BACKGROUND His bundle pacing (HBP) is the most physiologic form of pacing but associated with higher thresholds and lower success in patients with His-Purkinje conduction disease. Recent reports have described transvenous left bundle branch area pacing (LBBAP). OBJECTIVE We aimed to prospectively evaluate the feasibility and the electrophysiologic and echocardiographic characteristics of LBBAP. METHODS Patients requiring pacing for bradycardia or heart failure indications (failed left ventricular [LV] lead) were prospectively enrolled. LBBAP was performed with a Medtronic 3830 lead. Presence of left bundle branch (LBB) potential, paced QRS morphology/duration, and peak LV activation time (pLVAT) were recorded at implant. Pacing threshold and sensing was assessed at implant and follow-up. Echocardiography was performed to assess the approximate lead location and impact on tricuspid valve function. RESULTS LBBAP was successful in 93 of 100 (93%) patients. Mean age was 75 6 13 years; men 69%, left bundle branch block 24%, right bundle branch block 25%, intraventricular conduction defect 8%. Indications for pacing were atrioventricular (AV) block 54%, sinus node dysfunction 23%, AV node ablation 7%, cardiac resynchronization therapy 11%, HBP lead failure 7%. Baseline QRS duration was 133 6 35 ms. Paced QRS duration was 136 6 17 ms. LBB potentials were observed in 63 patients with left bundle branch-ventricle (LBB-V) interval of 27 6 6 ms. pLVAT was 75 6 16 ms. Pacing threshold at implant was 0.6 6 0.4 V @ 0.5 ms and R waves were 10 6 6 mV and remained stable at median follow-up of 3 months. The lead depth in the septum was approximately 1.4 6 0.23 cm. CONCLUSIONS LBBAP was feasible in a high percentage of patients with low thresholds during acute follow-up. HBP and LBBAP may significantly increase the overall success of physiologic pacing.

Animal reports suggest that reflex activation of cardiac sympathetic nerves can evoke coronary vasoconstriction. Conversely, physiological stress may induce coronary vasodilation to meet an increased metabolic demand. Whether the sympathetic nervous system can modulate coronary vasomotor tone in response to stress in humans is unclear. Coronary blood velocity (CBV), an index of coronary blood flow, can be measured in humans by noninvasive duplex ultrasound. We studied 11 healthy volunteers and measured beat-by-beat changes in CBV, blood pressure, and heart rate during 1) static handgrip for 20 s at 10% and 70% of maximal voluntary contraction; 2) lower body negative pressure at -10 and -30 mmHg for 3 min each; 3) cold pressor test for 90 s; and 4) hypoxia (10% O(2)), hyperoxia (100% O(2)), and hypercapnia (5% CO(2)) for 5 min each. At the higher level of handgrip, mean blood pressure increased (P < 0.001), whereas CBV did not change [P = not significant (NS)]. In addition, during lower body negative pressure, CBV decreased (P < 0.02; and P < 0.01, for -10 and -30 mmHg, respectively), whereas blood pressure did not change (P = NS). The dissociation between the responses of CBV and blood pressure to handgrip and lower body negative pressure is consistent with coronary vasoconstriction. During hypoxia, CBV increased (P < 0.02) and decreased during hyperoxia (P < 0.01), although blood pressure did not change (P = NS), suggesting coronary vasodilation during hypoxia and vasoconstriction during hyperoxia. In contrast, concordant increases in CBV and blood pressure were noted during the cold pressor test, and hypercapnia had no effects on either parameter. Thus the physiological stress known to be associated with sympathetic activation can produce coronary vasoconstriction in humans. Contrasting responses were noted during systemic hypoxia and hyperoxia where mechanisms independent of autonomic influences appear to dominate the vascular end-organ effects.

Based on animal studies, it has been speculated that muscle metabolites sensitize muscle mechanoreceptors and increase mechanoreceptor-mediated muscle sympathetic nerve activity (MSNA). However, this hypothesis has not been directly tested in humans. In this study, we tested the hypothesis that in healthy individuals passive stretch of forearm muscles would evoke significant increases in mean MSNA when muscle metabolite concentrations were increased. In 12 young healthy subjects, MSNA, ECG, and blood pressure were recorded. Subjects performed static fatiguing isometric handgrip at 30% maximum voluntary contraction followed by 4 min of postexercise muscle ischemia (PEMI). After 2 min of PEMI, wrist extension (i.e., wrist dorsiflexion) was performed. The static stretch protocol was also performed during 1) a freely perfused condition, 2) ischemia alone, and 3) PEMI after nonfatiguing exercise. Finally, repetitive short bouts of wrist extension were also performed under freely perfused conditions. This last paradigm evoked transient increases in MSNA but had no significant effect on mean MSNA over the whole protocol. During the PEMI after fatiguing handgrip, static stretch induced significant increases in MSNA (552 +/- 74 to 673 +/- 90 U/min, P < 0.01) and mean blood pressure (102 +/- 2 to 106 +/- 2 mmHg, P < 0.001). Static stretch performed under the other three conditions had no significant effects on mean MSNA and blood pressure. The present data verified that in healthy humans mechanoreceptor(s) stimulation evokes significant increases in mean MSNA and blood pressure when muscle metabolite concentrations are increased above a certain threshold.

