Microcirculatory and therapeutic effects of whole body periodic acceleration (pGz) applied after cardiac arrest in pigs.

AIMS: Cardiac arrest (CA) and resuscitation are models of whole body ischemia reperfusion injury. Interventions performed prior to (pre-treatment) or after (post-treatment) can result in cardioprotection. Myocardial stunning, characterized by microcirculatory and contractile dysfunction after CA, is an important component of the post-cardiac arrest syndrome. Periodic acceleration (pGz), produced by the cyclical motion of the supine body headward to footward, increases microcirculatory blood flow to vital organs and elicits production of endothelial derived cytoprotective factors in normal animals. We tested the hypothesis that application of pGz 30 min after return of circulation from CA, as a delayed post-treatment strategy, would improve regional microcirculatory blood flow to vital organs and functional indices of myocardial stunning in pigs. METHODS: 8 min of unsupported VF followed by cardiopulmonary resuscitation and defibrillation was carried out in twenty anesthetized and paralyzed male swine who were randomized to delayed post-treatment with pGz (dPost) or none (CONT). pGz was begun 30 min after return of circulation along with conventional mechanical ventilation. Hemodynamics, echocardiogram, and regional blood flows were measured as well as biochemical index of cardiac tissue injury. RESULTS: All animals had spontaneous return of circulation after cardiopulmonary resuscitation (CPR) and defibrillation. dPost animals had less myocardial stunning and greater regional blood flows to the heart, brain, kidneys, ileum and stomach than CONT. Post-treatment with pGz blunted the increase in Troponin I produced by CA and resuscitation, and, induced a greater rise in endothelial derived nitric oxide synthase (eNOS) and its phosphorylation (p-eNOS). CONCLUSIONS: Delayed post-treatment with pGz as a therapeutic strategy, protects against early myocardial stunning in VF cardiac arrest by improving microcirculatory blood flow to the heart and also protects other vital organs by this mechanism.

Myocardial perfusion grade after late infarct artery recanalization is associated with global and regional left ventricular function at one year: analysis from the Total Occlusion Study of Canada-2.

BACKGROUND: Whether myocardial perfusion grade (MPG) following late recanalization of infarct-related arteries (IRAs) predicts left ventricular (LV) function recovery beyond the acute phase of myocardial infarction (MI) is unknown. METHODS AND RESULTS: The Total Occlusion Study of Canada-2 enrolled stable patients with a persistently occluded IRA beyond 24 hours and up to 28 days post-MI. We studied the relationship between the initial MPG and changes in LV function and volume as well as the change in MPG from immediate post-percutaneous coronary intervention (PCI) to 1 year in 139 PCI patients with thrombolysis in myocardial infarction grade 3 epicardial flow post-PCI and with paired values grouped into impaired or good MPG groups (MPG 0/1 or MPG 2/3). MPG 0/1 patients were more likely to have received thrombolytic therapy and to have a left anterior descending IRA. They had lower blood pressure and LV ejection fraction (LVEF) and a higher heart rate and systolic sphericity index at baseline. Changes in the MPG 0/1 and MPG 2/3 groups from baseline to 1 year were LVEF, 3.3±9.0% and 4.8±8.9% (P=0.42); LV end-systolic volume index (LVESVI), -1.1±9.2 and -4.7±12.3 mL/m(2) (P=0.25); LV end-diastolic volume index (LVEDVI), 0.08±19.1 and -2.4±22.2 mL/m(2) (P=0.67); and SDs/chord for infarct zone wall motion index (WMI), 0.38±0.70 and 0.84±1.11 (P=0.01). By covariate-adjusted analysis, post-PCI MPG 0/1 predicted lower WMI (P<0.001), lower LVEF (P<0.001), and higher LVESVI (P<0.01) but not LVEDVI at 1 year. Of the MPG 0/1 patients, 60% were MPG 2 or 3 at 1 year. CONCLUSIONS: Preserved MPG is present in a high proportion of patients following late PCI of occluded IRAs post-MI. Poor MPG post-PCI frequently improves MPG over 1 year. MPG graded after IRA recanalization undertaken days to weeks post MI is associated with LV recovery, indicating that MPG determined in the subacute post-MI period remains a marker of viability. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00025766.

Renal impairment and heart failure with preserved ejection fraction early post-myocardial infarction.

