New Insights Into Pacemaker Activity

Dobrzynski, Halina; Boyett, Mark R.; Anderson, Robert H.

doi:10.1161/circulationaha.106.616011

Cited by 372 publications

(222 citation statements)

References 105 publications

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“…However, the idea that the sino-atrial node provides a single focus of origin for each beat has been superseded by the understanding that sinus rhythm is controlled by multiple dominant pacemaker sites integrated by a complex ganglionic network (11). It is possible therefore that erratic rhythm is a consequence of the breakdown of this system and might represent a pre-clinical form of sick sinus syndrome, although sick sinus syndrome per se is found in only 1 in 600 cardiac patients over 65 years old (12). Other evidence suggests that erratic rhythm can be a consequence of high sympathetic activation.…”

Section: Discussionmentioning

confidence: 99%

Development of more erratic heart rate patterns is associated with mortality post–myocardial infarction

Stein

Domitrovich

2008

Journal of Electrocardiology

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Cardiac patients often have sinus arrhythmia of non-respiratory origin [erratic sinus rhythm" (ESR)]. ESR was quantified using hourly Poincaré and power spectral HRV plots from normal-to-normal interbeat intervals (N-Ns) and hourly values of the short-term fractal scaling exponent and correlations of N-Ns in N=60 non-survivors and N=66 randomly-selected survivors in the Cardiac Arrhythmia Suppression Trial. Hours were coded (ABN) as normal (0), borderline (0.5) or ESR (1). T-tests compared ABN for N=2413 paired hours at baseline and on therapy. ABN was higher in nonsurvivors (0.38 ± 0.44 vs. 0.28 ± 0.40, baseline and 0.51 ± 0.45 vs. 0.34 ± 0.43, on therapy, p<0.001). Increased ABN with treatment was greater in non-survivors. Normal hours at baseline (RR=0.77, 095% CI=0.62−0.96, p=0.018) and on treatment (RR=0.47, 95%CI=0.39−0.58) were significantly associated with decreased mortality compared to ESR. Quantification of ESR may identify more vulnerable patients or help monitor the effects of pharmacological treatment. Keywordsheart rate; risk factor; mortality; post-MI; anti-arrhythmic The analysis of heart rate variability (HRV) provides information about cardiac autonomic function. However, we have found that many older subjects and patients with cardiovascular disease have an increased beat-to-beat variability that is irregular and does not reflect underlying respiratory sinus arrhythmia (1). We have called this erratic rhythm. The presence of erratic rhythm, which is frequently episodic, increases values for short-term HRV indices such as rMSSD [root mean square of successive differences of normal-to-normal (N-N) interbeat intervals in ms], pNN50 [the % of N-N intervals >50 ms different from the previous interval) and high frequency power (the amount of variance in N-N intervals at respiratory frequencies, i.e., 0.15−0.4 Hz) that quantify beat-to-beat variability. Thus, in the presence of erratic rhythm, increased short-term HRV does not, as it does for younger people, necessarily reflect greater parasympathetic control of heart rate. A high prevalence of erratic rhythm may also explain why HRV measures that are believed to reflect parasympathetic function have relatively little predictive value for outcomes. At the same time, some "non-linear" HRV measures like the short-term fractal scaling exponent, (DFA1), and (SD12), the ratio of the axes of an ellipse fitted to the Poincaré plot do capture the presence of erratic rhythm (2,3).

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Section: Discussionmentioning

confidence: 99%

Development of more erratic heart rate patterns is associated with mortality post–myocardial infarction

Stein

Domitrovich

2008

Journal of Electrocardiology

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“…3B). SAN dysfunction, which frequently coexists with AF in human patients (21), is a known AF risk factor (22) and significantly associated with prolonged atrial fibrillatory cycle length (23). Both 6-wk-old (n = 4) and 4-mo-old (n = 6) Nkx2.5 Cre ;miR-17-92 flox/flox ;miR-106b-25 null/+ mice had SAN dysfunction, with more frequent and longer arrhythmias in 4-mo-old mice.…”

Section: Sinoatrial-node Dysfunction In Mice With Mir-17-92 Cardiac-smentioning

confidence: 99%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3, that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility. irregular heart rate | single nucleotide variant | mouse genetics A trial fibrillation (AF), the most common arrhythmia in adult patients, increases in prevalence with age to almost 5% of the population over 65. Patients with AF have an increased risk of stroke, dementia, and heart failure (1). Electrical impulses that are critical for a coordinated, physiologic heartbeat originate in the sinoatrial node (SAN). In AF, abnormal fibrillatory atrial impulses override normal SAN function, with resultant irregular conduction to the ventricles. Many cases of ectopic electrical activity originate in the pulmonary vein (2). Other sites of ectopy include the left atrial posterior wall, superior vena cava, interatrial septum, crista terminalis, and coronary sinus myocardium (3, 4).Multiple approaches have been used to uncover genes that may contribute to the AF phenotype in adult patients. A seminal genome-wide association study (GWAS), subsequently replicated by multiple studies, uncovered a single nucleotide variant (SNV) on human 4q25 that was strongly associated with familial AF (5). Patients with the 4q25 variant exhibited early onset AF that was independent from other risk factors such as hypertension and diabetes, suggesting a novel biologic mechanism involving genes located on chromosome 4q25. The presence of the 4q25 SNV also had prognostic value because patients with the SNV are prone to cardioembolic str...

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“…Patients with HF have significant sinoatrial node (SAN) remodeling characterized by anatomic and structural changes with a reduction in functional sinus node reserve (1). HF causes extensive remodeling of ionic and gap junction channels in the SAN (2), which is associated with SAN dysfunction, leading to bradycardia and mortality (3)(4)(5). HF doubles the SAN recovery time and suppresses hyperpolarization-activated cyclic nucleotide-gated potassium channel (HCN) expression of the SAN at the mRNA and protein level (6).…”

Section: Introductionmentioning

confidence: 99%

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

Chang

Chuang

Chen

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 µM), a calmodulin kinase II inhibitor (KN-93; 0.3 or 3 µM), a sarcoplasmic reticulum Ca 2+ release inhibitor (ryanodine; 0.3 or 3 µM), a sodium current inhibitor (tetrodotoxin; 1, 3 or 10 µM) and a late sodium current inhibitor (ranolazine; 10 µM). Western blot analysis was used to investigate the protein expression in SANs from normal rabbits and those with HF. Control SANs had a higher beating rate than SANs from rabbits with HF (2.3±0.1 vs. 1.5±0.1 Hz; P<0.001). Similarly, ivabradine (10 µM), KN-93 (3 µM), ranolazine (10 µM) and ryanodine (3 µM) decreased the beating rates of SANs in the control (n=6) and HF (n=6) groups. Ivabradine treatment resulted in a higher incidence of AP block in HF vs. control SANs (66.7 vs. 0%; P<0.05). Tetrodotoxin (1, 3 or 10 µM) decreased the beating rate to a higher extent in SANs from rabbits with HF than in those from control rabbits and induced a higher incidence of AP block (66.7 vs. 0%; P<0.05). Furthermore, SANs from rabbits with HF had higher protein levels of phospholamban (PLB) and lower levels of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, ryanodine receptor and phosphorylated PLB than control SANs. In conclusion, HF modulates electropharmacological responses in the SAN by channel regulation, which may result in SAN dysfunction.

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New Insights Into Pacemaker Activity

Cited by 372 publications

References 105 publications

Development of more erratic heart rate patterns is associated with mortality post–myocardial infarction

Development of more erratic heart rate patterns is associated with mortality post–myocardial infarction

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

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