogenic shock, a state known as preshock or gray zone of cardiogenic shock, which is often associated with anterior STEMI and 46% in-hospital mortality. Methods: During 2010, we conducted this pilot study on patients with acute STEMI where the culprit lesion was left anterior descending artery, complicated by the preshock. Altogether 10 patients (8 male and 2 female patients) were treated with ivabradine as an additional therapy who had stable sinus tachycardia. Their heart rate (HR), blood pressure (BP), degree of diuresis, and overall clinical response were recorded before and after ivabradine therapy. Results: We observed a drop in HR from average 116−78/min, a rise in systolic BP from 99−108 mm Hg and a rise in diuresis from 55 to 85 mL/h within the first 48 h. Conclusion: Early observational data support use of ivabradine in STEMI with advanced AHF. We propose that ivabradine could help STEMI patients in grey zone of cardiogenic shock (preshock).

Slower Heart Rates for Healthy Hearts

The management of atrial fibrillation, even in the modern era, remains complex and challenging. Preventing atrial fibrillation occurrence by identifying and favorably improving modifiable risk factors thus assumes great importance. It is well known that hypertension and resultant structural heart disease contributes significantly to the incidence of atrial fibrillation.1,2 The Losartan Intervention For End point reduction in hypertension (LIFE) study thus far has shown us that angiotensin-receptor blockade and reduction in left ventricular hypertrophy, irrespective of blood pressure–lowering, reduces the incidence of new-onset atrial fibrillation.1,3 Article see p 337 In recent years, accumulating evidence has linked high resting sinus heart rates (HR) directly and indirectly to adverse cardiovascular outcomes.4,5 Epidemiological studies show resting HR to be an independent predictor of cardiovascular and all-cause mortality in general population as well as in hypertensive patients.6 The cardiovascular benefits offered by β-blockade in coronary artery disease and heart failure have, in part, been attributed to β-blocker–mediated HR reduction.7,8 Other studies have linked high baseline HR to the development of hypertension, to the progression of coronary artery disease, and to the triggering of myocardial infarction, ventricular dysfunction, and ventricular arrhythmias.6,9–11 In this issue of Circulation: Arrhythmia and Electrophysiology , Okin and colleagues12 examines the relationship of HR changes over time on risk of atrial fibrillation in hypertensive patients as part of the LIFE study. In this post hoc analysis of the prospective LIFE study, 8828 hypertensive patients with left ventricular hypertrophy by ECG but without a history of atrial fibrillation were followed for a mean of 4.7±1.1 years. New onset atrial fibrillation was determined by 12-lead ECG performed on an intermittent, infrequent basis (at baseline, 6 months, and yearly thereafter). Hypertension was treated with losartan or atenolol. Using a variety of analyses, higher in-treatment HR on serial …

Myokardiale Wirkung der Calciumantagonisten Nifedipin, Nisoldipin und Isradipin bei koronarer Herzkrankheit

Cardiac and peripheral effects of three calcium antagonists of the dihydropyridine group were compared in three groups of ten men each with coronary heart disease (mean age 56 +/- 6 years). Dosages (by 30 minutes intravenous infusions) were: 2 mg nifedipine in group I, 0.5 mg nisoldipine in group II and 0.5 mg isradipine in group III. In this dosage peripheral effects--decrease of peripheral vascular resistance and mean aortic pressure--did not differ significantly between them. As a consequence of different negative chronotropic properties the extent of the observed reflex tachycardia was different: there was no significant heart rate increase after isradipine, an increase by 9.8% (P less than or equal to 0.001) after nifedipine and by 20.4% (P less than or equal to 0.001) after nisoldipine. Left-ventricular pressure-rise velocity as a parameter of myocardial contractility rose by 15.3% in group II (P less than or equal to 0.001) and by 13.5% in group III (p less than or equal to 0.001), but not in group I. These data show, that peripheral equipotent dosages of the three calcium antagonists can have different myocardial effects.

Combination of calcium channel blockers and β‐adrenoceptor blockers for patients with exercise‐induced angina pectoris: a double‐blind parallel‐group comparison of different classes of calcium channel blockers

