Robert A. Bleasdale

Electrical and mechanical components of dyssynchrony in heart failure patients with normal QRS duration and left bundle-branch block:impact of left and biventricular pacing

Background—Resynchronization pacing is an effective symptomatic treatment for heart failure patients with prolongation of the QRS duration (QRSd). Dyssynchronous contraction of the left ventricle is also observed with normal QRSd. We set out to determine how electrical activation of the left ventricular (LV) free wall differed between patients with left bundle-branch block (LBBB) and normal QRSd and if synchrony improved during pacing in patients with normal QRSd. Methods and Results—Twenty-two patients were implanted with resynchronization pacemakers, 13 with LBBB (mean QRS, 171 ms) and 9 with normal QRSd <120 ms (mean, 100 ms). LV lead electrograms and surface ECGs in sinus rhythm (unpaced) were recorded. Conventional and tissue Doppler echocardiography were performed without pacing, with LV and biventricular pacing at optimal atrioventricular delay. Lead electrograms from the LV free wall were later in the LBBB patients in absolute terms (155 ms [SD 23] versus 65.5 ms [SD 25]; P =0.05) and also relative to the surface QRS (90.5% [SD 8] versus 65.5% [SD 24]). Improved synchrony of the left and right ventricles (interventricular synchrony) and of the LV myocardial segments (intraventricular synchrony) was observed for patients with LBBB and normal QRSd. Baseline LV synchrony correlated with timing of LV free-wall electrical activation. Improved intraventricular synchrony during pacing also correlated with LV free-wall electrical activation time. Conclusions—Resynchronization of systole can be achieved for patients with normal QRSd and LBBB during biventricular and LV pacing. The timing of LV free-wall electrical activation correlated with the improvement in synchrony.

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.

Left ventricular pacing minimizes diastolic ventricular interaction, allowing improved preload-dependent systolic performance

Background—Left ventricular (LV) pacing improves hemodynamics in patients with heart failure. We hypothesized that at least part of this benefit occurs by minimization of external constraint to LV filling from ventricular interaction. Methods and Results—We present median values (interquartile ranges) for 13 heart failure patients with LV pacing systems implanted for New York Heart Association class III/IV limitation. We used the conductance catheter method to measure LV pressure and volume simultaneously. External constraint was measured from the end-diastolic pressure-volume relation recorded during inferior vena caval occlusion, during LV pacing, and while pacing was suspended. External constraint to LV filling was reduced by 3.0 (4.6 to 0.6) mm Hg from 4.8 (0.6 to 7.5) mm Hg (P<0.01) in response to LV pacing; effective filling pressure (LV end-diastolic pressure minus external constraint) increased by 4.0 (2.2 to 5.8) mm Hg from 17.7 (13.3 to 22.6; P<0.01). LV end-diastolic volume increased by 10 (3 to 11) mL from 238 (169 to 295) mL (P=0.01), whereas LV end-systolic volume did not change significantly (−1 [−2 to 3] mL from 180 [124 to 236] mL, P=0.97), which resulted in an increase in stroke volume of 11 (5 to 13) mL from 49 (38 to 59) mL (P<0.01). LV stroke work increased by 720 (550 to 1180) mL · mm Hg from 3400 (2110 to 4480) mL · mm Hg (P=0.01), and maximum dP/dt increased by 120 (2 to 161) mm Hg/s from 635 (521 to 767) mm Hg/s (P=0.03). Conclusions—This study suggests a potentially important mechanism by which LV pacing may produce hemodynamic benefit. LV pacing minimizes external constraint to LV filling, resulting in an increase in effective filling pressure; the consequent increase in LV end-diastolic volume increases stroke volume via the Starling mechanism.

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 ≤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). Conclusion— 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.

Left ventricular pacing improves haemodynamic variables in patients with heart failure with a normal QRS duration

Objectives: To assess whether patients with congestive heart failure (CHF) and a normal QRS duration can benefit from left ventricular (VDD-LV) pacing. Design: Cardiac resynchronisation is reserved for patients with a broad QRS duration on the premise that systolic resynchronisation is the mechanism of benefit, yet improvement from pacing correlates poorly with QRS duration. In CHF patients with a broad QRS duration, those with a high resting pulmonary capillary wedge pressure (PCWP) > 15 mm Hg benefit. In this acute haemodynamic VDD-LV pacing study, patients with CHF with a normal QRS duration were divided into two groups—patients with a resting PCWP > 15 mm Hg and patients with a resting PCWP < 15 mm Hg—to determine whether benefit is predicted by a high resting PCWP. Patients: 20 patients with CHF, New York Heart Association functional class IIb–IV, all with a normal QRS duration (⩽ 120 ms). Interventions: Temporary pacing wires were positioned to enable VDD-LV pacing and a pulmonary artery catheter was inserted for measurement of PCWP, right atrial pressure, and cardiac output. Results: In patients with a PCWP > 15 mm Hg (n  =  10), cardiac output increased from 3.9 (1.5) to 4.5 (1.65) l/min (p < 0.01), despite a fall in PCWP from 24.7 (7.1) to 21.0 (6.2) mm Hg (p < 0.001). In patients with a PCWP < 15 mm Hg there was no change in PCWP or cardiac output. Combined data showed that PCWP decreased from 17.0 (9.1) to 15.3 (7.7) mm Hg during VDD-LV pacing (p < 0.014) and cardiac output increased non-significantly from 4.7 (1.5) to 4.9 (1.5) (p  =  0.125). Conclusions: Patients with CHF with a normal QRS duration and PCWP > 15 mm Hg derive acute haemodynamic benefit from VDD-LV pacing.

