P.C. Colombo

Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea

Background— Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. Methods and Results— Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP ≥4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP ≥4 hours daily. Conclusions— OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations.

Vascular Inflammation in Obesity and Sleep Apnea

Background— Unrecognized obstructive sleep apnea (OSA) is highly prevalent in obesity. Both obesity and OSA are associated with vascular endothelial inflammation and increased risk for cardiovascular diseases. We investigated directly whether the endothelial alterations that are attributed commonly to obesity are in fact related to OSA. Methods and Results— Seventy-one subjects with a body mass index ranging from normal to obese underwent attended polysomnography. To assess vascular inflammation and oxidative stress directly, we quantified the expression of nuclear factor-&kgr;B and nitrotyrosine by immunofluorescence in freshly harvested venous endothelial cells. To evaluate basal endothelial nitric oxide (NO) production and activity, we quantified the expression of endothelial NO synthase (eNOS) and phosphorylated eNOS. Vascular reactivity was measured by brachial artery flow-mediated dilation. Expression of eNOS and phosphorylated eNOS and flow-mediated dilation were significantly lower, whereas expression of nitrotyrosine was significantly greater in OSA patients (n=38) than in OSA-free subjects (n=33) regardless of central adiposity. Expression of nuclear factor-&kgr;B was greater in obese OSA patients than in obese OSA-free subjects (P=0.004). Protein expression and flow-mediated dilation were not significantly affected by increasing body mass index or central obesity in OSA patients and in OSA-free subjects. After 4 weeks of continuous positive airway pressure therapy, flow-mediated dilation and expression of eNOS and phosphorylated eNOS significantly increased whereas expression of nitrotyrosine and nuclear factor-&kgr;B significantly decreased in OSA patients who adhered to continuous positive airway pressure ≥4 hours daily. Conclusions— Untreated OSA rather than obesity is a major determinant of vascular endothelial dysfunction, inflammation, and elevated oxidative stress in obese patients.

Development of a Novel Echocardiography Ramp Test for Speed Optimization and Diagnosis of Device Thrombosis in Continuous-Flow Left Ventricular Assist Devices: The Columbia Ramp Study

OBJECTIVES This study sought to develop a novel approach to optimizing continuous-flow left ventricular assist device (CF-LVAD) function and diagnosing device malfunctions. BACKGROUND In CF-LVAD patients, the dynamic interaction of device speed, left and right ventricular decompression, and valve function can be assessed during an echocardiography-monitored speed ramp test. METHODS We devised a unique ramp test protocol to be routinely used at the time of discharge for speed optimization and/or if device malfunction was suspected. The patients left ventricular end-diastolic dimension, frequency of aortic valve opening, valvular insufficiency, blood pressure, and CF-LVAD parameters were recorded in increments of 400 rpm from 8,000 rpm to 12,000 rpm. The results of the speed designations were plotted, and linear function slopes for left ventricular end-diastolic dimension, pulsatility index, and power were calculated. RESULTS Fifty-two ramp tests for 39 patients were prospectively collected and analyzed. Twenty-eight ramp tests were performed for speed optimization, and speed was changed in 17 (61%) with a mean absolute value adjustment of 424 ± 211 rpm. Seventeen patients had ramp tests performed for suspected device thrombosis, and 10 tests were suspicious for device thrombosis; these patients were then treated with intensified anticoagulation and/or device exchange/emergent transplantation. Device thrombosis was confirmed in 8 of 10 cases at the time of emergent device exchange or transplantation. All patients with device thrombosis, but none of the remaining patients had a left ventricular end-diastolic dimension slope >-0.16. CONCLUSIONS Ramp tests facilitate optimal speed changes and device malfunction detection and may be used to monitor the effects of therapeutic interventions and need for surgical intervention in CF-LVAD patients.

