Mark Turner

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.

Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs

Background: Ischaemic preconditioning results in a reduction in ischaemic-reperfusion injury to the heart. This beneficial effect is seen both with direct local preconditioning of the myocardium and with remote preconditioning of easily accessible distant non-vital limb tissue. Ischaemic postconditioning with a comparable sequence of brief periods of local ischaemia, when applied immediately after the ischaemic insult, confers benefits similar to preconditioning. Objective: To test the hypothesis that limb ischaemia induces remote postconditioning and hence reduces experimental myocardial infarct size in a validated swine model of acute myocardial infarction. Methods: Acute myocardial infarction was induced in 24 pigs with 90 min balloon inflations of the left anterior descending coronary artery. Remote ischaemic postconditioning was induced in 12 of the pigs by four 5 min cycles of blood pressure cuff inflation applied to the lower limb immediately after the balloon deflation. Infarct size was assessed by measuring 72 h creatinine kinase release, MRI scan and immunohistochemical analysis. Results: Area under the curve of creatinine kinase release was significantly reduced in the postconditioning group compared with the control group with a 26% reduction in the infarct size (p<0.05). This was confirmed by MRI scanning and immunohistochemical analysis that revealed a 22% (p<0.05) and a 47.52% (p<0.01) relative reduction in the infarct size, respectively. Conclusion: Remote ischaemic postconditioning is a simple technique to reduce infarct size without the hazards and logistics of multiple coronary artery balloon inflations. This type of conditioning promises clear clinical potential.

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.

Balloon expandable stent implantation for native and recurrent coarctation of the aorta—prospective computed tomography assessment of stent integrity, aneurysm formation and stenosis relief

Background Stenting for aortic coarctation is known to be effective in the medium term. Aneurysm formation following stent implantation is a recognised complication. However, data regarding aortic wall injury and stent integrity following stent placement are sparse. Objectives We report comprehensive clinical, echocardiographic and prospective CT follow-up data following stenting for aortic coarctation from a single centre. Methods Full data analysis of all patients undergoing balloon expandable stent implantation and follow-up procedures in a single tertiary congenital cardiac unit. Results Between October 2002 and April 2008, we performed 102 coarctation stent procedures on 88 patients. Median age was 20.6 years (range 8.5–65) and median weight 65 kg (range 34–101). 94 stents (26 covered) were implanted. 12 procedures were re-dilatations. Stenting resulted in a reduction of the gradient across the site of coarctation, from a median of 20 mm Hg to 4 mm Hg. There were no procedure-related deaths. Four patients had immediate complications (one requiring emergency surgery). During median follow-up of 34.5 months (range 4.2–72.8), two patients had late complications requiring additional stent procedures. Follow-up CT data are available in 84 patients with MRI in one patient (96.5%). Only one patient developed a procedure-related aortic aneurysm. All stent fractures (n=7) occurred with a single stent design. Conclusions Stenting for aortic coarctation and re-coarctation is effective with low immediate complication rates. CT is useful in the longer term for assessment of stent integrity and post-procedural aneurysm formation. Overall incidence of post-procedural aneurysm is rare and stent fractures were not seen with newer generation stents.

Reversible Connexin 43 Dephosphorylation During Hypoxia and Reoxygenation Is Linked to Cellular ATP Levels

Altered gap junction coupling of cardiac myocytes during ischemia may contribute to development of lethal arrhythmias. The phosphoprotein connexin 43 (Cx43) is the major constituent of gap junctions. Dephosphorylation of Cx43 and uncoupling of gap junctions occur during ischemia, but the significance of Cx43 phosphorylation in this setting is unknown. Here we show that Cx43 dephosphorylation in synchronously contracting myocytes during ischemia is reversible, independent of hypoxia, and closely associated with cellular ATP levels. Cx43 became profoundly dephosphorylated during hypoxia only when glucose supplies were limited and was completely rephosphorylated within 30 minutes of reoxygenation. Similarly, direct reduction of ATP by various combinations of metabolic inhibitors and by ouabain was closely paralleled by loss of phosphoCx43 and recovery of phosphoCx43 accompanied restoration of ATP. Dephosphorylation of Cx43 could not be attributed to hypoxia, acid pH or secreted metabolites, or to AMP-activated protein kinase; moreover, the process was selective for Cx43 because levels of phospho-extracellular signal regulated kinase (ERK)1/2 were increased throughout. Rephosphorylation of Cx43 was not dependent on new protein synthesis, or on activation of protein kinases A or G, ERK1/2, p38 mitogen-activated protein kinase, or Jun kinase; however, broad-spectrum protein kinase C inhibitors prevented Cx43 rephosphorylation while also sensitizing myocytes to reoxygenation-mediated cell death. We conclude that Cx43 is reversibly dephosphorylated and rephosphorylated during hypoxia and reoxygenation by a novel mechanism that is sensitive to nonlethal fluctuations in cellular ATP. The role of this regulated phosphorylation in the adaptation to ischemia remains to be determined.

Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium

Background—Most clinical studies have shown that &bgr;-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective &bgr;-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium. Methods and Results—Myocardial strips (≈1 mm3) obtained from rat and nonfailing human hearts were confirmed to be viable for ≥48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to &bgr;-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full &bgr;-adrenergic agonist isoproterenol raised cAMP levels by >2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP levels, whereas metoprolol reduced basal cAMP by ≈25%. In contrast, bucindolol and xamoterol increased cAMP levels in a concentration-dependent manner in both rat and human myocardium (maximum 1.64±0.25-fold and 2.00±0.27-fold over control, respectively, P <0.01 for human tissue). Conclusions—Bucindolol exhibits ≈60% of the &bgr;-adrenergic agonist activity of xamoterol in normal human myocardial tissue.

