for the M-PATHY Study Investigators* Background-Dual-chamber pacing (DDD) has been proposed as a treatment alternative to surgery for severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), based largely on uncontrolled studies. Methods and Results-This prospective, multicenter trial assessed pacing in 48 symptomatic HCM patients with Ն50 mm Hg basal gradient, refractory to drug therapy. Patients were randomized to 3 months each of DDD pacing and pacing backup (AAI-30) in a double-blind, crossover study design, followed by an uncontrolled and unblinded 6-month pacing trial. With randomization, no significant differences were evident between pacing and no pacing for subjective or objective measures of symptoms or exercise capacity, including NYHA functional class, quality of life score, treadmill exercise time or peak oxygen consumption. After 6 additional months of unblinded pacing, functional class and quality of life score were improved compared with baseline (PϽ0.01), but peak oxygen consumption was unchanged. Outflow gradient decreased 40%, 82Ϯ32 mm Hg to 48Ϯ32 mm Hg (PϽ0.001), and was reduced in 57% of patients but showed no change or an increase in 43%. At 12 months, 6 individual patients (12%) showed improved functional capacity; each was 65 to 75 years of age. Left ventricular wall thicknesses in the overall study group showed no remodeling between baseline (22Ϯ5 mm) and 12 months (21Ϯ5 mm; PϭNS). Conclusions-(1)Pacing cannot be regarded as a primary treatment for obstructive HCM; (2) with randomization, perceived symptomatic improvement was most consistent with a substantial placebo effect; (3) longer, uncontrolled pacing periods were associated with some subjective benefit but unaccompanied by objective improvement in cardiovascular performance and should be interpreted cautiously; (4) modest reduction in outflow gradient was achieved in most patients; and (5) a small subset (12%) Ն 65 years of age showed a clinical response, suggesting that DDD pacing could be a therapeutic option for some elderly patients. (Circulation. 1999;99:2927-2933.)

Abstract-The role of baroreflexes in long-term control of arterial pressure is unresolved. To determine whether chronic activation of the baroreflex produces sustained hypotension, we developed a method for prolonged activation of the carotid baroreflex in conscious dogs. This was achieved by chronically implanting electrodes around both carotid sinuses and using an externally adjustable pulse generator to electrically activate the carotid baroreflex. Control values for mean arterial pressure (MAP) and heart rate were 93Ϯ3 mm Hg and 64Ϯ4 bpm, respectively. After control measurements, the carotid baroreflex was activated bilaterally for 7 days at a level that produced a prompt and substantial reduction in MAP, and for day 1 MAP was reduced to 75Ϯ4 mm Hg. Moreover, this hypotensive response was sustained throughout the entire 7 days of baroreflex activation (day 7, MAPϭ72Ϯ5 mm Hg). During prolonged baroreflex activation, heart rate decreased in parallel with MAP, although the changes were not as pronounced (day 7, heart rateϭ51Ϯ3 bpm). Prolonged baroreflex activation was also associated with Ϸ35% reduction in plasma norepinephrine concentration (controlϭ87Ϯ15 pg/mL). After baroreflex activation, hemodynamic measures and plasma levels of norepinephrine returned to control levels. Interestingly, despite the pronounced fall in MAP, plasma renin activity did not increase during prolonged baroreflex activation. These data indicate that prolonged baroreflex activation can lead to substantial reductions in MAP by suppressing the sympathetic nervous system. Furthermore, sustained sympathoinhibitory effects on renin secretion may play an important role in mediating the long-term hypotensive response. Key Words: baroreflex Ⅲ arterial pressure Ⅲ sympathetic nervous system Ⅲ renin-angiotensin system Ⅲ sodium S ince McCubbin et al 1 demonstrated a marked resetting of the arterial baroreflex in chronic hypertension, there has been considerable skepticism that baroreflexes participate in long-term control of arterial pressure. 2-5 Nonetheless, because of the importance of this neural feedback mechanism in the acute regulation of sympathetic activity and arterial pressure, there has been continued interest in the possibility that baroreflexes may play a role in the pathogenesis of hypertension. Indeed, a recurrent hypothesis to account for excessive sympathetic activation in hypertension is baroreflex dysfunction, an associated finding in some forms of experimental and clinical hypertension. 2,3,6,7 However, whether impaired baroreflex suppression of sympathetic activity plays a role in the hypertensive process would appear to depend on whether baroreflexes completely reset when exposed to chronic changes in arterial pressure. If, in fact, resetting is complete and baroreflexes do not chronically alter sympathetic activity, then they could not produce functional changes that influence the severity of hypertension.The fundamental question of whether baroreflexes completely reset and have the capacity to chronically alter sympathet...

Abstract-Despite recent evidence indicating sustained activation of the baroreflex during chronic infusion of angiotensin II (Ang II), sinoaortic denervation does not exacerbate the severity of the hypertension. Therefore, to determine whether Ang II hypertension is relatively resistant to the blood pressure-lowering effects of the baroreflex, the carotid baroreflex was electrically activated bilaterally for 7 days in 5 dogs both in the presence and absence of a continuous infusion of Ang II (5 ng/kg per minute) producing high physiological plasma levels of the peptide. Under control conditions, basal values for mean arterial pressure (MAP) and plasma norepinephrine concentration (NE) were 93Ϯ1 mm Hg and 99Ϯ25 pg/mL, respectively. By day 7 of baroreflex activation, MAP and NE were reduced to 72Ϯ4 mm Hg (Ϫ21Ϯ3 mm Hg) and 56Ϯ15 pg/mL, respectively, but PRA was unchanged (controlϭ0.41Ϯ0.06 ng ANG I/mL per hour). All values returned to basal levels by the end of a 7-day recovery period. After 7 days of Ang II infusion, MAP increased from 93Ϯ3 to 129Ϯ3 mm Hg, whereas NE fell from 117Ϯ15 to 86Ϯ23 pg/mL. During the next 7 days of baroreflex activation/Ang II infusion, further reductions in NE were not statistically significant, and on the final day of baroreflex activation, the reduction in MAP was only 5Ϯ1 mm Hg, compared with 21Ϯ3 mm Hg in the control normotensive state.

Prolonged electrical activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure in normotensive dogs. The main goal of this study was to assess the influence of prolonged baroreflex activation on arterial pressure and neurohormonal responses in 6 dogs with obesity-induced hypertension. After control measurements, the diet was supplemented with cooked beef fat for 6 weeks, whereas sodium intake was held constant. After 4 weeks of the high-fat diet, there were increments in body weight from 25.8+/-0.7 to 38.6+/-1.0 kg, mean arterial pressure from 97+/-2 to 110+/-3 mm Hg, heart rate from 67+/-3 to 91+/-4 bpm, and plasma norepinephrine concentration from 141+/-35 to 280+/-52 pg/mL. Plasma glucose and insulin concentrations were elevated, but increases in plasma renin activity during the initial weeks of the high-fat diet were not sustained. During week 5, baroreflex activation resulted in sustained reductions in mean arterial pressure, heart rate, and plasma norepinephrine concentration; at the end of week 5, these values were 87+/-2 mm Hg, 77+/-4 bpm, and 166+/-45 pg/mL, respectively. These suppressed values returned to week 4 levels during a 7-day recovery period after baroreflex activation. There were no changes in plasma glucose or insulin concentrations, or plasma renin activity during prolonged baroreflex activation. These findings indicate that baroreflex activation can chronically suppress the sympathoexcitation associated with obesity and abolish the attendant hypertension while having no effect on hyperinsulinemia or hyperglycemia.