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 CO2 rebreathing, from −43.0 ± 27.1 to −25.0 ± 16.9 mmHg m s−2, P = 0.02. This reduction in regative 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 pCO2. Wave intensity may provide a simple noninvasive means of assessing changes in cerebral vasomotor tone in vivo.

Cardiac resynchronisation therapy: when the drugs don’t work.

Heart failure effects 1–2% of the population1 and accounts for approximately 5% of all medical admissions2; despite the undoubted improvements in treatment over the past two decades, the outcome remains poor. One third of those patients admitted with decompensated heart failure die within one year of their first hospitalisation3 and up to 50% will be readmitted within the first six months after the initial hospitalisation.4 There appears little scope for further advances aimed at blocking neurohumoral maladaptive mechanisms, and other strategies, including cytokine blockade, have been disappointing. While cellular transplantation holds out considerable promise in the longer term, medically refractory heart failure remains a huge (and growing) clinical problem. Over the past decade an emerging body of evidence has suggested that biventricular and/or left ventricular pacing may provide effective palliation in some of these patients. Initial attention regarding the potential use of pacing therapy in heart failure focused on short atrioventricular (AV) delay right sided pacing to reduce pre-systolic mitral regurgitation. This phenomenon is most pronounced in patients with long AV delays, especially when left ventricular end diastolic pressure is notably raised. Despite impressive improvements in acute haemodynamic measurements in selected patients,5–7 long term results were disappointing.8,9 The next target for pacing therapy was the dysynchronous contraction associated with the presence of left bundle branch block in patients with heart failure. Overall, approximately one third of patients with heart failure have a left bundle branch block pattern,10 although this figure rises in patients with more severe left ventricular dysfunction.11 By causing a dysynchronous left ventricular activation sequence, left bundle branch block impairs left ventricular contractile performance.12 It is not surprising, therefore, that the presence of left bundle branch block is associated with more severe symptoms and greater mortality …

Modulation of interaction between left ventricular ejection and the arterial compartment: assessment of aortic wave travel

Ventriculo-arterial (V-A) interaction is a term used to describe the dynamic interplay between the left ventricle and the arterial system. It may be regarded as a process contributing to disturbed cardiovascular physiology in disease states or as one that allows such disease to be treated by manipulation of the peripheral circulation. It mediates left ventricular hypertrophy or dilatation in hypertension and operates to both advantage and disadvantage in the vasoconstricted patient with pre-existing left ventricular dysfunction. Arguably, V-A interaction is, along with atherosclerosis, a process that has more than others motivated the expanding science of vascular biology. It embraces ideas of circulatory efficiency and is central in cardiovascular disease. The overall physiological process is probably less well understood than its contributing cellular mechanisms, mirroring a general problem in the diminished but crucial science of integrated physiology. The concept of afterload is appreciated by many but it is a difficult abstract concept and probably less helpful than it seems. In this short review we consider the evidence for V-A interaction, its mechanisms and mediators, and its quantification. The aim is to demonstrate that the process touches many areas of basic and clinical cardiology ranging from the details of cellular biochemistry and physiology to the overarching principles of myocardial, arterial, and fluid dynamics. The prevalent problems of heart failure and hypertensive left ventricular hypertrophy are considered. Finally, the V-A interaction is described in terms of bidirectional wave travel, so that upstream (left ventricular) and downstream (arterial) events may be resolved separately. This approach, which originates in compressible gas mechanics, adds novel concepts to cardiac physiology and thus a new appreciation of how the left ventricle ejects blood in the intact self-regulating system.

CARDIAC RESYNCHRONIZATION THERAPY: EFFECT OF OPTIMIZING THE V-V INTERVAL IN HEART FAILURE

Aims: Despite a marked difference in the QRS width induced by biventricular (BIVP) and left ventricular pacing (LVP), both modes of pacing are eficacious at improving cardiac function in heart failure patients with left ventricular dyssynchrony, and in a recent study we demonstrated comparable beneits from BIVP and LVP in a patient group with a narrow QRS duration and no observable dyssynchrony. We hypothesised that optimisation of the interventricular pacing interval may further improve LV function. Methods: Twenty ive heart failure patients with a narrow QRS duration and 12 with a broad QRS duration underwent invasive haemodynamic pressure-volume studies at the time of pacemaker implantation. Absolute left ventricular stroke work (LVSW) and dP/dtMAX were determined during no pacing (VVI), in biventricular (BIVP), left ventricular (LVP) pacing mode, and over a range of interventricular timing delays. Results: Both dP/dtMAX and LVSW increased signiicantly in response to V-V delays in which the LV led by >20ms. In patients with external constraint, there was a trend towards a greater increase in LVSW with those interventricular delays where the LV was the irst chamber paced, compared with patients without external constraint, in whom near-simultaneous interventricular delays ranging from the RV leading by 12ms to the LV leading by 20ms appeared to be optimal. Conclusion: Although many would argue that the optimal V-V delay shows great variability and must be individualized, we have demonstrated optimal V-V delays in patient groups based on the presence or absence of external constraint.