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.

Early clinical experience with the new Amplatzer Ductal Occluder II for closure of the persistent arterial duct.

Objectives: To describe the early single‐center clinical experience with the Amplatzer Ductal Occluder II (ADO II). Methods: All patients undergoing attempted transcatheter closure of persistent arterial duct (PDA) with the ADO II were included. Data collected included demographic, clinical, and echocardiographic parameters. Results: From March until September 2008, 29 procedures were undertaken in 27 patients (21 female). Median age was 1.4 years (range 0.4–76 years) with median weight 9.4 kg (range 4.7–108 kg). A transarterial approach was used in 2 patients. The median minimum ductal diameter was 2.7 mm (range 1.7–5). ADO II was released in 25 patients (92.5%). Two patients had significant residual shunting following deployment of ADO II and underwent closure with Amplatzer ductal occluder (ADO I). Postprocedural echocardiography identified one occluder had changed position with development of a significant leak and one occluder had embolized to the left pulmonary artery. Both occluders were retrieved successfully at a second catheter procedure. Complete occlusion was noted predischarge in 22 of the remaining 23 occluders (96%). One patient had mild flow acceleration in the left pulmonary artery which has resolved. Conclusions: The ADO II is highly effective at providing rapid occlusion of morphologically varied PDAs. Occluder design allows closure with arterial or venous approach and delivery with 4 or 5 F delivery catheters. Stable occluder position is dependent on correct positioning of both aortic and pulmonary discs. A larger range of sizes and configurations of this occluder may be required to successfully occlude all ductal sizes and morphologies.

Physiological and Phenotypic Characteristics of Late Survivors of Tetralogy of Fallot Repair Who Are Free From Pulmonary Valve Replacement

Background— Pulmonary valve replacement (PVR) after repair of tetralogy of Fallot is commonly required and is burdensome. Detailed anatomic and physiologic characteristics of survivors free from late PVR and with good exercise capacity are not well described in a literature focusing on the indications for PVR. Methods and Results— Survival and freedom from PVR were tracked in 1085 consecutive patients receiving standard tetralogy of Fallot repair in a single institution from 1964 to 2009. Of 152 total deaths, 100 occurred within the first postoperative year. Surviving patients between 10 and 50 years of age had an annual risk of death of 4 (confidence limit, 2.8–5.4) times that of normal contemporaries. To date, 189 patients have undergone secondary PVR at mean age of 20±13 years (36% of those alive at 40 years of age). A random sample of 50 survivors (age, 4–57 years) free from PVR underwent cardiovascular magnetic resonance, echocardiography, and exercise testing. These patients had mildly dilated right ventricles (right ventricular end-diastolic volume=101±26 mL/m2) with good systolic function (right ventricular ejection fraction=59±7%). Most had exercise capacity within normal range (z peak O2=−0.91±1.3; z E/ CO2=0.20±1.5). In patients >35 years of age with normal exercise capacity, there was mild residual right ventricular outflow tract obstruction (mean gradient, 24±13 mm Hg), pulmonary annulus diameters <0.5z, and unobstructed branch pulmonary arteries. Conclusions— An important proportion of patients require PVR late after tetralogy of Fallot repair. Patients surviving to 35 years of age without PVR and with a normal exercise capacity may have had a definitive primary repair; their right ventricular outflow tracts are characterized by mild residual obstruction and pulmonary annulus diameter <0.5z.

Results of Screening for Intracranial Aneurysms in Patients with Coarctation of the Aorta

BACKGROUND AND PURPOSE: IAs are found in 2.3% of adults; the mean age at detection is 52 years. Prevalence is <0.5% in young adults. Early studies suggest that 10%–50% of patients with aortic coarctation have IAs. Screening recommendations are variable. We sought to examine the prevalence of IAs through screening with MRA. MATERIALS AND METHODS: Consecutive patients older than 16 years of age with coarctation undergoing brain MRA between May 1999 and October 2007 were included. MRA was performed by using a 1.5T scanner with a 3D time-of-flight protocol; simultaneous MR imaging was performed of the heart and aorta. Cerebral MRAs were double-reported by a neuroradiologist. Statistics are described as mean ± SD and median ± range. Continuous variables were compared by using Student t tests and Mann-Whitney U tests (categoric variables, by using the Fisher exact test). RESULTS: One hundred seventeen MRAs were double-reported. The median age was 29 ± 11 years (range, 16–59 years). IAs were found in 12 patients (10.3%). The mean diameter of IAs was 3.9 mm (range, 2.0–8.0 mm). Patients with aneurysms were older (median, 37 years; range, 16–50 years) than those without (median, 23 years; range, 16–59 years; Z = −2.01, P = .04). Hypertension was more common in those with IAs (IA 83% versus no IA 43%, P = .01). There was no association between ascending aortopathy, bicuspid aortic valves, and IAs. CONCLUSIONS: Patients with coarctation have a higher prevalence of IAs, occurring at an earlier age than in population studies. Whether routine screening is appropriate for this group of patients is unclear. Hypertension is likely to be an important pathophysiologic factor.