Kalyanam Shivkumar

Molecular and Cellular Biology Program, Seattle, Washington, United States

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Publications (293)1372.65 Total impact

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    ABSTRACT: Objective: Sympathoexcitation is associated with ventricular arrhythmogenesis. The aim of this study was to determine the role of thoracic dorsal root afferent neural inputs to the spinal cord in modulating ventricular sympathetic control of normal heart electrophysiology. We hypothesize that dorsal root afferent input tonically modulates basal and evoked efferent sympathetic control of the heart. Methods: A 56-electrode sock placed on the epicardial ventricle in anesthetized Yorkshire pigs (n=17) recorded electrophysiological function; Activation Recovery Interval (ARI) and Dispersion in ARI, at baseline conditions and during stellate ganglion electrical stimulation. Measures were compared between intact states and sequential unilateral T1-T4 dorsal root transection (DRTx), ipsilateral ventral root transection (VRTx), and contralateral dorsal and ventral root transections (DVRTx). Results: Left or right DRTx decreased global basal ARI; Lt.DRTx 369 ± 12 to 319 ± 13 ms (p < 0.01) and Rt.DRTx 388 ± 19 to 356 ± 15 ms (p < 0.01). Subsequent unilateral VRTx followed by contralateral DRx+VRTx induced no further change. In intact states, left (LSS) and right (RSS) stellate ganglion stimulation shortened ARIs (6±2% vs 17±3%), while increasing dispersion (+139% vs +88%,). There was no difference in magnitude of ARI or dispersion change with stellate stimulation following spinal root transections. Conclusions: Interruption of thoracic spinal afferent signaling results in enhanced basal cardiac sympathoexcitability without diminishing the sympathetic response to stellate ganglion stimulation. This suggests spinal dorsal root transection releases spinal cord mediated tonic inhibitory control of efferent sympathetic tone while maintaining intrathoracic cardio-centric neural networks.
    No preview · Article · Dec 2015 · AJP Regulatory Integrative and Comparative Physiology
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    ABSTRACT: Introduction: The safety of ventricular tachycardia (VT) ablation in patients with laminated left ventricular (LV) thrombus has not been examined. Methods: Patients with laminated LV thrombus on transthoracic echocardiogram who underwent scar-mediated VT ablation at two centers from 2010-2013 were retrospectively analyzed. All patients had failed medical therapy. Acute procedural outcomes, complications, and clinical outcomes at one year were assessed. Results: Eight patients (4 ischemic, 4 nonischemic cardiomyopathy) underwent VT ablation in the presence of laminated intracavitary thrombus. Six out of 8 (75%) had electrical storm (ES). The mapping and ablation approach was LV endocardial-only in 3 patients, epicardial-only in 2, combined epicardial-RV endocardial in 2, and combined epicardial-LV endocardial in 1. Major complication (ischemic stroke) occurred in 1 patient 9 days post-procedure. There was no procedural mortality. Complete acute procedural success (noninducibility of any VT after ablation) was achieved in 5 (63%), and partial success (ablation of only clinical VT) in an additional 3 (37%). At 1 year, freedom from VT and survival were achieved in 6 (75%) and 7 (88%) patients, respectively. Conclusion: Initial data suggest ablation of VT in the presence of intracavitary thrombus is feasible, is associated with a similar success rate to historical studies in patients without thrombus, and has an acceptable risk of complications given the high risk nature of patients with ES. Further data is needed; however, the presence of a laminated thrombus should not necessarily preclude ablation in patients who have failed medical therapy for VT in whom ablation is otherwise indicated. This article is protected by copyright. All rights reserved.
    Full-text · Article · Dec 2015 · Journal of Cardiovascular Electrophysiology
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    ABSTRACT: Autonomic dysregulation following myocardial infarction (MI) is an important pathogenic event. The intrinsic cardiac nervous system (ICNS) is a neural network located on the heart that is critically involved in autonomic regulation. The aims of this study were to characterize structural and functional remodeling of the ICNS post-MI in a porcine model (control (n = 16) vs. healed anteroapical MI (n = 16)). In vivo microelectrode recordings of basal activity, as well as responses to afferent and efferent stimuli, were recorded from intrinsic cardiac neurons. 118 neurons from control and 102 neurons from MI animals were functionally classified as afferent, efferent, or convergent (receiving both afferent and efferent inputs). In control and MI, convergent neurons represented the largest subpopulation (47% and 48%, respectively) and had enhanced transduction capacity following MI. Efferent inputs to neurons were maintained post-MI. Afferent inputs were attenuated from the infarcted region (19% in control vs. 7% in MI; P = 0.03), creating a 'neural sensory border zone', or heterogeneity in afferent information. MI reduced transduction of changes in preload (54% in control vs. 41% in MI; P = 0.05). The overall functional network connectivity, or the ability of neurons to respond to independent pairs of stimuli, within the ICNS was reduced following MI. The neuronal response was differentially decreased to ventricular vs. atrial pacing post-MI (63% in control vs. 44% in MI to ventricular pacing; P < 0.01). MI induced morphological and phenotypic changes within the ICNS. The alteration of afferent neural signals, and remodeling of convergent neurons, represents a 'neural signature' of ischemic heart disease. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · The Journal of Physiology
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    O.A. Ajijola · L. Shahabi · S. Khalsa · B.D. Naliboff · K. Shivkumar

