Samer Khouri

Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy.

Patients with chronic renal failure develop a “uremic” cardiomyopathy characterized by diastolic dysfunction, cardiac hypertrophy, and systemic oxidant stress. Patients with chronic renal failure are also known to have increases in the circulating concentrations of the cardiotonic steroid marinobufagenin (MBG). On this background, we hypothesized that elevations in circulating MBG may be involved in the cardiomyopathy. First, we observed that administration of MBG (10 &mgr;g/kg per day) for 4 weeks caused comparable increases in plasma MBG as partial nephrectomy at 4 weeks. MBG infusion caused increases in conscious blood pressure, cardiac weight, and the time constant for left ventricular relaxation similar to partial nephrectomy. Decreases in the expression of the cardiac sarcoplasmic reticulum ATPase, cardiac fibrosis, and systemic oxidant stress were observed with both MBG infusion and partial nephrectomy. Next, rats were actively immunized against a MBG-BSA conjugate or BSA control, and partial nephrectomy was subsequently performed. Immunization against MBG attenuated the cardiac hypertrophy, impairment of diastolic function, cardiac fibrosis, and systemic oxidant stress seen with partial nephrectomy without a significant effect on conscious blood pressure. These data suggest that the increased concentrations of MBG are important in the cardiac disease and oxidant stress state seen with renal failure.

Cardiovascular antioxidant therapy: a review of supplements, pharmacotherapies, and mechanisms.

Oxidant stress plays an important role in the pathogenesis of atherosclerosis. In the late 1980s, biological studies demonstrated that oxygen-free radicals oxidize low-density lipoprotein-cholesterol, resulting in the creation of foam cells and inciting the cascade of biological events that ultimately result in the formation of atherosclerosis. In vitro studies showed the ability of antioxidant vitamins to scavenge free radicals and block the oxidation of low-density lipoprotein. This data was supported in vivo by early observational studies suggesting the benefit of antioxidants, particularly vitamin E, in the prevention of coronary artery disease. On the basis of these studies, the use of antioxidant supplements by the general population increased substantially and became a multibillion dollar industry. Despite strong biological evidence and promising observational data, more rigorous scientific evaluation did not support a causational relationship between vitamin supplements and lowering coronary artery disease risk. Several prospective, double-blind, placebo-controlled trials showed no benefit and possibly harmful effects. Therapies such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins, which are known to have benefit in preventing and treating atherosclerosis by reducing blood pressure and cholesterol, also have a “pleiotropic” effect in reducing the formation of reactive oxygen species (ROS). Advances in molecular biology and the study of ROS led to a better understanding of the mechanisms that govern their production and role in atherogenesis. This progress identified unforeseen pathways by which these drugs favorably alter the balance in ROS production, and have raised possibilities for future targeted therapies in the prevention of atherosclerosis.

The Diagnostic Accuracy of Doppler Echocardiography in Assessment of Pulmonary Artery Systolic Pressure: A Meta-Analysis

Background: Transthoracic echocardiography is commonly used to estimate pulmonary arterial systolic pressure (PASP) and to diagnose pulmonary hypertension (PH). However, some recent studies have questioned the accuracy of Doppler echocardiography (DE) in the assessment of PASP. The present meta‐analysis was performed to estimate the accuracy, sensitivity, and specificity of DE in the assessment of PASP. Methods: A literature search and data extraction of English and non‐English articles reported from May 1984 to January 2009 was performed independently by 2 investigators using MEDLINE and EMBASE databases. Articles were included if they compared DE with right heart catheterization (RHC) in the assessment of PASP. Nine articles met our criteria and were included in our meta‐analysis. We conducted a meta‐analysis of the results of these articles using fixed‐ and random‐effect models to estimate the accuracy, sensitivity, and specificity of DE in the assessment of PASP. Results: The correlation between PASP estimated by DE and RHC ranged from (r = 0.65, P < 0.001) to (r = 0.97, P < 0.001). The pooled sensitivity, specificity, and accuracy of DE for the diagnosis of PH were 88% (95% confidence interval [CI], 84–92%), 56% (95% CI, 46–66%), and 63% (95% CI, 53–73%), respectively. Conclusion: DE is a useful noninvasive modality to screen for PH and can reliably determine whether PASP is normal, mildly elevated, or markedly elevated. However, abnormal results from DE need to be confirmed by RHC.