Animal studies suggest that prostaglandins in skeletal muscles stimulate afferents and contribute to the exercise pressor reflex. However, human data regarding a role for prostaglandins in this reflex are varied, in part because of systemic effects of pharmacological agents used to block prostaglandin synthesis. We hypothesized that local blockade of prostaglandin synthesis in exercising muscles could attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing exercise. Blood pressure (Finapres), heart rate, and MSNA (microneurography) were assessed in 12 young healthy subjects during static handgrip and postexercise muscle ischemia (PEMI) before and after local infusion of 6 mg of ketorolac tromethamine in saline via Bier block (regional intravenous anesthesia). In the second experiment (n ϭ 10), the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased the prostaglandins synthesis to ϳ33% of the baseline. After ketorolac Bier block, the increases in MSNA from the baseline during the fatiguing handgrip was significantly lower than that before the Bier block (before ketorolac: ⌬502 Ϯ 111; post ketorolac: ⌬348 Ϯ 62%, P ϭ 0.016). Moreover, the increase in total MSNA during PEMI after ketorolac was significantly lower than that before the Bier block (P ϭ 0.014). Saline Bier block had no similar effect. The observations indicate that blockade of prostaglandin synthesis attenuates MSNA responses seen during fatiguing handgrip and suggest that prostaglandins contribute to the exercise pressor reflex.prostaglandins; exercise; nervous system; sympathetic; regional blood flow EXERCISE ELICITS INCREASES in muscle sympathetic nerve activity (MSNA), peripheral vasoconstriction, heart rate, cardiac output, and blood pressure (27,29). It is believed that inputs from mechanically and chemically sensitive afferents from the exercising muscles are primarily responsible for this exercise pressor reflex (19,28,29). Group III and IV afferent fibers in muscles are suggested to be involved in this reflex (21,35). Kaufman and colleagues demonstrated that anesthetized cat triceps surae group III muscle afferents were predominantly mechanically sensitive, whereas unmyelinated group IV muscle afferents were chemically sensitive (15,16).A number of substances are potential muscle afferent stimulants (14). Metabolism of free arachidonic acid by cyclooxygenases (COX) and lipoxygenases leads to the formation of prostaglandins, thromboxanes, and leukotrienes. It is known that arachidonic acid stimulates group III mechano-sensitive afferent nerve fibers in the anesthetized cat (26). Moreover, prostaglandin levels rise during exercise in healthy humans (36). Animal studies showed that arachidonic acid and the metabolites of the COX (i.e., prostaglandins) stimulate muscle afferents and can alter the pressor response to muscle contraction (12,25,26,32). Middlekauff et al. showed that COX inhibition with intrabrachial arterial indomethacin eliminated the reflex sympathetic activation during low levels o...

Introduction Permanent His bundle pacing is feasible and effective in patients with atrioventricular block or left bundle branch block. However, pacing thresholds to capture the distal His bundle is often higher. Recently left bundle branch area pacing (LBBP) has been shown to be feasible by advancing the lead transvenously, deep into the interventricular septum to reach the left ventricular endocardial surface. In this article we describe the utility of three dimensional (3D) mapping to achieve LBBP. Methods Ensite Precision (Abbott) mapping system was used to perform LBBP. A decapolar catheter was used to create 3D map of right atrium and right ventricle (RV). Regions of interest (His bundle, potential LBBP sites of interest in RV) were tagged in the 3D map. The LBBP lead was implanted utilizing the 3D map. The lead depth in the septum was assessed in the 3D map. Results LBBP was performed in three patients: chronic LBBB and intermittent 2:1 atrioventricular block; atrioventricular (AV) node ablation and conduction system pacing; and bifascicular block and intermittent AV block in a patient with severe left ventricular hypertrophy. LBBP was successful in all three patients. The lead depth in the interventricular septum was 12, 11, and 21 mm, respectively as assessed by 3D mapping. Conclusions Three‐dimensional mapping was helpful in achieving LBBP in patients with LBBB, severe left ventricular hypertrophy or during AV node ablation. 3D mapping also facilitated easy assessment of lead depth during and after lead fixation. 3D mapping techniques may be a valuable tool to reduce the learning curve of implanters with minimal experience in LBBP.