A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure

Background Continuous‐flow left ventricular assist systems increase the rate of survival among patients with advanced heart failure but are associated with the development of pump thrombosis. We investigated the effects of a new magnetically levitated centrifugal continuous‐flow pump that was engineered to avert thrombosis. Methods We randomly assigned patients with advanced heart failure to receive either the new centrifugal continuous‐flow pump or a commercially available axial continuous‐flow pump. Patients could be enrolled irrespective of the intended goal of pump support (bridge to transplantation or destination therapy). The primary end point was a composite of survival free of disabling stroke (with disabling stroke indicated by a modified Rankin score >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove the device at 6 months after implantation. The trial was powered for noninferiority testing of the primary end point (noninferiority margin, ‐10 percentage points). Results Of 294 patients, 152 were assigned to the centrifugal‐flow pump group and 142 to the axial‐flow pump group. In the intention‐to‐treat population, the primary end point occurred in 131 patients (86.2%) in the centrifugal‐flow pump group and in 109 (76.8%) in the axial‐flow pump group (absolute difference, 9.4 percentage points; 95% lower confidence boundary, ‐2.1 [P<0.001 for noninferiority]; hazard ratio, 0.55; 95% confidence interval [CI], 0.32 to 0.95 [two‐tailed P=0.04 for superiority]). There were no significant between‐group differences in the rates of death or disabling stroke, but reoperation for pump malfunction was less frequent in the centrifugal‐flow pump group than in the axial‐flow pump group (1 [0.7%] vs. 11 [7.7%]; hazard ratio, 0.08; 95% CI, 0.01 to 0.60; P=0.002). Suspected or confirmed pump thrombosis occurred in no patients in the centrifugal‐flow pump group and in 14 patients (10.1%) in the axial‐flow pump group. Conclusions Among patients with advanced heart failure, implantation of a fully magnetically levitated centrifugal‐flow pump was associated with better outcomes at 6 months than was implantation of an axial‐flow pump, primarily because of the lower rate of reoperation for pump malfunction. (Funded by St. Jude Medical; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.)

Prevalence of de novo aortic insufficiency during long-term support with left ventricular assist devices

BACKGROUND Left ventricular assist devices (LVADs) are increasingly used as long-term therapy for end-stage heart failure patients. We compared the prevalence of aortic insufficiency (AI) after HeartMate II (HMII) vs HeartMate XVE (HMI) support and assessed the role of aortic root diameter and aortic valve opening in the development of AI. METHOD Pre-operative and post-operative echocardiograms of 93 HMI and 73 HMII patients who received implants at our center between January 2004 and September 2009 were retrospectively reviewed. After excluding patients with prior or concurrent surgical manipulation of the aortic valve, with baseline AI, or without baseline echoes, 67 HMI and 63 HMII patients were studied. AI was deemed significant if mild to moderate or greater. Pathology reports were reviewed for 77 patients who underwent heart transplant. RESULTS AI developed in 4 of 67 HMI (6.0%) and in 9 of 63 HMII patients (14.3%). The median times to AI development were 48 days for HMI patients and 90 days for HMII patients. For patients who remained on device support at 6 and 12 months, freedom from AI was 94.5% and 88.9% in HMI patients and 83.6% and 75.2% in HMII patients (log rank p = 0.194). Aortic root diameters, as determined by echocardiography for the patients with AI, trended to be larger at baseline (3.43 ± 0.43 vs 3.15 ± 0.40; p = 0.067) and follow-up (3.58 ± 0.54 vs 3.29 ± 0.50; p = 0.130) compared with those who did not have AI. Aortic root circumferences were assessed directly by a pathologist in those patients who underwent transplant and were significantly larger in HMII patients who had developed AI compared with those patients who did not (8.44 ± 0.89 vs 7.36 ± 1.02 cm; p = 0.034). Lastly, AI was more common in patients whose aortic valve did not open (11 of 26 vs 1 of 14; p = 0.03). CONCLUSION Aortic insufficiency occurs frequently in patients who receive continuous-flow support with a HMII LVAD, and may be associated with aortic root diameter enlargement and aortic valve opening. These findings warrant a more thorough preoperative patient evaluation and additional studies to investigate the factors, that may be associated with AI development.

