Abstract-The sinus node (or sinoatrial node [SAN]), the pacemaker of the heart, is a functionally and structurally heterogeneous tissue, which consists of a large "head" within the right caval vein myocardium and a "tail" along the terminal crest. Here, we investigated its cellular origin and mechanism of formation. Using genetic lineage analysis and explant assays, we identified T-box transcription factor Tbx18-expressing mesenchymal progenitors in the inflow tract region that differentiate into pacemaker myocardium to form the SAN. We found that the head and tail represent separate regulatory domains expressing distinctive gene programs. Tbx18 is required to establish the large head structure, as seen by the existence of a very small but still functional tail piece in Tbx18-deficient fetuses. In contrast, Tbx3-deficient embryos formed a morphologically normal SAN, which, however, aberrantly expressed Cx40 and other atrial genes, demonstrating that Tbx3 controls differentiation of SAN head and tail cardiomyocytes but also demonstrating that Tbx3 is not required for the formation of the SAN structure. Our data establish a functional order for Tbx18 and Tbx3 in SAN formation, in which Tbx18 controls the formation of the SAN head from mesenchymal precursors, on which Tbx3 subsequently imposes the pacemaker gene program. Key Words: heart development Ⅲ progenitors Ⅲ Hcn4 Ⅲ Cx43 Ⅲ transgenic mice T he sinoatrial node (SAN) or sinus node is the most upstream component of the cardiac conduction system. As the primary pacemaker, it serves to initiate and control the rate of electric impulses for the ordered stimulation and contraction of the cardiac chambers. The critical importance of the SAN is reflected in dysfunctions that arise on aging and disease, including sick sinus syndrome, leading to implantation in about one-half of all pacemaker recipients in the United States. 1 The SAN consists of a small group of primitive variably sized myocytes with little contractile filaments and intermingled fibroblasts at the junction of the right venous entrance and the atrium. 2 They form an elongated "comma-shaped" structure that is subdivided into a large "head" in the right superior caval vein bordering the atrium, and a "tail" along the terminal crest. 3,4 The leading pacemaker usually originates from a small number of cells within the SAN, but its location shifts under altered physiological conditions, a phenomenon that likely contributes to both controllability and stability of pacemaker activity. 2,5,6 For example, ␤-adrenergic stimulation in rat causes dominant pacemaker activity to shift cranially into the SAN head region, 7 supporting the notion that functional specialization correlates with structural regionalization in the SAN.The mechanisms underlying the functional regionalization, as well as the pathological mechanisms underlying SAN dysfunction, are only insufficiently understood. Histological studies initially indicated that the mouse SAN forms at approximately embryonic day (E)10 to E11 from myocardium of t...

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AimsVentricular arrhythmias (VA) occur frequently after permanent left ventricular assist device (LVAD) implantation in end stage heart failure. Left ventricular assist device patients require rhythm control in contrast to patients with biventricular support. However, the rationale for implantable cardioverter-defibrillator (ICD) utilization in LVAD patients remains unclear. This study investigated the safety and efficacy of primary prevention ICD therapy and the rate of appropriate ICD interventions in LVAD patients. Methods and resultsWe prospectively collected data from patients receiving LVADs. Patients without previous ICD received an ICD after LVAD implantation for primary prevention. Sixty-one patients with LVAD and ICD were followed prospectively for 365 + 321 days. Nine patients died from thromboembolism or haemorrhage. Overall, the rate of appropriate ICD interventions was 34%, mostly for treatment of monomorphic VT in 52%, polymorphic VT in 13%, and VF in 35%. Seventy-one percent of VA were terminated by overdrive pacing, 29% by shock. Patients with a history of VA before LVAD implantation had a significantly higher 1-year rate for ICD therapy compared with LVAD patients with a primary prevention ICD indication LVAD patients (50 vs. 24%). Similarly, patients with non-ischaemic cardiomyopathy had a significantly higher risk for ICD therapy than patients with ischaemic heart disease (50 vs. 22%). ConclusionImplantable cardioverter-defibrillator therapy is safe and effective in LVAD patients. Ventricular arrhythmias leading to ICD intervention occur frequently in 34% of LVAD patients after 1 year, with large variations depending on the underlying cardiac disease and previous arrhythmia history. Primary prevention ICD indication after LVAD implantation yields high rates of ICD intervention. A history of previous VA strongly predicts future use of ICD treatment after LVAD implantation.--

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Cryoballoon PV isolation significantly modulates the ICANS, but only temporarily for up to 3 months, measured by HRV changes after ablation.