Cui J, Moradkhan R, Mascarenhas V, Momen A, Sinoway LI. Cyclooxygenase inhibition attenuates sympathetic responses to muscle stretch in humans. Am J Physiol Heart Circ Physiol 294: H2693-H2700, 2008. First published April 25, 2008; doi:10.1152/ajpheart.91505.2007.-Passive muscle stretch performed during a period of post-exercise muscle ischemia (PEMI) increases muscle sympathetic nerve activity (MSNA), and this suggests that the muscle metabolites may sensitize mechanoreceptors in healthy humans. However, the responsible substance(s) has not been studied thoroughly in humans. Human and animal studies suggest that cyclooxygenase products sensitize muscle mechanoreceptors. Thus we hypothesized that local cyclooxygenase inhibition in exercising muscles could attenuate MSNA responses to passive muscle stretch during PEMI. Blood pressure (Finapres), heart rate, and MSNA (microneurography) responses to passive muscle stretch were assessed in 13 young healthy subjects during PEMI before and after cyclooxygenase inhibition, which was accomplished by a local infusion of 6 mg ketorolac tromethamine in saline via Bier block. In the second experiment, the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased prostaglandin synthesis to ϳ34% of the baseline. Before ketorolac Bier block, passive muscle stretch evoked significant increases in MSNA (P Ͻ 0.005) and mean arterial blood pressure (P Ͻ 0.02). After ketorolac Bier block, passive muscle stretch did not evoke significant responses in MSNA (P ϭ 0.11) or mean arterial blood pressure (P ϭ 0.83). Saline Bier block had no effect on the MSNA or blood pressure response to ischemic stretch. These observations indicate that cyclooxygenase inhibition attenuates MSNA responses seen during PEMI and suggest that cyclooxygenase products sensitize the muscle mechanoreceptors.exercise pressor reflex; passive exercise; autonomic nervous system; muscle afferents; regional intravenous anesthesia EXERCISE IS A POTENT STIMULUS to activate the sympathetic nervous system (36). Increases in muscle sympathetic nerve activity (MSNA) during exercise are caused, reflexively, by the stimulation of mechanosensitive and chemosensitive afferents within the contracting muscle (27). Groups III and IV afferent fibers in muscles are suggested to be involved in this reflex (28,43). Whereas group III muscle afferents are predominantly mechanically sensitive, unmyelinated group IV muscle afferents are mainly chemically sensitive (1,2,22,24).A number of animal studies have shown that mechanoreceptor stimulation in cats activates sympathetic efferents to muscles (21) and kidneys (17, 42) and can evoke pressor responses to exercise (16,25,39). Recently, we demonstrated in healthy humans that passive stretch of leg or arm muscles evokes a significant increase in MSNA during the first few seconds of the muscle stretch; however, under freely perfused conditions, the magnitude of the response is small and transient, and the evoked hemodynamic consequences are limited (9, 10).Animal st...

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Momen A, Kozak M, Leuenberger UA, Ettinger S, Blaha C, Mascarenhas V, Lendel V, Herr MD, Sinoway LI. Transthoracic Doppler echocardiography to noninvasively assess coronary vasoconstrictor and dilator responses in humans. Am J Physiol Heart Circ Physiol 298: H524 -H529, 2010. First published November 25, 2009 doi:10.1152/ajpheart.00486.2009.-Human studies of coronary circulation are limited because of methodological issues. Recently, a noninvasive transthoracic duplex ultrasound (TTD) technique has emerged as an important tool to measure coronary blood flow velocity (CBV) in conscious humans. We employed two protocols to determine whether noninvasive "native" coronary artery velocity responses to constrictor or dilator stimuli assessed by TTD provide reliable data. In the first protocol, coronary vascular resistance (CVR ϭ diastolic blood pressure/CBV) responses to static handgrip were examined in the left internal mammary artery (LIMA) and native left anterior descending artery (LAD) into which the graft was inserted (patient age 63 Ϯ 3 years). Our prior report documented increased CVR in the LIMA graft during static handgrip (Momen et al., J Appl Physiol 102: 735-739, 2007). We hypothesized that the magnitude of increases in CVR during handgrip would be similar in the LIMA graft and LAD in the same individual. Percent increases in CVR were similar in the LIMA and distal native LAD (27 Ϯ 4% vs. 28 Ϯ 6%). In the second protocol, we studied six patients (age 61 Ϯ 3 years) who underwent cardiac catheterization of the LAD. We compared coronary vasodilator responses to intravenous adenosine infusion (0.14 mg⅐kg Ϫ1 ⅐min Ϫ1) obtained by intracoronary Doppler guidewire technique and TTD on separate studies. The relative increases in CBV with adenosine obtained by intracoronary Doppler guidewire and TTD were similar (62 Ϯ 10% vs. 65 Ϯ 12%). Noninvasive TTD provides reliable human coronary circulatory constrictor and dilator data. coronary flow velocity; duplex ultrasound; handgrip FROM A PHYSIOLOGICAL STANDPOINT there are relatively few human studies of coronary circulatory function. This has largely been due to methodological issues. Specifically, until recently, invasive measurements of coronary blood flow velocity (CBV) were needed to determine an index of coronary flow velocity. Although these invasive approaches are certainly possible, studies in large groups of patients and in those not already undergoing cardiac catheterization are not feasible. Thus important issues pertaining to the cardiac circulation have been impossible to study. Recently, transthoracic duplex ultrasound (TTD) has been introduced as a promising tool for the assessment of coronary circulatory parameters (5-12). This technique allows investigators to measure real-time changes in CBV in a segment of the left anterior descending artery (LAD) that is in close proximity to the chest wall. TTD has the potential to measure rapid and sequential changes in CBV during a variety of stressful maneuvers in a safe and noninvasive way.We have recently ...