AIM: To study if impaired renal function is associated with increased risk of peri-infarct heart failure (HF) in patients with preserved ejection fraction (EF). METHODS: Patients with occluded infarct-related arteries (IRAs) between 1 to 28 d after myocardial infarction (MI) were grouped into chronic kidney disease (CKD) stages based on estimated glomerular filtration rate (eGFR). Rates of early post-MI HF were compared among eGFR groups. Logistic regression was used to explore independent predictors of HF. RESULTS: Reduced eGFR was present in 71.1% of 2160 patients, with significant renal impairment (eGFR < 60 mL/min every 1.73 m(2)) in 14.8%. The prevalence of HF was higher with worsening renal function: 15.5%, 17.8% and 29.4% in patients with CKD stages 1, 2 and 3 or 4, respectively (P < 0.0001), despite a small absolute difference in mean EF across eGFR groups: 48.2 ± 10.0, 47.9 ± 11.3 and 46.2 ± 12.1, respectively (P = 0.02). The prevalence of HF was again higher with worsening renal function among patients with preserved EF: 10.1%, 13.6% and 23.6% (P < 0.0001), but this relationship was not significant among patients with depressed EF: 27.1%, 26.2% and 37.9% (P = 0.071). Moreover, eGFR was an independent correlate of HF in patients with preserved EF (P = 0.003) but not in patients with depressed EF (P = 0.181). CONCLUSION: A significant proportion of post-MI patients with occluded IRAs have impaired renal function. Impaired renal function was associated with an increased rate of early post-MI HF, the association being strongest in patients with preserved EF. These findings have implications for management of peri-infarct HF.

Periodic acceleration (pGz) prior to whole body ischemia reperfusion injury provides early cardioprotective preconditioning.

AIMS: Periodic acceleration (pGz) is a method that applies repetitive sinusoidal head-to-foot motion to the horizontally positioned body. pGz adds pulses to the circulation as a function of frequency, thereby increasing shear stress to the endothelium. Pulsatile shear stress increases release of cardioprotective endothelial-derived nitric oxide prostaglandin E-2 and prostacyclin into the circulation. We investigated whether pGz may be effective as an early preconditioning strategy when applied one hour prior to whole body ischemia reperfusion injury induced by ventricular fibrillation (VF). MAIN METHODS: Twenty anesthetized and paralyzed male swine were randomized to one hour of pGz and conventional mechanical ventilation [PC] or solely conventional mechanical ventilation [Control] prior to VF and resuscitation. After eight minutes of unsupported VF, cardiopulmonary resuscitation was carried out followed by defibrillation. Hemodynamics, electrocardiogram, echocardiogram, regional blood flows, and markers of global myocardial injury were measured. Protein expression of endothelial-derived nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), serine/threonine kinase Akt total (t-Akt), and phosphorylated (p-Akt) were determined by immunoblotting. KEY FINDINGS: All animals had spontaneous return of circulation after cardiopulmonary resuscitation (CPR) and defibrillation. Preconditioned animals had less hemodynamically significant arrhythmias, less myocardial stunning, and greater regional blood flows to the brain, heart, kidneys, and ileum than Controls. Troponin I and creatine phosphokinase values in PC were 65% of the values present in Controls. In addition, preconditioned animals had higher protein expression of cardiac eNOS, p-eNOS, t-Akt, and p-Akt than Controls. SIGNIFICANCE: pGz preconditioning confers early cardioprotection in a model of whole body ischemia reperfusion injury.

Should saphenous vein grafts be the conduits of last resort for coronary artery bypass surgery?

There is overwhelming evidence that internal mammary artery grafts improve survival and clinical outcomes after coronary artery bypass graft surgery. It has therefore become standard practice to use the left internal mammary artery as the graft of first choice. Given the overwhelming evidence for the superiority of internal mammary artery grafts, the question that naturally follows is whether the conduit of second choice should be the contralateral internal mammary artery, rather than a saphenous venous graft. This article reviews the evidence supporting the superiority of internal mammary artery grafts over other available conduits and addresses the selection of the second conduit after the left internal mammary artery. The current body of evidence, encompassing multiple clinical studies and employing different methodologies consistently, demonstrates that bilateral internal mammary artery grafting improves survival and long-term clinical outcome. The increasing longevity of postcoronary bypass patients with modern advances in medical and electrical therapies would augment the benefit of this procedure and argue for its greater utilization. Higher patency of arterial grafts may translate to a decreased need for repeat target vessel revascularization and may increase the cost-effectiveness of bilateral internal mammary artery use. However, in 2003, only 3% to 4% of patients undergoing surgical coronary revascularization received bilateral internal mammary artery grafts. There appears to be a potential to increase utilization of this procedure above the current rate. Increased utilization of this procedure would need a concerted effort by the cardiology and cardiac surgery community.

