Low-dose sodium nitrite attenuates myocardial ischemia and vascular ischemia-reperfusion injury in human models.

OBJECTIVES: The aim of this study was to assess the potential benefits of inorganic nitrite in 2 clinical models: stress-induced myocardial ischemia and whole-arm ischemia-reperfusion. BACKGROUND: Inorganic nitrite, traditionally considered a relatively inert metabolite of nitric oxide, may exert vasomodulatory and vasoprotective effects. Despite promising results from animal models, few have shown effectiveness in human model systems, and none have fully translated to the clinical setting. METHODS: In 10 patients with inducible myocardial ischemia, saline and low-dose sodium nitrite (NaNO2) (1.5 µmol/min for 20 min) were administered in a double-blind fashion during dobutamine stress echocardiography, at separate visits and in a random order; long-axis myocardial function was quantified by peak systolic velocity (Vs) and strain rate (SR) responses. In 19 healthy subjects, flow-mediated dilation was assessed before and after whole-arm ischemia-reperfusion; nitrite was given before ischemia or during reperfusion. RESULTS: Comparing saline and nitrite infusions, Vs and SR at peak dobutamine increased in regions exhibiting ischemia (Vs from 9.5 ± 0.5 cm/s to 12.4 ± 0.6 cm/s, SR from -2.0 ± 0.2 s(-1) to -2.8 ± 0.3 s(-1)), whereas they did not change in normally functioning regions (Vs from 12.6 ± 0.4 cm/s to 12.6 ± 0.6 cm/s, SR from -2.6 ± 0.3 s(-1) to -2.3 ± 0.1 s(-1)) (p < 0.001, analysis of variance). With NaNO2, the increment of Vs (normalized for increase in heart rate) increased only in poorly functioning myocardial regions (+122%, p < 0.001). Peak flow-mediated dilation decreased by 43% after ischemia-reperfusion when subjects received only saline (6.8 ± 0.7% vs. 3.9 ± 0.7%, p < 0.01); administration of NaNO2 before ischemia prevented this decrease in flow-mediated dilation (5.9 ± 0.7% vs. 5.2 ± 0.5%, p = NS), whereas administration during reperfusion did not. CONCLUSIONS: Low-dose NaNO2 improves functional responses in ischemic myocardium but has no effect on normal regions. Low-dose NaNO2 protects against vascular ischemia-reperfusion injury only when it is given before the onset of ischemia.

Short-term hemodynamic effects of cardiac resynchronization therapy in patients with heart failure, a narrow QRS duration, and no dyssynchrony.

BACKGROUND: Cardiac resynchronization therapy produces both short-term hemodynamic and long-term symptomatic/mortality benefits in symptomatic heart failure patients with a QRS duration >120 ms. This is conventionally believed to be due principally to relief of dyssynchrony, although we recently showed that relief of external constraint to left ventricular filling may also play a role. In this study, we evaluated the short-term hemodynamic effects in symptomatic patients with a QRS duration <120 ms and no evidence of dyssynchrony on conventional criteria and assessed the effects on contractility and external constraint. METHODS AND RESULTS: Thirty heart failure patients (New York Heart Association class III/IV) with a left ventricular ejection fraction < or =35% who were in sinus rhythm underwent pressure-volume studies at the time of pacemaker implantation. External constraint, left ventricular stroke work, dP/dtmax, and the slope of the preload recruitable stroke work relation were measured from the end-diastolic pressure-volume relation before and during delivery of biventricular and left ventricular pacing. The following changes were observed during delivery of cardiac resynchronization therapy: Cardiac output increased by 25+/-5% (P<0.05), absolute left ventricular stroke work increased by 26+/-5% (P<0.05), the slope of the preload recruitable stroke work relation increased by 51+/-15% (P<0.05), and dP/dtmax increased by 9+/-2% (P<0.05). External constraint was present in 15 patients and was completely abolished by both biventricular and left ventricular pacing (P<0.05). CONCLUSIONS: Cardiac resynchronization therapy results in an improvement in short-term hemodynamic variables in patients with a QRS <120 ms related to both contractile improvement and relief of external constraint. These findings provide a potential physiological basis for cardiac resynchronization therapy in this patient population.

The complete array of electrocardiogram abnormalities secondary to myocardial contusion in a single case.

Myocardial contusion is a complication of blunt thoracic injuries. Transthoracic echocardiography and electrocardiography (ECG) monitoring are important in suspected cases. We report a 54-year-old man, who sustained a number of injuries including blunt chest injury as a consequence of a road traffic accident. Electrocardiography monitoring over a 48 h period demonstrated sequential degrees of conduction system block coupled with a temporary cardio-version from persistent atrial fibrillation to sinus rhythm, suggesting coincident pulmonary vein contusion.

Mechanisms of reduction of mitral regurgitation by cardiac resynchronization therapy.