A Novel Approach to Standard Techniques in the Assessment and Quantification of the Interventricular Systolic Relationship

BackgroundBlood flow between the right and left ventricles is subject to the continuity equation and systolic ventricular interdependence. Quantification of this relationship might aid in understanding inter-ventricular function. The purpose of this study was to evaluate and quantify ventricular interdependence by directly comparing right and left ventricular systolic function though echocardiographic surrogates of right and left ventricular systolic function such as MAPSE, TAPSE, RV TVI and LV TVI.MethodsThis study prospectively evaluated 51 healthy participants (mean age, 41 ± 17 years) by resting echocardiography. In addition to standard measurements, tricuspid annular plane of systolic excursion, (TAPSE), mitral annular plane of systolic excursion (MAPSE), and the peak annulus systolic velocity of the right ventricular (RVs) and left ventricular (LVs) free walls were measured by M-mode and pulsed wave Doppler tissue echocardiography and further evaluated for variance across age, gender, and body surface area.ResultsTAPSE (22.1 ± 2.9 mm) was over 54.5% greater than MAPSE (14.3 ± 2.6 mm) and RVs was 64.4% greater than LVs. The LV to RV systolic relationship measured by MAPSE/TAPSE and LVs/RVs ratios were 0.66 ± 0.14 and 0.76 ± 0.21 respectively. These values were not significantly affected by age, gender or body surface area (BSA).ConclusionMAPSE/TAPSE and LVs/RVs ratios appear stable across age, gender, and BSA potentially making them good surrogates of systolic ventricular relationship and interdependence.

Mitral valve repair and bioprosthetic replacement without postoperative anticoagulation does not increase the risk of stroke or mortality

OBJECTIVES The study aimed to determine if mitral valve repair (MVRR) or bioprosthetic mitral valve replacement (BMVR) without postoperative anticoagulation is associated with a similar risk of thromboembolism and death as anticoagulation. METHODS We retrospectively reviewed our 2004-09 experience in 249 MVRR and bioprosthetic replacement patients (53% female; 63 year mean age). Concurrent procedures principally included antiarrhythmic surgery, aortic valve replacement, tricuspid valve repair and coronary bypass grafting. Warfarin therapy was instituted at the discretion of the surgeon. Thirty-day, a period known to have the highest risk of valve-related thromboembolism, outcomes were compared relying on the incidence of stroke and death as surrogates of thromboembolic complications. Intermediate-term survival was compared between the groups using Cox proportional hazard models. The mean follow-up was 2.9 years. Given the non-randomized warfarin use, a propensity score using patient comorbidities and concurrent procedures was created and added to the Cox models. RESULTS One hundred and ninety-two (77%) patients were discharged on warfarin and 57 (23%) were discharged without warfarin. Thirty-day mortality in patients discharged from the index hospitalization was 1.2% and was similar for the two groups (P = 0.99). Four ischaemic perioperative strokes were detected; 3 in the warfarin group and 1 in the no warfarin group (P = 0.99). Overall survival was 84%, with 84% survival in the warfarin group and 86% in the no warfarin group (P = 0.79). Bleeding complications were comparable between the two groups (P = 0.72). In a multivariate analysis, warfarin was not related to mortality. CONCLUSIONS Despite current guidelines recommending postoperative anticoagulation following MVRR or bioprosthetic replacement, the avoidance of warfarin does not increase perioperative complications and has no impact on intermediate survival. Accordingly, a prospective randomized study to adjudicate the role of extended warfarin thromboprophylaxis in mitral valve surgery is warranted.

Practical Considerations for the Pharmacotherapy of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a devastating disease. Before the 1990s, when pharmacologic treatment was finally approved, only supportive therapy was available, consisting of anticoagulation, digoxin, diuretics, and supplemental oxygen. Calcium channel blocker therapy was also an option, but only a small percentage of patients respond to it. However, starting with epoprostenol in 1996, the number of drugs approved to treat pulmonary arterial hypertension increased. Three distinct classes of drugs were developed based on the pathophysiology of the disease: the prostanoids, endothelin‐1 receptor antagonists, and phosphodiesterase type 5 inhibitors. The prostanoids are administered either parenterally or by inhalation to replace the lack of prostacyclin within the pulmonary arterial vasculature. The endothelin‐1 receptor antagonists were the first class of oral drugs to be developed, but drug interactions and adverse effects are prominent with this class. The phosphodiesterase type 5 inhibitors increase the second messenger cyclic guanosine monophosphate (GMP) that is induced by nitric oxide stimulation. All of the drugs within these three classes are distinct in and of themselves, and their clinical use requires in‐depth knowledge of pulmonary arterial hypertension and its pathophysiology. Because these drugs have different mechanisms of action, combination therapy has shown promise in patients with severe disease, although data are still lacking. This article should serve as a practical guide for clinicians who encounter patients with pulmonary arterial hypertension and the drugs used for the treatment of this devastating disease.

Endovascular therapy for radiation-induced pulmonary artery stenosis: A case report and review of the literature

Although pulmonary artery stenosis and its treatment has been well characterized in pediatric populations, its diagnosis and even how to determine the significance of a stenosis can be difficult and optimal management is currently unknown. This case report and review of the literature outlines how we successfully diagnosed, evaluated, and stented a patient with radiation induced pulmonary artery stenosis. This case further adds support to a very limited data pool suggesting that percutaneous angioplasty of pulmonary artery stenosis may be a safe and effective treatment option for this unique patient population.