    Preview · Article · Nov 2015
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    ABSTRACT: Background: New approaches to ablation of atrial fibrillation (AF) include focal impulse and rotor modulation (FIRM); studies of this technology with short-term follow-up have shown favorable outcomes. Objective: We sought to characterize the long-term results of FIRM ablation in a cohort of patients treated at two academic medical centers. Methods: All FIRM-guided ablation procedures (n=43) at UCLA Medical Center and Virginia Commonwealth University Medical Center performed between 1/2012 and 10/2013 were included for analysis. During AF, FIRM software constructed phase maps from unipolar atrial electrograms to identify putative AF sources. These sites were targeted for ablation, along with pulmonary vein isolation (PVI) in 77% of patients. Results: AF was paroxysmal in 56%, and 67% had prior AF ablation. All patients had rotors identified (mean 2.6±1.2 per patient, 77% in LA). Pre-specified acute procedural endpoint was achieved in 47% of patients (n=20): AF termination (n=4), organization (n=7), or >10% slowing of AF cycle length (n=9). Acute complications occurred in 4 patients (9.3%). At 18±7 months of follow-up, 37% were free from documented recurrent AF after a 3-month blanking period; 21% were free from documented atrial tachyarrhythmias and off antiarrhythmic drugs. Multivariate analysis did not reveal any significant predictors of AF recurrence, including pattern of AF, acute procedural success, or prior failed ablation. Conclusions: Long-term clinical results after FIRM ablation in this cohort of patients showed poor efficacy, different from previously published studies. Randomized studies are needed to evaluate the efficacy and clinical utility of this ablation approach for treating AF.
    No preview · Article · Oct 2015 · Heart rhythm: the official journal of the Heart Rhythm Society

  • No preview · Article · Oct 2015 · Circulation Arrhythmia and Electrophysiology
  • Eric Buch · Kalyanam Shivkumar

    No preview · Article · Sep 2015 · Journal of the American College of Cardiology
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    Full-text · Dataset · Sep 2015
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    ABSTRACT: Aims: Vagal nerve stimulation (VNS) has been shown to have anti-arrhythmic effects, but many of these benefits were demonstrated in the setting of vagal nerve decentralization. The purpose of this study was to evaluate the role of afferent fiber activation during VNS on efferent control of cardiac hemodynamic and electrophysiological parameters. Methods and results: In 37 pigs a 56-electrode sock was placed over the ventricles to record local activation recovery intervals (ARIs), a surrogate of action potential duration. In 12 of 37 animals atropine was given systemically. Right and left VNS were performed under six conditions: both vagal trunks intact (n=25), ipsilateral right (n=11), ipsilateral left (n=14), contralateral right (n=7), contralateral left (n=10), and bilateral (n=25) VNTx. Unilateral VNTx significantly affected heart rate, PR interval, Tau, and global ARIs. Right VNS after ipsilateral VNTx had augmented effects on hemodynamic parameters and increase in ARI, while subsequent bilateral VNTx did not significantly modify this effect (% change in ARI in intact condition: 2.2±0.9% vs. ipsilateral VNTx: 5.3±1.7% and bilateral VNTx: 5.3±0.8%, p<0.05). Left VNS after left VNTx tended to increase its effects on hemodynamics and ARI response (p=0.07), but only after bilateral VNTx did these changes reach significance (intact 1.1±0.5% vs. ipsilateral VNTx 3.6±0.7% and bilateral VNTx 6.6±1.6%, p<0.05 vs. intact). Contralateral VNTx did not modify VNS response. Effect of atropine on ventricular ARI was similar to bilateral VNTx. Conclusions: VNS activates afferent fibers in the ipsilateral vagal nerve, which reflexively inhibit cardiac parasympathetic efferent electrophysiological and hemodynamic effects.
    No preview · Article · Sep 2015 · AJP Heart and Circulatory Physiology
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    Preview · Article · Sep 2015

  • No preview · Article · Sep 2015
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    Preview · Article · Sep 2015
  • Jorge Romero · Olujimi A. Ajijola · Noel Boyle · Kalyanam Shivkumar · Roderick Tung