Physical training in patients with chronic heart failure enhances the expression of genes encoding antioxidative enzymes

OBJECTIVES We sought to determine whether the benefit of training for vasodilation in the skeletal muscle vasculature of patients with chronic heart failure (CHF) is likely to be caused at the molecular level primarily by increased nitric oxide (NO) production or decreased inactivation of NO. BACKGROUND Physical training reverses endothelium dysfunction in patients with CHF, mediated by increased NO bioactivity. Some animal studies support a mechanism whereby training results in increased vascular NO levels by sustained transcriptional activation of the endothelial NO synthase (eNOS) gene, presumably due to shear stress. The mechanism has not been addressed in patients with CHF. METHODS The steady state transcript levels for eNOS and two other shear stress regulated genes (angiotensin-converting enzyme [ACE] and prostacyclin synthase [PGI2S]) were measured in samples of skeletal muscle from patients with CHF before and after 12 weeks of training. Transcript levels were measured in the same samples for two genes encoding antioxidant enzymes, copper zinc superoxide dismutase (Cu/Zn SOD) and glutathione peroxidase (GSH-Px). Untrained patients served as controls. RESULTS As expected, training significantly enhanced peak oxygen uptake in the patients with CHF. Training did not increase steady-state transcript levels for eNOS, ACE or PGI2S. In striking contrast, training increased the expression of the antioxidative enzyme genes by approximately 100%. CONCLUSIONS Our results do not support a model of benefit from training by increased eNOS expression. However, the data are entirely consistent with the alternative hypothesis, that reduced oxidative stress may account for the increase in vascular NO-mediated vasodilation. Insight into the mechanism may be relevant when considering therapies for exercise-intolerant patients with CHF.

Endothelial Cell Activation in Patients With Decompensated Heart Failure

Background—Vascular endothelial functions, other than nitric oxide (NO)–mediated control of vasomotor tone, are poorly characterized in patients with chronic heart failure (CHF). Veins and arteries are exposed to the same circulating proinflammatory mediators in patients with CHF. The present study tested whether endothelial cell activation occurs in veins of patients with decompensated CHF and whether activation, if present, subsides with return to a clinically compensated state. Methods and Results—Fifteen patients with decompensated CHF requiring transient inotropic support and 6 age-matched, healthy controls were studied. Endothelial cells and blood were collected from a forearm vein, and brachial artery flow–mediated dilation (FMD) was measured before and 24 hours after discontinuation of short-term inotropic therapy, when patients had returned to a steady compensated state. Nitrotyrosine immunoreactivity (an intracellular marker of oxidative stress), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS) expression were significantly higher in venous endothelial cells of patients in clinical decompensation when compared with healthy subjects. Return to a compensated state resulted in a significant reduction in nitrotyrosine immunoreactivity, COX-2, and iNOS expression. Concomitantly, a significant increase in FMD and a decline in plasma total 8-isoprostane and bicycloprostaglandin E2 levels were observed. Venous endothelial NOS expression was unaffected by clinical decompensation. Conclusions—Clinical decompensation in CHF is associated with activation of the venous endothelium. Return to a compensated state after short-term inotropic therapy results in a significant reduction in endothelial nitrotyrosine formation, COX-2, and iNOS expression.

Clinical outcome of mechanical circulatory support for refractory cardiogenic shock in the current era