Distribution and determinants of myocardial perfusion grade following late mechanical recanalization of occluded infarct-related arteries postmyocardial infarction: a report from the occluded artery trial.

OBJECTIVE: To evaluate the distribution and determinants of myocardial perfusion grade (MPG) following late recanalization of persistently occluded infarct-related arteries (IRA). BACKGROUND: MPG reflects microvascular integrity. It is an independent prognostic factor following myocardial infarction, but has been studied mainly in the setting of early reperfusion. The occluded artery trial (OAT) enrolled stable patients with persistently occluded IRAs beyond 24 hr and up to 28 days post-MI. METHODS: Myocardial blush was assessed using TIMI MPG grading in 261 patients with TIMI 3 epicardial flow following IRA PCI. Patients demonstrating impaired (0-1) versus preserved (2-3) MPG were compared with regard to baseline clinical and pre-PCI angiographic characteristics. RESULTS: Impaired MPG was observed in 60 of 261 patients (23%). By univariate analysis, impaired MPG was associated with failed fibrinolytic therapy, higher heart rate, lower systolic blood pressure, lower ejection fraction, LAD occlusion, absence of collaterals (P < 0.01) and ST elevation MI, lower diastolic blood pressure, and higher systolic sphericity index (P < 0.05). By multivariable analysis, higher heart rate, LAD occlusion, absence of collaterals and higher systolic sphericity index (P < 0.01), and lower systolic blood pressure (P < 0.05) were independently associated with impaired MPG. CONCLUSION: Preserved microvascular integrity was present in a high proportion of patients following late recanalization of occluded IRAs post-MI. Presence of collaterals was independently associated with preserved MPG and likely accounted for the high frequency of preserved myocardial perfusion in this clinical setting. Impaired MPG was associated with baseline clinical and angiographic features consistent with larger infarct size.

Acute effects of "delayed postconditioning" with periodic acceleration after asphyxia induced shock in pigs.

Asphyxia cardiac arrest and shock are models for whole body ischemia reperfusion injury. Periodic acceleration (pGz) achieved by moving the body on a platform is a novel method for inducing pulsatile vascular shear stress and endogenous production of endothelial nitric oxide, prostaglandin E2, tissue plasminogen activator, and adrenomedullin. The aforementioned are cardioprotective during and after ischemia reperfusion injury. We investigated whether pGz, applied 15 min after return of spontaneous circulation (ROSC) would serve as an effective "delayed" post conditioning tactic to lessen acute reperfusion injury markers in a pediatric swine model of asphyxia induced shock. Asphyxia shock was induced in 20 swine weight 3.9 +/- 0.6 kg. Fifteen minutes after ROSC, the animals were randomized to receive conventional mechanical ventilation (CMV, [Control]) or CMV with pGz. All animals had ROSC and no significant differences in blood gases or hemodynamics after ROSC. pGz treated had significantly less myocardial dysfunction post resuscitation, (i.e. better % ejection fraction (EF), % fractional shortening (FS), and wall motion score index) and lower biochemical indices of reperfusion injury (lower TNF-alpha, IL-6, and Troponin I, and myeloperoxidase activity). Delayed postconditioning with pGz ameliorates acute post resuscitation reperfusion injury and improves myocardial dysfunction after asphyxia-induced shock.

Periodic acceleration (pGz) CPR in a swine model of asphyxia induced cardiac arrest. Short-term hemodynamic comparisons.

