Fadi Shamoun

Symptomatic and asymptomatic carotid artery plaque

Carotid atherosclerotic plaques represent both stable and unstable atheromatous lesions. Atherosclerotic plaques that are prone to rupture owing to their intrinsic composition such as a large lipid core, thin fibrous cap and intraplaque hemorrhage are associated with subsequent thromboembolic ischemic events. At least 15–20% of all ischemic strokes are attributable to carotid artery atherosclerosis. Characterization of plaques may enhance the understanding of natural history and ultimately the treatment of atherosclerotic disease. MRI of carotid plaque and embolic signals during transcranial Doppler have identified features beyond luminal stenosis that are predictive of future transient ischemic attacks and stroke. The value of specific therapies to prevent stroke in symptomatic and asymptomatic patients with severe carotid artery stenosis are the subject of current research and analysis of recently published clinical trials that are discussed in this article.

Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque

Evolution of plaque that is prone to rupture is characterized by inflammation and physical changes. Accumulation of low-density lipoprotein in the sub-intima provides esterified cholesterol (ESC) to macrophages and smooth muscle cells that convert it into free cholesterol (FRC) by cholesteryl ester hydrolases (CEHs). Membrane-bound cholesterol carriers transport FRC to high-density lipoprotein (HDL). Impaired HDL transport function and altered composition can lead to extracellular accumulation of FRC, whereas impaired membrane carrier activity can lead to intracellular FRC accumulation. Saturation of FRC can result in cholesterol crystallization with cell death and intimal injury. Disequilibrium between ESC and FRC can impact foam cell and cholesterol crystal (CC) formation. Cholesterol crystals initiate inflammation via NLRP3 inflammasome leading to interleukin-1β (IL-1β) production inducing C-reactive protein. Eventually, crystals growing from within the plaque and associated inflammation destabilize the plaque. Thus, inhibition of inflammation by antagonists to IL-1β or agents that dissolve or prevent CC formation may stabilize vulnerable plaques.

Meta-Analysis on Risk of Bleeding With Apixaban in Patients With Renal Impairment

Apixaban is a novel oral anticoagulant which is approved for the management of atrial fibrillation and venous thromboembolism prophylaxis. There have been concerns regarding bleeding risks with apixaban in patients with renal impairment. We performed a systematic review and meta-analysis to evaluate the risk of bleeding with apixaban in these patients. Relevant studies were identified through electronic literature searches of MEDLINE, EMBASE, Cochrane library, and clinicaltrials.gov (from inception to February 24, 2014). Phase III randomized controlled trials that compared apixaban with conventional agents (vitamin K antagonist and/or warfarin, low molecular weight heparin, aspirin, and placebo) were included. We defined mild renal impairment as creatinine clearance of 50 to 80 ml/min and moderate to severe renal impairment as creatinine clearance <50 ml/min. Study-specific risk ratios were calculated, and between-study heterogeneity was assessed using the I(2) statistics. In 6 trials involving 40,145 patients, the risk of bleeding with apixaban in patients with mild renal impairment was significantly less (risk ratio 0.80, 95% confidence interval 0.66 to 0.96, I(2) = 13%) compared with conventional anticoagulants. In patients with moderate to severe renal impairment, the risk of bleeding with was found to be similar (risk ratio 1.01, 95% confidence interval 0.49 to 2.10, I(2) = 72%). In conclusion, compared with the conventional agents, bleeding risk with apixaban in patients with mild and moderate to severe renal insufficiency is lower and similar, respectively.

Peripheral artery disease: therapeutic advances

Peripheral arterial disease (PAD), usually caused by atherosclerosis, is defined as an obstructive arterial disease of the lower extremities that reduces arterial flow during exercise or, in advanced stages, at rest. It affects more than 8.5 million people in the USA. PAD may appear as an asymptomatic arterial disease with abnormal noninvasive test results, or as a symptomatic disease presenting with atypical limb pain, classic intermittent claudication, or critical limb ischemia. The spectrum of PAD is not a continuum. Patients who present with critical limb ischemia may have experienced minimum symptoms. PAD results in limitation of exercise and walking ability, described as intermittent claudication. Patients with PAD are physically impaired and have a higher risk of cardiovascular events; therefore, the treatment goals are aimed at decreasing their cardiovascular risk, as well as improving exercise and daily functional performance. Apart from supervised exercise, which is a major treatment modality for patients with PAD, as of yet there have been very few significant pharmacological breakthroughs in the treatment of PAD that increases blood flow to the ischemic limb. Although percutaneous intervention has markedly improved the treatment of PAD, bypass surgery continues to play an important role. For the most part medical therapy for PAD is designed as a secondary prevention for cardiovascular risk. These include antiplatelet therapy, statins, ACE-inhibitors, smoking cessation and possibly antihypertensive therapy. Revascularization is most beneficial for patients with lifestyle limiting symptoms, acute or chronic limb ischemia with resting pain or nonhealing ulcers. In the following review article we will try to explore the clinical role of some of the latest developments in this field.

Novel Anticoagulants in Atrial Fibrillation: A Primer for the Primary Physician

Atrial fibrillation is a common arrhythmia encountered in clinical practice. The prevalence increases with age. A devastating complication of atrial fibrillation is cardioembolic stroke with central nervous system sequelae. Based on stroke risk scores (CHADS and CHA2DS2VASc) and bleeding risk (HAS-BLED), the optimal use of anticoagulation in atrial fibrillation is feasible. Warfarin is a proven medication for this specific indication but requires frequent monitoring and dose adjustments, and it has multiple food, drug, and disease-state interactions. In addition, management of anticoagulation during the perioperative period may be challenging. In this regard, novel oral anticoagulants (NOACs) have shown promise in the shift toward the “ideal” anticoagulant therapy, in that fixed dosing is the norm, drug interactions are few, food interactions are absent, onset is fairly immediate and offset predictable, and, in the majority of patients, therapeutic monitoring is not required. This article provides a review of recent published trials of the use of NOACs in atrial fibrillation. Practical points on indications, contraindications, mechanism of action, interactions, and perioperative management tips are discussed with a view toward the safe and effective use of these new medications. When patients are transitioned between different anticoagulant medications, the risks of thrombosis and bleeding need to be considered. When switching from warfarin to a NOAC, the NOAC can be started once the international normalized ratio is ≤2.0.

