Raghuveer Dendi

Orthostatic hypotension from sympathetic denervation in Parkinson's disease

Background Patients with PD often have signs or symptoms of autonomic failure, including orthostatic hypotension. Cardiac sympathetic denervation occurs frequently in PD, but this has been thought to occur independently of autonomic failure. Methods Forty-one patients with PD (18 with and 23 without orthostatic hypotension) and 16 age-matched healthy volunteers underwent PET scanning to visualize sympathetic innervation after injection of 6-[18F]fluorodopamine. Beat-to-beat blood pressure responses to the Valsalva maneuver were used to identify sympathetic neurocirculatory failure and plasma norepinephrine to indicate overall sympathetic innervation. Results All patients with PD and orthostatic hypotension had abnormal blood pressure responses to the Valsalva maneuver and septal and lateral ventricular myocardial concentrations of 6-[18F]fluorodopamine-derived radioactivity >2 SD below the normal mean. In contrast, only 6 of the 23 patients without orthostatic hypotension had abnormal Valsalva responses (p < 0.0001 compared with patients with orthostatic hypotension), and only 11 had diffusely decreased 6-[18F]fluorodopamine-derived radioactivity in the left ventricular myocardium (p = 0.0004). Of the 12 remaining patients without orthostatic hypotension, 7 had locally decreased myocardial radioactivity. Supine plasma norepinephrine was lower in patients with than in those without orthostatic hypotension (1.40 ± 0.15 vs 2.32 ± 0.26 nmol/L, p = 0.005). 6-[18F]fluorodopamine-derived radioactivity was less not only in the myocardium but also in the thyroid and renal cortex of patients with PD than in healthy control subjects. Conclusions In PD, orthostatic hypotension reflects sympathetic neurocirculatory failure from generalized sympathetic denervation.

Cardiac Sympathetic Dysautonomia in Chronic Orthostatic Intolerance Syndromes

Background—In postural tachycardia syndrome (POTS) and repeated neurocardiogenic presyncope (NCS), orthostatic intolerance occurs without persistent sympathetic neurocirculatory failure. Whether these conditions involve abnormal cardiac sympathetic innervation or function has been unclear. Methods and Results—Patients with POTS or NCS underwent measurements of neurochemical indices of cardiac release, reuptake, and synthesis of the sympathetic neurotransmitter norepinephrine based on entry of norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover), cardiac extraction of circulating 3H-norepinephrine, and cardiac production of dihydroxyphenylalanine and measurement of left ventricular myocardial innervation density using 6-[18F]fluorodopamine positron emission tomographic scanning. Mean cardiac norepinephrine spillover in POTS (171±30 pmol/min, N=16) was higher and in NCS (62±9 pmol/min, N=20) was lower than in a large group of healthy volunteers (102±9 pmol/min, N=52) and in a subgroup of age-matched healthy women (106±18 pmol/min, N=11). Both patient groups had normal cardiac extraction of 3H-norepinephrine, normal cardiac production of dihydroxyphenylalanine, and normal myocardial 6-[18F]fluorodopamine-derived radioactivity. Conclusions—POTS and NCS differ in tonic cardiac sympathetic function, with increased cardiac norepinephrine release in the former and decreased release in the latter. Both groups had normal values for indices of function of the cell membrane norepinephrine transporter, norepinephrine synthesis, and density of myocardial sympathetic innervation. Because POTS and NCS both include specific abnormalities of cardiac sympathetic function, both can be considered forms of dysautonomia.

Radiofrequency Ablation of Premature Ventricular Ectopy Improves the Efficacy of Cardiac Resynchronization Therapy in Nonresponders

OBJECTIVES This study sought to examine whether suppressing premature ventricular contractions (PVC) using radiofrequency ablation improves effectiveness of the cardiac resynchronization therapy (CRT) in nonresponders. BACKGROUND CRT is an effective strategy for drug refractory congestive heart failure. However, one-third of patients with CRT do not respond clinically, and the causes for nonresponse are poorly understood. Whether frequent PVC contribute to CRT nonresponse remains unknown. METHODS In this multicenter study, CRT nonresponders with >10,000 PVC in 24 h who underwent PVC ablation were enrolled from a prospective database. RESULTS Sixty-five subjects (age 66.6 ± 12.4 years, 78% men, QRS duration of 155 ± 18 ms) had radiofrequency ablation of PVC from 76 foci. Acute and long-term success rates of ablation were 91% and 88% in 12 ± 4 months of follow-up. There was significant improvement in left ventricular (LV) ejection fraction (26.2 ± 5.5% to 32.7 ± 6.7 %, p < 0.001), LV end-systolic diameter (5.93 ± 0.55 cm to 5.62 ± 0.32 cm, p < 0.001), LV end-diastolic diameter (6.83 ± 0.83 cm to 6.51 ± 0.91 cm, p < 0.001), LV end-systolic volume (178 ± 72 to 145 ± 23 ml, p < 0.001), LV end-diastolic volume (242 ± 85 ml to 212 ± 63 ml, p < 0.001), and median New York Heart Association functional class (3.0 to 2.0, p < 0.001). Modeling of pre-ablation PVC burden revealed an improvement in ejection fraction when the pre-ablation PVC burden was >22% in 24 h. CONCLUSIONS Frequent PVC is an uncommon yet significant cause of CRT nonresponse. Radiofrequency ablation of PVC foci improves LV function and New York Heart Association class and promotes reverse remodeling in CRT nonresponders. PVC ablation may be used to enhance CRT efficacy in nonresponders with significant PVC burden.