    No preview · Article · Sep 2015
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    ABSTRACT: Selective, bilateral cervicothoracic sympathectomy has proven to be effective for managing ventricular arrhythmias in the setting of structural heart disease. The procedure currently employed removes the caudal portions of both stellate ganglia, along with thoracic chain ganglia down to T4 ganglia. To define the relative contributions of T1-T2 and the T3-T4 paravertebral ganglia in modulating ventricular electrical function. In anesthetized vagotomised porcine subjects (n=8), the heart was exposed via sternotomy along with right and left paravertebral sympathetic ganglia to the T4 level. A 56-electrode epicardial sock was placed over both ventricles to assess epicardial activation recovery intervals (ARI) in response to individually stimulating right and left stellate vs T3 paravertebral ganglia. Responses to T3 stimuli were repeated following surgical removal of the caudal portions of stellate ganglia and T2 bilaterally. In intact preparations, stellate ganglion vs T3 stimuli (4Hz, 4ms duration) were titrated to produce equivalent decreases in global ventricular ARIs (right-side 85±6 vs 55±10 ms; left-side 24±3 vs 17±7 ms). Threshold of stimulus intensity applied to T3 ganglia to achieve threshold was 3 times that of T1 threshold. ARIs in unstimulated states were unaffected by bilateral stellate-T2 ganglion removal. Following acute decentralization, T3 stimulation failed to change ARIs. Preganglionic sympathetic efferents arising from the T1-T4 spinal cord that project to the heart transit through stellate ganglia via the paravertebral chain. T1-T2 surgical excision is thus sufficient to functionally interrupt central control of peripheral sympathetic efferent activity. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Heart rhythm: the official journal of the Heart Rhythm Society
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    ABSTRACT: The incidence of myocardial inflammation in patients with unexplained cardiomyopathy referred for ventricular arrhythmias (VA) is unknown. To report fasting PET scan findings in consecutive patients referred with unexplained cardiomyopathy and VA. 18-FDG PET/CT scans with a >16 hour fasting protocol were prospectively ordered for patients referred for VA and unexplained cardiomyopathy (EF<55%). Patients with focal myocardial FDG uptake were labeled as arrhythmogenic inflammatory cardiomyopathy (AIC) and classified into four groups based on the presence of lymph node uptake (AIC+) and perfusion abnormalities (early vs late stage). Over a 3-year period, 103 PET scan were performed with 49% (AIC+=17, AIC=33) exhibiting focal FDG uptake. The mean age was 52±12 years with an EF of 36±16%. Patients with AIC were more likely to have a history of pacemaker (32% vs 6%, p=0.002) compared to those with normal PET. When biopsy was performed, histologic diagnosis revealed non-granulomatous inflammation in 6 patients and sarcoidosis in 18 patients. 90% of patients with AIC/AIC+ were prescribed immunosuppressive therapy and 58% underwent ablation. Correlation between areas of perfusion abnormalities and FDG uptake with electro-anatomic mapping was observed in 79% patients and MRI findings matched in only 33%. Nearly 50% of patients referred with unexplained cardiomyopathy and VA demonstrate ongoing focal myocardial inflammation on FDG PET. These data suggests that a significant proportion of patients labeled "idiopathic" may have occult arrhythmogenic inflammatory cardiomyopathy, which may benefit from early detection and immunosuppressive medical therapy. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Aug 2015 · Heart rhythm: the official journal of the Heart Rhythm Society
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    Una Buckley · Kalyanam Shivkumar · Jeffrey L Ardell
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    ABSTRACT: Autonomic regulation therapy (ART) is a rapidly emerging therapy in the management of congestive heart failure secondary to systolic dysfunction. Modulation of the cardiac neuronal hierarchy can be achieved with bioelectronics modulation of the spinal cord, cervical vagus, baroreceptor, or renal nerve ablation. This review will discuss relevant preclinical and clinical research in ART for systolic heart failure. Understanding mechanistically what is being stimulated within the autonomic nervous system by such device-based therapy and how the system reacts to such stimuli is essential for optimizing stimulation parameters and for the future development of effective ART.
    Full-text · Article · Jun 2015 · Current Heart Failure Reports
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    ABSTRACT: Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem, and higher centers), which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes to hours), and long term (days to years). This important neurovisceral/autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death. Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extracardiac neural remodeling has also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention.
    Full-text · Article · Jun 2015 · Circulation Research