BACKGROUND: Asphyxia is one of the most common causes of pediatric cardiac arrest, and becoming a more frequently recognized cause in adults. Periodic acceleration (pGz) is a novel method of cardiopulmonary resuscitation (CPR). pGz is achieved by rapid motion of the supine body headward-footward that generates adequate perfusion and ventilation during cardiac arrest. In a swine ventricular fibrillation cardiac arrest model, pGz produced a higher return of spontaneous circulation (ROSC), superior neurological outcome, less echocardiography evidence of post resuscitation myocardial stunning, and decreased indices of tissue injury. In contrast to standard chest compression CPR, pGz does not produce rib fractures. We investigated the feasibility of pGz in severe asphyxia cardiac arrest and assessed whether beneficial effects seen in the VF model of cardiac arrest could be realized. METHODS AND RESULTS: Sixteen swine weight 4+/-1 kg were anesthetized, tracheally intubated, and instrumented to measure, hemodynamics and echocardiography. Asphyxia was induced by occlusion of the tracheal tube. After loss of aortic pulsations (median time 10 min) animals were observed for three additional minutes following which all were in cardiac arrest. The animals were then randomized to receive 10 min of pGz or standard chest compression ventilation performed with a commercial device (Thumper). A single dose of epinephrine (adrenaline) and sodium bicarbonate were given and defibrillation attempted if appropriate for a maximum of 10 min. Both groups received fractional inspired O2 concentration of 100% during CPR and after resuscitation. Four animals in each group (50%) had an initial ROSC, however only two of the four initial survivors remained alive 3h after ROSC. There were no significant differences in blood pressure, coronary perfusion pressure during CPR and after early ROSC between groups. pGz treated animals had significantly lower pulmonary artery pressure; 20+/-4 mmHg compared to Thumper 46+/-5 mmHg, 30 min after ROSC (p<0.01). Surviving animals in both groups had severe myocardial dysfunction at 30 min after ROSC. At necropsy, 25% of the Thumper treated animals had rib fractures, while none occurred in the pGz group. CONCLUSIONS: In a lethal model of asphyxia cardiac arrest, pGz is equivalent to standard CPR, with respect to acute outcomes and resuscitation survival rates but is associated with significantly lower pulmonary artery pressures and does not produce traumatic rib fractures.

Impact of rate-modulated pacing on quality of life and exercise capacity--evidence from the Advanced Elements of Pacing Randomized Controlled Trial (ADEPT).

BACKGROUND: Ninety-nine percent of pacemakers implanted in the United States include an option for rate modulation. OBJECTIVE: The purpose of this study was to determine whether dual-chamber rate-modulated pacing, when compared with dual-chamber pacing alone, improved quality of life. METHODS: This was a single-blind randomized controlled trial comparing dual-chamber with rate-modulated dual-chamber pacing. Patients were enrolled between January 12, 2000, and January 10, 2002, with 1-year follow-up ending December 19, 2002. The study was a U.S. multicenter trial, with 95 sites participating. All patients received a rate modulation-capable dual-chamber pacemaker for standard indications. Patients were screened with an exercise test (Chronotropic Assessment Exercise Protocol) 1 month later. One thousand two hundred seventy-three patients were enrolled; 401 proved ineligible, and 872 (68%) made up the randomized patient cohort. Randomized patients had a mean age of 71 years, 64% were men, and 64% had sinus node dysfunction. Randomization was in a factorial design to (1) dual-chamber rate-modulated pacing versus dual-chamber pacing and (2) automatic mode switching versus no automatic mode switching. The present report is limited to the comparison of rate modulation with no rate modulation (DDDR vs. DDD). The primary endpoint was the score on the Specific Activity Scale, an activity-based cardiovascular disease-specific instrument at 1 year. Secondary endpoints included 6-month treadmill time and additional cardiovascular disease-specific, and generic health-related quality-of-life instruments at 1 year. RESULTS: At 6 months, patients with rate modulation had a higher peak exercise heart rate (rate modulation 113.3 +/- 19.6, no rate modulation 101.1 +/- 21.1; P <.0001). Total exercise time was not different between groups. At 1 year, there were no significant differences between groups with respect to Specific Activity Scale or the secondary quality-of-life endpoints. CONCLUSIONS: We conclude that rate modulation is ineffective in improving the functional status or quality of life of patients with a bradycardia indication for dual-chamber pacing.

Effect of mechanical coronary reperfusion on QT dispersion in acute coronary syndrome.