The combination of calcium channel blockers and beta-adrenoceptor blockers is more effective for the treatment of exercise-induced angina pectoris than beta-adrenoceptor blocker monotherapy. As ischaemia in exercise-induced angina is preceded by increase in heart rate, calcium channel blockers with negative chronotropic properties may perform better for this purpose than nonchronotropic compounds. A 335 patient double-blind parallel-group study comparing 14 day treatment with amlodipine 5 and 10 mg, with diltiazem 200 and 300 mg, and mibefradil 50 and 100 mg added to baseline beta-adrenoceptor blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. Although none of the calcium channel blockers improved duration of exercise or amount of workload, all significantly delayed onset of 1 mm ST-segment depression on ETT (P<0.001 for any treatment vs baseline). In addition, mibefradil, both low and high dose treatment, produced the longest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 s, respectively, P<0. 003 and <0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 s, respectively, P<0.001 and <0.001). These effects were linearly correlated with the reduction in rate pressure product (RPP). Serious symptoms of dizziness occurred significantly more frequently on mibefradil (P<0.05), and 19 patients on mibefradil withdrew from trial. Calcium channel blockers with negative chronotropic properties provide greater delay of ischaemia in patients with exercise-induced angina, but the concomitant risk of intolerable dizziness attenuates this benefit.

Fetal atrial flutter: Diagnosis, clinical features, treatment, and outcome

Objectives: To assess clinical features, treatment efficacy, and outcome of fetal atrial flutter. Study design: All atrial flutter cases seen in our unit between 1988 and 1995 were reviewed retrospectively and compared with the pooled data of 37 echocardiographically documented and published cases. Results: Atrial flutter was found in 15 of 49 (30.6%) fetuses who had been referred because of clinically relevant tachyarrhythmia. Mean age at detection was 34 ± 4 weeks' gestation. Atrial flutter was incessant in 11 and intermittent in 4, with a mean atrial rate of 442 ± 65 beats/min and a mean ventricular rate of 216 ± 28 beats/min. A predominance of 2:1 atrioventricular conduction was observed. In 5 of 15 cases another form of arrhythmia (supraventricular tachycardia, chaotic atrial rhythm, ventricular extrasystoles) coexisted with atrial flutter. Eleven fetuses were treated with maternal digoxin, and five subsequently converted to sinus rhythm. Four fetuses received no medication; of these four, two showed brief self-limited episodes of atrial flutter and two were delivered after detection of the arrhythmia. Only one fetus (6.7%), who did not respond to drug therapy, was delivered prematurely because of mild congestive heart failure. Seven neonates were in atrial flutter at birth; rhythm control could be easily achieved with sotalol or digoxin ( n = 5), flecainide ( n = 1), or electroconversion ( n = 1) within the first 2 days of life without any relapse. Conclusion: Fetal atrial flutter accounts for approximately one third of all clinically relevant tachyarrhythmia. Although the suppression rate of incessant atrial flutter with digoxin is only 50%, this therapy may be useful for its positive inotropic and negative chronotropic properties. In our experience most fetuses with therapy-resistant atrial flutter and absence of 1:1 atrioventricular conduction do not experience congestive heart failure and do not need to be delivered prematurely. After birth, conversion to sinus rhythm was easily achieved in all neonates. (J Pediatr 1998;132:335-9)

Can neurons in the nucleus ambiguus selectively regulate cardiac rate and atrio-ventricular conduction?

Previous anatomic data have described the distribution of presumptive negative chronotropic and negative dromotropic neurons in the ventro-lateral nucleus ambiguus (NA-VL) following injections of retrograde tracers into physiologically selective parasympathetic intracardiac ganglia. Negative dromotropic neurons were preferentially distributed in the rostral NA-VL (rNA-VL). Negative chronotropic neurons were preferentially distributed in the caudal NA-VL (cNA-VL). Significant numbers of both types of cardio-inhibitory neurons were observed to overlap in an intermediate level of the NA-VL (iNA-VL). In the present report, we have examined the effects of microinjections of the excitatory amino-acid glutamate (GLU) into the cNA-VL and iNA-VL on cardiac rate and AV conduction while recording the electrocardiogram in paced and non-paced cat hearts. The data indicate that: (i) excitation of neurons in the cNA-VL causes a 58 ± 17% reduction in cardiac rate, without influencing AV conduction; and (ii) excitation of neurons in the iNA-VL causes both a reduction in heart rate (68 ± 12%) and a decrease in the rate of AV conduction (38 ± 7%). These physiological results support the anatomical inference that neurons in the cNA-VL that are retrogradely labeled from physiologically selective parasympathetic intracardiac ganglia selectively exhibit negative chronotropic properties. Furthermore, the data indicate that there is a longitudinal cardiotopic organization of both negative chronotropic and negative dromotropic neurons in the NA-VL. This CNS organization mirrors the peripheral organization of functionally selective cardiac components of the vagus nerve. Finally, the data are consistent with the hypothesis that anatomically separated and functionally selective parasympathetic preganglionic vagal motoneurons in the NA independently control cardiac rate and AV conduction.

Diaspirin crosslinked hemoglobin (DCLHb): control of pressor effect with anti-hypertensive agents.