OBJECTIVES: We sought to investigate the effects of improved left ventricular (LV) synchrony on secondary mitral regurgitation in patients receiving cardiac resynchronization therapy for severe heart failure. METHODS: A total of 22 patients, aged 63 +/- 8 years, were studied during sinus rhythm (unpaced), during LV pacing, and during biventricular pacing. Echocardiography was used to assess LV shape, mitral valve morphology and function, and global systolic and diastolic function. Mechanical ventricular synchrony was calculated from regional systolic timings and velocities, using tissue Doppler. RESULTS: Synchronicity index of LV longitudinal function improved from 36 +/- 19 to 14 +/- 8 milliseconds with LV pacing, and from 31 +/- 17 to 12 +/- 7 milliseconds with biventricular pacing (both P < .01). Heterogeneity of myocardial velocities decreased and mean systolic longitudinal velocity increased. Long-axis and short-axis systolic dimensions decreased, and the LV became less spherical. Apical displacement of coaptation from the plane of the mitral annulus, and annular diameter, were reduced. The severity of mitral regurgitation decreased: vena contracta diameter decreased from 5.3 +/- 1.7 to 4.1 +/- 1.5 mm with LV pacing, and from 5.2 +/- 1.7 to 4.0 +/- 1.7 mm with biventricular pacing (both P < .05), correlating with the increase in mean systolic longitudinal velocity (r = -0.49 for LV pacing and r = -0.67 for biventricular pacing, both P < .05). CONCLUSIONS: Cardiac resynchronization reduces mitral regurgitation by improving LV mechanical synchrony, which leads to an increase in LV longitudinal function and a reduction in subvalvar traction.

Red blood cell nitric oxide as an endocrine vasoregulator: a potential role in congestive heart failure.

BACKGROUND: A respiratory cycle for nitric oxide (NO) would involve the formation of vasoactive metabolites between NO and hemoglobin during pulmonary oxygenation. We investigated the role of these metabolites in hypoxic tissue in vitro and in vivo in healthy subjects and patients with congestive heart failure (CHF). METHODS AND RESULTS: We investigated the capacity for red blood cells (RBCs) to dilate preconstricted aortic rings under various O2 tensions. RBCs induced cyclic guanylyl monophosphate-dependent vasorelaxation during hypoxia (35+/-4% at 1% O2, 4.7+/-1.6% at 95% O2; P<0.05). RBC-induced relaxations during hypoxia correlated with S-nitrosohemoglobin (SNO-Hb) (R2=0.88) but not iron nitrosylhemoglobin (HbFeNO) content. Relaxation responses for RBCs were compared with S-nitrosoglutathione across a range of O2 tensions. The fold increases in relaxation evoked by RBCs were significantly greater at 1% and 2% O2 compared with relaxations induced at 95% (P<0.05), consistent with an allosteric mechanism of hypoxic vasodilation. We also measured transpulmonary gradients of NO metabolites in healthy control subjects and in patients with CHF. In CHF patients but not control subjects, levels of SNO-Hb increase from 0.00293+/-0.00089 to 0.00585+/-0.00137 mol NO/mol hemoglobin tetramer (P=0.005), whereas HbFeNO decreases from 0.00361+/-0.00109 to 0.00081+/-0.00040 mol NO/mol hemoglobin tetramer (P=0.03) as hemoglobin is oxygenated in the pulmonary circulation. These metabolite gradients correlated with the hemoglobin O2 saturation gradient (P<0.05) and inversely with cardiac index (P<0.05) for both CHF patients and control subjects. CONCLUSIONS: We confirm that RBC-bound NO mediates hypoxic vasodilation in vitro. Transpulmonary gradients of hemoglobin-bound NO are evident in CHF patients and are inversely dependent on cardiac index. Hemoglobin may transport and release NO bioactivity to areas of tissue hypoxia or during increased peripheral oxygen extraction via an allosteric mechanism.

Wave intensity analysis from the common carotid artery: a new noninvasive index of cerebral vasomotor tone.

Cerebral vasomotor tone is difficult to assess in patients. Wave intensity analysis has been applied to resolve complex upstream and downstream events within the vascular system. We hypothesized that the backward-traveling wave measured in the common carotid artery was caused by reflection from the cerebrovascular "beach", and that the magnitude of this reflected wave would be altered by changes in cerebral vasomotor tone. We measured common carotid arterial diameter and velocity of flow to calculate wave intensity in ten healthy male volunteers (age mean 31 +/- 3 years). Applying a rebreathing technique, we were able to increase the inspired carbon dioxide concentration to a mean of 5.9% +/- 1.7% and to compare baseline wave intensity readings to those recorded during hypercapnia. The magnitude of the reflected wave decreased significantly after CO(2) rebreathing, from -43.0 +/- 27.1 to -25.0 +/- 16.9 mmHg m s(-2), P = 0.02. This reduction in negative wave reflections in mid-systole during hypercapnia remained significant when it was analyzed as the reflection coefficient (the magnitude of the reflected wave normalized for the magnitude of the initiating forward wave, which fell from -2.8 +/- 1.5 to -1.6 +/- 1.4 ms (P = 0.01). Carotid wave reflection was significantly decreased during cerebral vasodilatation induced by increased arterial pCO(2). Wave intensity may provide a simple noninvasive means of assessing changes in cerebral vasomotor tone in vivo.