Baroreflex Failure as a Late Sequela of Neck Irradiation

Abstract—Combined chemotherapy and radiotherapy increase long-term survival in patients with head and neck tumors. Late complications of treatment, however, are being recognized increasingly. Surgery or radiotherapy of the carotid sinuses or brain stem can evoke labile hypertension and orthostatic intolerance from acute or subacute baroreflex failure. Here we report cases in which chronic baroreflex failure appeared to develop as a late sequela of neck irradiation. Three patients referred for autonomic nervous system function testing had labile blood pressure and chronic orthostatic intolerance that developed years after neck irradiation for cancer. In each patient, heart rate remained constant during performance of the Valsalva maneuver, suggesting baroreflex-cardiovagal failure. All 3 patients had virtually zero baroreflex-cardiovagal gain, quantified by interbeat interval–systolic blood pressure relationships after intravenous phenylephrine or nitroglycerine. Ambulatory blood pressure monitoring revealed highly variable blood pressure, with sudden pressor and depressor episodes, a characteristic feature of baroreflex failure. Cardiovagal efferent function, assessed by power spectral analysis of heart rate variability during slow, deep respiration, was normal. Sympathetic noradrenergic efferent function, assessed by cold pressor testing and plasma catecholamine levels during supine rest and orthostasis, was also normal or increased. These findings indicated a primarily afferent lesion. Carotid ultrasonography revealed intimal thickening and atheromatous plaques in all 3 patients. We propose that labile hypertension and orthostatic intolerance can develop as a late sequela of neck irradiation, due to chronic carotid baroreflex failure, which in turn is due to radiation-induced accelerated development of carotid arteriosclerosis. Splinting of carotid sinus mechanoreceptors in rigidified arterial walls would impede detection of alterations in blood pressure and thereby disrupt baroreflex regulation of cardiovagal and sympathetic outflows.

Progressive loss of cardiac sympathetic innervation in Parkinson's disease.

This study addressed whether cardiac sympathetic denervation progresses over time in Parkinsons disease. In 9 patients without orthostatic hypotension, 6‐[18F]fluorodopamine positron emission tomography scanning was repeated after a mean of 2 years from the first scan. 6‐[18F]fluorodopamine‐derived radioactivity was less in the second scan than in the first scan, by 31% in the left ventricular free wall and 16% in the septum. In Parkinsons disease, loss of cardiac sympathetic denervation progresses in a pattern of loss suggesting a dying‐back mechanism.

Pandysautonomia associated with impaired ganglionic neurotransmission and circulating antibody to the neuronal nicotinic receptor

Abstract. We report the case of a patient with chronic autonomic failure who had evidence of decreased postganglionic traffic to intact sympathetic nerve terminals. The patient complained mainly of decreased salivation, constipation, dry skin, and orthostatic intolerance. There was no evidence of central neurodegeneration. Autonomic function testing showed orthostatic hypotension without tachycardia and abnormal blood pressure and pulse rate responses to the Valsalva maneuver, indicating combined sympathetic and parasympathetic neurocirculatory failure. In contrast to patients with pure autonomic failure, the patient had normal left ventricular myocardial concentrations of 6-[18F]fluorodopamine-derived radioactivity, establishing intact postganglionic sympathetic innervation; and in contrast to patients with multiple system atrophy or baroreflex failure, the patient had a low plasma norepinephrine concentration and brisk norepinephrine response to orthostasis. These findings indicated an impediment to ganglionic neurotransmission. Serologic testing demonstrated a circulating antibody to the ganglionic nicotinic acetylcholine receptor. The findings in this case support the concept that circulating antibodies to this receptor can interfere with ganglionic neurotransmission and produce autoimmune autonomic neuropathy.

Liquid ventilation with perfluorocarbons facilitates resumption of spontaneous circulation in a swine cardiac arrest model