In vivo assessment of arterial stiffness in the isoflurane anesthetized spontaneously hypertensive rat

BackgroundRodent models are increasingly used to study the development and progression of arterial stiffness. Both the non-invasive Doppler derived Pulse Wave Velocity (PWV) and the invasively determined arterial elastance index (EaI) have been used to assess arterial stiffness in rats and mice, but the need for anesthetic agents to make these in vivo estimates may limit their utility. Thus, we sought to determine: 1) if known differences in arterial stiffness in spontaneously hypertensive rats (SHR) are detectable by PWV and EaI measurements when made under isoflurane anesthesia, and 2) if these two uniquely acquired assessments of arterial elasticity correlate.MethodsWe obtained PWV and EaI measurements in isoflurane anesthetized young and old SHRs, which are known to have significant differences in arterial stiffness. Doppler pulse waves were recorded from carotid and iliac arteries and the distance (D) between probe applantation sites was recorded. Simultaneously, an EKG was obtained, and the time intervals between the R-wave of the EKG to the foot of the Doppler waveforms were measured and averaged over three cardiac cycles. Pulse-transit time (T) of the carotid to iliac artery was determined, and PWV was calculated as Distance (D)/Time (T), where D = the distance from the carotid to the iliac notch and T = (R to iliac foot) - (R to carotid foot). EaI was subsequently determined from pressure volumes loops obtained via left ventricle catheterization.ResultsPWV and EaI were found to be significantly faster in the older rats (13.2 ± 2.0 vs. 8.0 ± 0.8 m/sec, p < 0.001; 120 ± 20 vs. 97 ± 16 mmHg/μl/g, p <0.05). Bland-Altman analyses of intra- and inter-observer measures demonstrate a statistically significant relationship between readings (p < 0.0001). PWV and EaI measurements were found to be significantly and positively correlated with a correlation coefficient of 0.53 (p < 0.05).ConclusionOur study suggests that isoflurane administration does not limit Doppler PWV or EaI measures in their ability to provide accurate, in vivo assessments of relative arterial stiffness in isoflurane anesthetised SHR rats. Furthermore, PWV data obtained in these rats correlate well with invasively determined EaI.

Practical echocardiographic approach for risk stratification of patients with acute pulmonary embolism

Acute pulmonary embolism remains a common cause of mortality. Early diagnosis and appropriate risk stratification is necessary to individualize treatment strategy. Computed tomography scan of the pulmonary arteries is routinely used to diagnose acute pulmonary embolism and in some cases is useful to assess right ventricular dilation. In patients with acute pulmonary embolism, right ventricular dilation and dysfunction indicates a high-risk situation where immediate administration of thrombolytic agent, catheter-directed thrombolysis, or surgical embolectomy could be considered. A bedside 2D echocardiogram at the time of presentation could provide additional morphological, functional, and hemodynamic parameters including right ventricular dilation, McConnell’s sign, reduced tricuspid annular plane systolic excursion (TAPSE), interventricular septal flattening, abnormal right ventricular hemodynamics and in rare cases thrombi in the inferior vena cava, right atrium or ventricle en route to pulmonary arteries may also be visualized. This additional information is useful for selection of appropriate treatment modality. Thus, our objective is to provide a practical echocardiographic approach for risk stratification of patients with acute pulmonary embolism.

Post-reperfusion syndrome during renal transplantation: a retrospective study.

Post-reperfusion syndrome (PRS) is a serious, widely reported complication following the reperfusion of an ischemic tissue or organ. We sought to determine the prevalence, risk factors and short-term outcomes of PRS related renal transplantation. We conducted a retrospective, case-control study of patients undergoing renal transplantation between July 2006 and March 2008. Identification of PRS was based on a drop in mean arterial pressure by at least 15% within 5 minutes of donor kidney reperfusion. Of the 150 consecutive renal transplantations reviewed, 6 patients (4%) met criteria for post-reperfusion syndrome. Univariate analysis showed that an age over 60, diabetes mellitus, Asian race, and extended criteria donors increased the odds of developing PRS by 4.8 times (95% CI [1.2, 20]; P=.0338), 4.5 times (95% CI [1.11, 18.8]; P=.0378), 35.5 times (95% CI [3.94, 319.8]; P=0.0078) and 9.6 times (95% CI [1.19, 76.28] P=0.0115) respectively. Short term follow-up revealed increased graft failure rate within 6 months (6% vs. 16% P=0.0125) and almost twice the number of hospital days post-transplant in PRS cohorts (5.43 ± 2.29 vs. 10.8 ± 7.29 P=<0.0001). Despite limited reporting, PRS appears to be a relatively common complication of renal transplantation and is associated with increase morbidity.