BACKGROUND Mortality for refractory cardiogenic shock (RCS) remains high. However, with improving mechanical circulatory support device (MCSD) technology, the treatment options for RCS patients are expanding. We report on a recent 5-year single-center experience with MCSD for treatment of RCS. METHODS This study was a retrospective review of adult patients who required an MCSD due to RCS in the past 5 years. We excluded those patients with post-cardiotomy shock and post-transplant cardiac graft dysfunction. In the setting of RCS, a short-term ventricular assist device (VAD) was inserted as a bridge-to-decision device. Veno-arterial extracorporeal membrane oxygenation (VA ECMO) was chosen in cases of unknown neurologic status, complete hemodynamic collapse or severe coagulopathy. RESULTS From January 2007 through January 2012, 90 patients received an MCSD for RCS, 21 (23%) of whom had active cardiopulmonary resuscitation (CPR). The etiology of RCS included acute myocardial infarction in 49% and acute decompensated heart failure in 27%. Mean age was 53±14 years, 71% were male, and 60% had an intra-aortic balloon pump. The initial approach utilized was short-term VAD in 49% and VA ECMO in 51%. Median length of support was 8 days (IQR 4 to 18 days). Exchange to implantable VAD was performed in 26% of patients. Other destinations included myocardial recovery in 18% and heart transplantation in 11%. Survival to hospital discharge was 49%. Multivariate analysis showed ongoing CPR to be an independent risk factor for mortality (OR = 5.79, 95% CI 1.285 to 26.08, p = 0.022). CONCLUSIONS In the current era, roughly half of the patients who need an MCSD for RCS survive, and roughly half of these survivors require an implantable VAD. Ongoing CPR is predictive of in-hospital mortality.

Ventricular arrhythmias and implantable cardioverter-defibrillator therapy in patients with continuous-flow left ventricular assist devices: Need for primary prevention?

OBJECTIVES This study sought to evaluate the prevalence and significance of ventricular arrhythmia (VA) and the role of an implantable cardioverter-defibrillator (ICD) in patients supported by a continuous-flow left ventricular assist device (CF-LVAD). BACKGROUND VAs are common in patients supported by CF-LVADs but prospective data to support the routine use of ICDs in these patients are lacking. METHODS All patients supported by long-term CF-LVAD receiving care at our institution were enrolled. The ICDs were interrogated at baseline and throughout prospective follow-up. The VA was defined as ventricular tachycardia/fibrillation lasting >30 s or effectively terminated by appropriate ICD tachytherapy. The primary outcome was the occurrence of VA >30 days after CF-LVAD implantation. RESULTS Ninety-four patients were enrolled; 77 had an ICD and 17 did not. Five patients with an ICD had it deactivated or a depleted battery not replaced during the study. Twenty-two patients had a VA >30 days after LVAD implantation. Pre-operative VA was the major predictor of post-operative arrhythmia. Absence of pre-operative VA conferred a low risk of post-operative VA (4.0% vs. 45.5%; p < 0.001). No patients discharged from the hospital without an ICD after CF-LVAD implantation died during 276.2 months of follow-up (mean time without ICD, 12.7 ± 12.3 months). CONCLUSIONS Patients with pre-operative VA are at risk of recurrent VA while on CF-LVAD support and should have active ICD therapy to minimize sustained VA. Patients without pre-operative VA are at low risk and may not need active ICD therapy.

Prevalence, Significance, and Management of Aortic Insufficiency in Continuous Flow Left Ventricular Assist Device Recipients

Background— Aortic insufficiency (AI) is increasingly recognized as a complication of continuous flow left ventricular assist device support; however, its long-term prevalence, clinical significance, and efficacy of potential interventions are not well known. Methods and Results— We studied the prevalence and management of AI in 232 patients with continuous flow left ventricular assist device at our institution. Patients with aortic valve (AV) surgery before left ventricular assist device implantation were excluded from analysis. To examine the prevalence of de novo AI, patients without preoperative AI were divided into a retrospective and a prospective cohort based on whether a dedicated speed optimization study had been performed at the time of discharge. Forty-three patients underwent AV repair at the time of implant, and 3 subsequently developed greater than mild AI. In patients without surgical AV manipulation and no AI at the time of implant, Kaplan–Meier analysis revealed that freedom from greater than mild de novo AI at 1 year was 77.6±4.2%, and that at least moderate AI is expected to develop in 37.6±13.3% after 3 years. Nonopening of the AV was strongly associated with de novo AI development in patients without prospective discharge speed optimization. Seven of 21 patients with at least moderate AI developed symptomatic heart failure requiring surgical intervention. Conclusions— AI is common in patients with continuous flow left ventricular assist devices and may lead to clinical decompensation requiring surgical correction. The prevalence of AI is substantially less in patients whose AV opens, and optimized loading conditions may reduce AI prevalence in those patients in whom AV opening cannot be achieved.