BACKGROUND Induced external hypothermia during ventricular fibrillation (VF) improves resuscitation outcomes. Our objectives were twofold (1) to determine if very rapid hypothermia could be achieved by intrapulmonary administration of cold perfluorocarbons (PFC), thereby using the lungs as a vehicle for targeted cardiopulmonary hypothermia, and (2) to determine if this improved resuscitation success. METHODS Part 1: Nine female swine underwent static intrapulmonary instillation of cold perfluorocarbons (PFC) during electrically induced VF. Part 2: Thirty-three female swine in VF were immediately ventilated via total liquid ventilation (TLV) with pre-oxygenated cold PFC (-15 degrees C) or warm PFC (33 degrees C), while control swine received no ventilation during VF. All swine in both Parts 1 and 2 underwent VF arrest for 11 min, then defibrillation, ventilation and closed chest massage until resumption of spontaneous circulation (ROSC). The endpoint was continued spontaneous circulation for 1h without pharmacologic support. RESULTS Static intrapulmonary instillation of cold PFC achieved rapid cardiopulmonary hypothermia; pulmonary artery (PA) temperature of 33.5+/-0.2 degrees C was achieved by 10 min. Nine of 9 achieved ROSC. Hypothermia was achieved faster using TLV: at 6 min VF, cold TLV temperature was 32.9+/-0.4 degrees C vs. cold static instillation temperature 34.3+/-0.2 degrees C. Nine of 11 cold TLV swine achieved ROSC for 1h vs. 3 of 11 control swine (p=0.03). Warm PFC also appeared to be beneficial, with a trend toward greater achievement of ROSC than control (ROSC; warm PFC 8 of 11 vs. control 3 of 11, p=0.09). CONCLUSION Targeted cardiopulmonary intra-arrest moderate hypothermia was achieved rapidly by static intrapulmonary administration of cold PFC and more rapidly by total liquid ventilation with cold PFC; resumption of spontaneous circulation was facilitated. Warm PFC showed a trend toward facilitating ROSC.

Neurotransmitter specificity of sympathetic denervation in Parkinson’s disease

In PD, orthostatic hypotension reflects sympathetic noradrenergic denervation. The authors assessed sympathetic cholinergic innervation by the quantitative sudomotor axon reflex test (QSART) in 12 patients who had sympathetic neurocirculatory failure, markedly decreased cardiac 6-[18F] fluorodopamine-derived radioactivity, and subnormal plasma norepinephrine increments during standing. All 12 had normal QSART results. The sympathetic nervous system lesion in PD involves loss of postganglionic catecholaminergic but not cholinergic nerves.

Radiofrequency ablation of atrial fibrillation in patients with mitral or aortic mechanical prosthetic valves: A feasibility, safety, and efficacy study

BACKGROUND Patients with prosthetic valves have a high prevalence of atrial fibrillation (AF). We report a multicenter experience of performing pulmonary vein antral isolation (PVAI) in this challenging, high-risk cohort of patients. OBJECTIVE The purpose of this study was to assess the feasibility, safety, and efficacy of radiofrequency (RF) ablation for sinus rhythm restoration in AF patients with mitral or aortic mechanical prosthetic valves. METHODS A total of 50 patients with prosthetic valves (group I) who underwent RF ablation for AF between January 1, 2007, and April 30, 2009, were identified prospectively at four tertiary care centers. A matched group of 50 patients (group II) acted as controls. RESULTS Total procedural time (199.4 ± 49 minutes vs 166.6 ± 27.5 minutes, P <.001) and fluoroscopy time (60 ± 17 minutes vs 53.8 ± 6.8 minutes, P <.01) were prolonged, with a higher incidence of atrial flutter at 3 months in group I (18% vs 6%, P = .1) compared to group II. At 12 months, 80% of patients in the valve group were in sinus rhythm after an average of 1.3 procedures, and 82% of controls were in sinus rhythm after an average 1.2 procedures (P = .9). There was a trend toward a higher nonfatal complication rate in the valve group than in the control group (8% vs 4%, P = .1). CONCLUSION In patients with prosthetic valves, RF ablation for AF is feasible, safe, and efficacious, with a trend toward a higher nonfatal complication rate and an increased rate of postablation atrial flutter.

Sex and Catheter Ablation for Ventricular Tachycardia: An International Ventricular Tachycardia Ablation Center Collaborative Group Study.

Importance Significant differences have been described between women and men regarding presentation, mechanism, and treatment outcome of certain arrhythmias. Previous studies of ventricular tachycardia (VT) ablation have not included sufficient women for meaningful comparison. Objective To compare outcomes between women and men with structural heart disease undergoing VT ablation. Design, Setting, and Participants Investigator-initiated, multicenter, observational study performed between 2002 and 2013, conducted by the International VT Ablation Center Collaborative Group, consisting of 12 high-volume ablation centers. Consecutive patients with structural heart disease undergoing VT ablation were studied. Structural heart disease was defined as left ventricular ejection fraction less than 55%, hypertrophic cardiomyopathy, or right ventricular cardiomyopathy, with scar confirmed during electroanatomic mapping. Exposures Catheter ablation. Main Outcomes and Measures Ventricular tachycardia-free survival and transplant-free survival were compared between women and men. Cox proportional hazard modeling was performed. Results Of 2062 patients undergoing ablation, 266 (12.9%) were women. Mean (SD) age was 62.4 (13.3) years and 1095 (53.1%) had ischemic cardiomyopathy. Compared with men, women were younger, with higher left ventricular ejection fraction and less VT storm. Despite this, women had higher rates of 1-year VT recurrence following ablation (30.5% vs 25.3%; P = .03). This difference was only partially explained by higher prevalence of nonischemic cardiomyopathy among women and was actually most pronounced among those with ischemic cardiomyopathy. Conclusions and Relevance In 12 high-volume ablation centers, women with structural heart disease have worse VT-free survival following ablation than men. Whether this is owing to differences in referral pattern, arrhythmia substrate, or undertreatment requires further study.