Cardiac pacemaking is produced by the slow diastolic depolarization phase of the action potential. The hyperpolarization-activated cation current (If) forms an important part of the pacemaker depolarization and consists of two kinetic components (fast and slow). Recently, three full-length cDNAs encoding hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN1-3) have been cloned from mouse brain. To elucidate the molecular identity of cardiac pacemaker channels, we screened a human heart cDNA library using a highly conserved neuronal HCN channel segment and identified two cDNAs encoding HCN channels. The hHCN2 cDNA codes for a protein of 889 amino acids. The HCN2 gene is localized on human chromosome 19p13.3 and contains eight exons spanning approximately 27 kb. The second cDNA, designated hHCN4, codes for a protein of 1203 amino acids. Northern blot and PCR analyses showed that both hHCN2 and hHCN4 are expressed in heart ventricle and atrium. When expressed in HEK 293 cells, either cDNA gives rise to hyperpolarization-activated cation currents with the hallmark features of native If. hHCN2 and hHCN4 currents differ profoundly from each other in their activation kinetics, being fast and slow, respectively. We thus conclude that hHCN2 and hHCN4 may underlie the fast and slow component of cardiac If, respectively.

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Two pacemaker channels from human heart with profoundly different activation kinetics

Pacemaker activity of automatic cardiac myocytes controls the heartbeat in everyday life. Cardiac automaticity is under the control of several neurotransmitters and hormones and is constantly regulated by the autonomic nervous system to match the physiological needs of the organism. Several classes of ion channels and proteins involved in intracellular Ca2+ dynamics contribute to pacemaker activity. The functional role of voltage-gated calcium channels (VGCCs) in heart automaticity and impulse conduction has been matter of debate for 30 years. However, growing evidence shows that VGCCs are important regulators of the pacemaker mechanisms and play also a major role in atrio-ventricular impulse conduction. Incidentally, studies performed in genetically modified mice lacking L-type Cav1.3 (Cav1.3-/-) or T-type Cav3.1 (Cav3.1-/-) channels show that genetic inactivation of these channels strongly impacts pacemaking. In cardiac pacemaker cells, VGCCs activate at negative voltages at the beginning of the diastolic depolarization and importantly contribute to this phase by supplying inward current. Loss-of-function of these channels also impairs atrio-ventricular conduction. Furthermore, inactivation of Cav1.3 channels promotes also atrial fibrillation and flutter in knockout mice suggesting that these channels can play a role in stabilizing atrial rhythm. Genomic analysis demonstrated that Cav1.3 and Cav3.1 channels are widely expressed in pacemaker tissue of mice, rabbits and humans. Importantly, human diseases of pacemaker activity such as congenital bradycardia and heart block have been attributed to loss-of-function of Cav1.3 and Cav3.1 channels. In this article, we will review the current knowledge on the role of VGCCs in the generation and regulation of heart rate and rhythm. We will discuss also how loss of Ca2+ entry through VGCCs could influence intracellular Ca2+ handling and promote atrial arrhythmias.

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Functional role of voltage gated Ca2+ channels in heart automaticity

Background: Cardiac arrhythmias in critically ill patients often cause severe hemodynamic impairment or medical complications, precipitating rapid deterioration of patients’ conditions. This manuscript describes common or fatal cardiac arrhythmias occurring in patients hospitalized at intensive care units. Results: Differential diagnosis of wide QRS tachycardias includes ventricular tachycardias (VTs), supraventricular tachycardias with aberrant conduction and noise artifacts. Idiopathic VTs in patients with structurally normal hearts are responsive to antiarrhythmic agents and are cured by catheter ablation. Ventricular tachycardias in structural heart diseases require amiodarone for acute suppression and implantable defibrillator for longterm management. Polymorphic VTs or Torsades de Pointes are effectively suppressed by intravenous infusion of magnesium. Discontinuation of offending agents and, in some refractory cases, installation of temporary pacing is necessary. Atrial fibrillation (AF) is the most commonly observed tachyarrhythmias in intensive care settings. When combined with sepsis or congestive heart failure, AF with rapid ventricular response induces hypotension and sympathetic stimulation, which again aggravates rapid ventricular responses. This viscious cycle continues until adequate rate control measures are initiated. Intravenous amiodarone and anticoagulation are important initial management. In rare cases, electrical noises mimic ventricular tachycardias. Noises are distinguished from true VTs by identification of sharp QRS notches and stable hemodynamics during the events. Conclusion: Proper interpretation of monitoring or standard ECG is crucial for differential diagnosis of cardiac arrhythmias occurring in intensive care units. Management should be tailored based upon arrhythmia characteristics and individual medical conditions. J Neurocrit Care 2014;7(1):25-32

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Cardiac Arrhythmias in the Intensive Care Units

Klinische Beobachtungen einer gestorten Sinusknotenfunktion bzw. sinu-atrialen Uberleitung weisen auf das Jahr 1902 zuruck, als MacKenzie [28] erstmals einen sinuaurikularen Block beschrieb. Laslett [26] konnte bereits im Jahre 1909 Adams-Stokes-Anfalle bei Sinusknotenstillstand graphisch dokumentieren. Uber synkopale Anfalle bei alternierenden Brady-und Tachyarrhythmien berichtete 1954 erstmals Short [38]. Greenwood und Finkelstein [18] publizierten im Jahre 1964 eine Sammlung der Weltliteratur von 224 Fallen eines SA-Blockes. Ferrer [14] gebuhrt mit der zusammenfassenden Bezeichnung Sick-Sinus-Syndrom das Verdienst, im Jahre 1968 auf eine Erkrankung hingewiesen zu haben, die durch verschiedene Storungen der Sinusknotenfunktion bedingt ist und sich in unterschiedlicher Form manifestiert.

Pathophysiologie und Klinik des Sick-Sinus-Syndroms

An 30 Patienten mit gesundem Sinusknoten wurde der Einflus von artifizieller Frequenzerhohung, Atropin und Betarezeptorenblockade auf die „sogenannte” Sinusknotenerholungszeit (SKE) gepruft. Die Untersuchungen wurden bei 3 Stimulationszykluslangen vor und nach intravenoser Gabe von 1 mg Atropin (13 Patienten) oder 0,4 mg Visken®) (17 Patienten) durchgefuhrt.

Die Wirkung von artifizieller Frequenzsteigerung, Atropin und Betarezeptorenblockade auf das funktionelle Verhalten des gesunden menschlichen Sinusknotens

Just H

Papers

Sinus node disease