BACKGROUND: The time for cardiac repolarization and homogeneity of repolarization on surface electrocardiogram is denoted by QT interval and QT dispersion, respectively. Numerous studies suggest an association between an increased dispersion of the QT interval obtained from the 12-lead electrocardiogram and increased risk for serious cardiac events. METHODS AND RESULTS: We evaluated the effect of thrombolysis and percutaneous transluminal coronary angioplasty on QT dispersion in acute coronary syndrome in 45 patients (age: 55 +/- 6 years). QT dispersion was calculated on admission and immediately after the procedure (thrombolysis and percutaneous transluminal coronary angioplasty). There was a significant decrease in QT dispersion after percutaneous transluminal coronary angioplasty (75 +/- 21 ms to 38 +/- 20 ms, p < 0.0001). In a subset of these patients with acute myocardial infarction (n = 29) who underwent thrombolysis, QT dispersion decreased only marginally (78 +/- 19 ms to 67 +/- 22 ms, p < 0.05). Even in this subgroup, there was a significant decrease in QT dispersion after percutaneous transluminal coronary angioplasty (to 37 +/- 22 ms, p < 0.0001). In patients with unstable angina (n = 16), there were similar significant changes after percutaneous transluminal coronary angioplasty (p < 0.0001). CONCLUSIONS: These results suggest a highly significant decrease in QT dispersion after percutaneous transluminal coronary angioplasty compared to a less significant decrease after thrombolysis, which may have clinical implications.

Quantification of annular dilatation and papillary muscle separation in functional mitral regurgitation: role of anterior mitral leaflet length as reference.

BACKGROUND: We hypothesized that anterior mitral leaflet length (ALL) does not differ significantly between normal subjects and patients with functional mitral regurgitation (FMR) and hence may be used as a reference measurement to quantify annular dilatation and papillary muscle separation. METHODS AND RESULTS: We prospectively studied 50 controls, 15 patients with systolic left ventricular dysfunction (LVD) with significant FMR, and 15 patients with LVD without significant FMR. Significant MR was defined as an effective regurgitant orifice area > or = 0.2 cm2 as measured by the flow convergence method. Annular diameter, interpapillary distance, and ALL were measured, and the following ratios were derived: annular diameter indexed to ALL (ADI) and interpapillary distance indexed to ALL (IPDI). There was no significant difference in ALL among the three groups. The mean ADI was 1.26 times controls in patients with LVD without significant FMR compared to 1.33 times controls in patients with LVD with significant FMR (P = 0.06, no significant difference between groups). The mean IPDI was 1.42 times controls in patients with LVD without significant FMR compared to 2.1 times controls in patients with LVD with significant FMR (P < 0.0001, significant difference between groups). CONCLUSION: There was no significant difference in ALL between controls and patients with LVD. ALL can be used as a reference measurement to quantify annular dilatation and papillary muscle separation in patients with FMR. Interpapillary distance but not annular diameter indexed to ALL correlates with severity of FMR.

Role of immunosuppressive therapy on clinical, immunological, and angiographic outcome in active Takayasu's arteritis.

OBJECTIVE: To evaluate the role of an immunosuppressive regimen consisting of azathioprine and prednisolone on the clinical, immunological, and angiographic outcome in patients with active Takayasu's arteritis (TA). METHODS: Between January 1996 and January 2001, of 65 consecutive newly diagnosed patients with TA not previously treated by any immunosuppressive therapy, 15 fulfilled the criteria for disease activity. Detailed clinical and laboratory evaluation was carried out in these patients. They were treated with a combination of azathioprine and prednisolone for one year, and aortography was carried out in all patients before and after completion of the treatment. RESULTS: All patients had improvement in systemic symptoms and laboratory measures of disease activity within a period of 3 months of onset of treatment. Erythrocyte sedimentation rate decreased from a mean of 55.5 +/- 14.7 mm/h to 21.9 +/- 9.5 mm/h within 3 months (p < 0.001) and further to 20.8 +/- 15.2 at one year (p = NS). C-reactive protein concentrations fell from 4.8 +/- 5.2 mg/dl to 0.5 +/- 0.2 mg/dl at 3 months (p = 0.004) and remained at 0.5 +/- 0.3 mg/dl at one year (p = NS). No changes in the peripheral pulses or differences in limb blood pressures were noted. Repeat angiograms revealed no significant changes compared to baseline. No new lesion appeared in any patient. The immunosuppressive therapy was well tolerated with no notable side effects. CONCLUSION: An immunosuppressive regimen of azathioprine and prednisolone is safe, well tolerated, and effective in ameliorating systemic symptoms and laboratory measures of disease activity in TA, and at least halts progression in angiographic lesions at one year of followup, although it does not seem to lead to a regression of the arterial lesions.