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    ABSTRACT: Objectives This study reports multicenter outcomes and complications for catheter ablation of premature ventricular complexes (PVCs) and investigates predictors of procedural success, as well as development of PVC-induced cardiomyopathy. Background Catheter ablation of frequent idiopathic PVCs is used to eliminate symptoms and treat PVC-induced cardiomyopathy. Large-scale multicenter outcomes and complication rates have not been reported. Methods This retrospective cohort study included 1,185 patients (55% female; mean age 52 ± 15 years; mean ejection fraction 55 ± 10%; mean PVC burden 20 ± 13%) who underwent catheter ablation for idiopathic PVCs at 8 centers between 2004 and 2013. The following factors were evaluated: patient demographics, procedural characteristics, complication rates, and clinical outcomes. Results Acute procedural success was achieved in 84% of patients. In centers at which patients were followed up routinely with post-ablation Holter monitoring, continued success at clinical follow-up without use of antiarrhythmic drugs was 71%. Including the use of antiarrhythmic medications, the success rate at a mean of 1.9 years of follow-up was 85%. In a multivariate analysis, the significant predictors of acute success were PVC location and number of distinct PVC configurations (p < 0.03). The only significant predictor of continued success at clinical follow-up was a right ventricular outflow tract PVC location (p < 0.01). In 245 patients (21%) with PVC-induced cardiomyopathy, the mean ejection fraction improved from 38% to 50% (p < 0.01) after ablation. Independent predictors for development of PVC-induced cardiomyopathy were male gender, PVC burden, lack of symptoms, and epicardial PVC origin (p < 0.05). The overall complication rate was 5.2% (2.4% major complications and 2.8% minor complications), and complications were most commonly related to vascular access (2.8%). There was no procedure-related mortality. Conclusions Catheter ablation of frequent PVCs is a low-risk and often effective treatment strategy to eliminate PVCs and associated symptoms. In patients with PVC-induced cardiomyopathy, cardiac function is frequently restored after successful ablation. © 2015 American College of Cardiology Foundation Published By Elsevier Inc.
    No preview · Article · Jun 2015 · JACC Clinical Electrophysiology
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    ABSTRACT: The impact of catheter ablation of ventricular tachycardia (VT) on all-cause mortality remains unknown. To examine the association between VT recurrence after ablation and survival in patients with scar-related VT. Analysis of 2,061 patients with structural heart disease referred for catheter ablation of scar-related VT from 12 international centers was performed. Data on clinical and procedural variables, VT recurrence, and mortality were analyzed. Kaplan-Meier analysis was used to estimate freedom from recurrent VT, transplant, and death. Cox proportional hazards frailty models were used to analyze the effect of risk factors on VT recurrence and mortality. One-year freedom from VT recurrence was 70% (72% in ischemic and 68% in non-ischemic cardiomyopathy). 57 (3%) patients underwent cardiac transplantation and 216 (10%) died during follow-up. At one year, the estimated rate of transplant and/or mortality was 15% (same for ischemic and non-ischemic cardiomyopathy). Transplant-free survival was significantly higher in patients without VT recurrence compared to those with recurrence (90% vs. 71%, p<0.001). In multivariable analysis, recurrence of VT after ablation showed the highest risk for transplant and/or mortality (HR 6.9 (5.3-9.0); p<0.001). In patients with EF<30% and across all NYHA classes, improved transplant-free survival was seen in those without VT recurrence. Catheter ablation of VT in patients with structural heart disease results in 70% freedom from VT recurrence, with an overall transplant and/or mortality rate of 15% at 1 year. Freedom from VT recurrence is associated with improved transplant-free survival, independent of heart failure severity. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · May 2015 · Heart rhythm: the official journal of the Heart Rhythm Society
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    Una Buckley · Kalyanam Shivkumar

    Full-text · Article · May 2015 · Trends in cardiovascular medicine

Publication Stats

3k Citations
1,372.65 Total Impact Points

Institutions

  • 2015
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
  • 2004-2015
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 2001-2015
    • University of California, Los Angeles
      • • Department of Medicine
      • • Division of Cardiology
      • • Department of Radiology
      • • Cardiac Arrhythmia Center
      Los Ángeles, California, United States
    • University of Iowa
      Iowa City, Iowa, United States
  • 2014
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 2000-2014
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 2012
    • Loma Linda University
      • Division of Pediatric Cardiology
      لوما ليندا، كاليفورنيا, California, United States
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 2010-2011
    • Stanford University
      • E. L. Ginzton Laboratory
      Palo Alto, California, United States
    • Canadian Hemochromatosis Society
      Canada
    • Southlake Regional Health Centre
      Bradford West Gwillimbury, Ontario, Canada
  • 2009
    • Oregon Health and Science University
      • Department of Diagnostic Radiology
      Portland, Oregon, United States
    • Keck School of Medicine USC
      Los Ángeles, California, United States
  • 2002
    • Cedars-Sinai Medical Center
      • Division of Cardiology
      Los Angeles, California, United States
  • 2001-2002
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States