Diaspirin crosslinked hemoglobin (DCLHb) administration elevates mean arterial pressure (MAP). The purpose of this study was to determine whether commonly used antihypertensive agents could control this pressor effect in rats. Awake rats were injected intravenously (i.v.) with 280 mg/kg of DCLHb. Fifteen minutes later when MAP was 25-30% above baseline and heart rate (HR) was reciprocally decreased, prazosin (2 mg/kg;an alpha adrenergic blocker), nitroglycerine (NTG; 10-150 mcg/min; a nitrovasodilator), nicardipine (0.204-0.08 mg/hr; a calcium channel blocker) or labetalol (5 mg/kg; an alpha/beta adrenergic blocker) was administered i.v. All four classes of antihypertensive agents promptly restored MAP to baseline. Coincident with the return of MAP to baseline, HR was restored to baseline in prazosin and NTG treated animals, however, bradycardia persisted in those animals treated with nicardipine and labetalol, most likely due to the negative chronotropic properties of these agents. We conclude that the pressor effect of DCLHb can be readily controlled with at least four different classes of commonly used antihypertensive agents.

Diltiazem and the reduction of reperfusion-induced arrhythmias in the rat: Protection is secondary to modification of ischemic injury and heart rate

We have used the isolated rat heart with transient coronary artery occlusion to investigate whether diltiazem has an anti-arrhythmic action against reperfusion-induced ventricular arrhythmias. In the first series of studies (early administration group) the drug was administered 5 min prior to the induction of regional ischemia, this resulted in a dose-dependent reduction in reperfusion-induced ventricular fibrillation. With 5 X 10(-8), 10(-7), 5 X 10(-7), 10(-6) and 5 X 10(-6) mols of diltiazem/l, total ventricular fibrillation (reversible plus irreversible) was reduced from its control incidence of 100% (12/12) to 91%, 58% (P = less than 0.05), 17% (P = less than 0.001), 0% (P = less than 0.001) and 0% (P = less than 0.001) respectively. Heart rate was also reduced in a dose-dependent manner, falling from its control value of 268 +/- 6 beats/min to less than 50% with the highest concentration of diltiazem. Coronary flow was increased in a dose-dependent manner in the diltiazem treated groups. In additional studies with an anti-arrhythmic dose of diltiazem (5 X 10(-7) mols/l), hearts were paced to their drug free control value; under these conditions the anti-arrhythmic effect of diltiazem was lost. In further studies, diltiazem (10(-7) and 5 X 10(-7) mols/l) was administered just prior to reperfusion (late administration group), no anti-arrhythmic effects were observed. In additional studies we determined whether, with early administration, diltiazem (5 X 10(-7) mols/l) exerted its anti-arrhythmic effect by altering the relationship between the vulnerability to reperfusion-induced arrhythmias and the duration of preceding ischemia. In diltiazem-free control hearts a bell-shaped profile was observed with a maximum vulnerability after 10 min of ischemia (100% incidence of reperfusion-induced ventricular fibrillation). In diltiazem-treated hearts, a bell-shaped curve was also observed, however, its optimum was shifted to the right and downwards (20 min of ischemia gave maximum vulnerability [41%] to reperfusion-induced arrhythmias). We conclude that the ability of diltiazem to protect the isolated rat heart against reperfusion-induced arrhythmias is secondary to its anti-ischemic effect and in particular to its negative chronotropic properties.

Acute cardiovascular toxicity of thallium (I) ions.

The acute cardiovascular toxicity of thallium (I)-ions was studied in anesthetized rats and also in some isolated preparations. In pentobarbital-anesthetized rats, intravenously applied Tl2SO4 (range 3 to 100 mg/kg) caused a significant, dose-dependent decrease in mean arterial blood pressure and heart rate. In spontaneously beating guinea pig isolated atria, thallium (I)-ions (10(-5) to 10(-3) M) caused a concentration-dependent decrease in frequency, which was not influenced by atropine, cocaine, or by considerable changes in the potassium concentration of the medium. A direct influence of Tl+ on the sinus node is presumed. Thallium decreases contractile force probably as a result of its negative chronotropic properties, since the amplitude of contraction remained uninfluenced in electrically driven atria. Thallium (I)-ions were readily taken up by the guinea pig isolated atria. At a bath concentration of 5 times 10(-5) M Tl+ a tissue/medium ratio of approximately 45 was achieved. Probably, an exchange against cellular potassium takes place. Relaxation of vascular smooth muscle by Tl+ was demonstrated both in isolated aortic strips (rabbit) and in the isolated perfused rabbit ear preparation. Both the vascular smooth muscle relaxation and the decrease in heart rate would explain the acute hypotensive effect of thallium.