The novel anticoagulants: The surgeons' prospective

Anticoagulants can complicate the approach to the management of patients undergoing operative interventions. We review new anticoagulants that have been introduced recently to the market or that are undergoing investigations for treatment of nonvalvular atrial fibrillation and venous thromboembolism prophylaxis: Dabigatran, rivaroxaban, apixiban, and edoxaban.

Catheter-Directed Treatment of Pulmonary Embolism: A Systematic Review and Meta-Analysis of Modern Literature:

We summarize the evidence for the safety and efficacy of catheter-directed thrombolysis (CDT) with and without ultrasound-assisted therapy for treating submassive and massive pulmonary embolism (PE) in a systematic review. The primary efficacy outcome was mortality. Outcomes were pooled across studies with the random-effects model. Twenty-four studies enrolled 700 patients in total; 653 received mechanical thromboembolectomy treatments for PE (mortality rate, 9% [95% confidence interval (CI), 6%-13%], P = .12; rate of minor complications, 6% [95% CI, 2%-13%]). In the ultrasound-accelerated thrombolysis (USAT) studies, the mortality rate was 4% (95% CI, 1%-11%) and in the non-USAT studies, it was 9% (95% CI, 6%-13%). Secondary safety outcomes were all bleeding events, which occurred in 12% (95% CI, 7%-20%) of the USAT studies and in 10% (95% CI, 5%-20%) of the non-USAT studies. Current clinical evidence does not prove USAT is superior over CDT methods.

Cerebral Venous Thrombosis: Current and Newer Anticoagulant Treatment Options.

Background:Cerebral venous thrombosis (CVT) is rare and involves thrombosis of the veins and sinuses of the brain, most commonly the superior sagittal sinus. Approximately 5 CVT cases occur per 1 million persons in western countries. CVT causes 0.5% of strokes. Early diagnosis is crucial to prevent such outcomes as hydrocephalus, intracranial hypertension, and further seizures. Standard medical treatment of CVT consists of low-molecular-weight heparin and endovascular thrombolysis. Small case reports have found that the newer oral anticoagulants can be used for CVT treatment; however, they are associated with increased risk of bleeding and other adverse effects. Review Summary:CVT can be triggered by an imbalance of the body’s homeostasis or reduced action of the intrinsic antithrombotic mechanism. Factors influencing this change include infection, brain tumor, inflammatory conditions, genetic thrombophilias, head trauma that causes intracranial bleeding, and certain medications. CVT may cause brain infarction and increased intracranial pressure. Sometimes, idiopathic intracranial hypertension presents as the only clinical manifestation. Confirmation of the diagnosis typically is through neuroimaging. Current CVT treatment depends on disease extent and severity. Conclusions:CVT is a rare neurological disease with potentially serious implications and high neurological morbidity and mortality rates. Understanding the role of risk factors—such as genetic or acquired thrombophilia, pregnancy, use of oral contraceptives, and hyperhomocysteinemia—in CVT development is important. Although heparin and warfarin have been used for more than 50 years, newer oral anticoagulants (eg, dabigatran, rivaroxaban, apixaban) might offer an alternative to traditional therapy.

Deep vein thrombosis: pathogenesis, diagnosis, and medical management

Deep vein thrombosis (DVT) is a major preventable cause of morbidity and mortality worldwide. Venous thromboembolism (VTE), which includes DVT and pulmonary embolism (PE), affects an estimated 1 per 1,000 people and contributes to 60,000-100,000 deaths annually. Normal blood physiology hinges on a delicate balance between pro- and anti-coagulant factors. Virchows Triad distills the multitude of risk factors for DVT into three basic elements favoring thrombus formation: venous stasis, vascular injury, and hypercoagulability. Clinical, biochemical, and radiological tests are used to increase the sensitivity and specificity for diagnosing DVT. Anticoagulation therapy is essential for the treatment of DVT. With few exceptions, the standard therapy for DVT has been vitamin K-antagonists (VKAs) such as warfarin with heparin or fractionated heparin bridging. More recently, a number of large-scale clinical trials have validated the use of direct oral anticoagulants (DOACs) in place of warfarin in select cases. In this review, we summarize the pathogenesis, diagnosis, and medical management of DVT, with particular emphasis on anticoagulation therapy and the role of DOACs in the current treatment algorithm.

Frequency of Cholesterol Crystals in Culprit Coronary Artery Aspirate During Acute Myocardial Infarction and Their Relation to Inflammation and Myocardial Injury

Cholesterol crystals (CCs) have been associated with plaque rupture through mechanical injury and inflammation. This study evaluated the presence of CCs during acute myocardial infarction (AMI) and associated myocardial injury, inflammation, and arterial blood flow before and after percutaneous coronary intervention. Patients presenting with AMI (n = 286) had aspiration of culprit coronary artery obstruction. Aspirates were evaluated for crystal content, size, composition, and morphology by scanning electron microscopy, crystallography, and infrared spectroscopy. These were correlated with inflammatory biomarkers, cardiac enzymes, % coronary stenosis, and Thrombolysis in Myocardial Infarction (TIMI) blush and flow grades. Crystals were detected in 254 patients (89%) and confirmed to be cholesterol by spectroscopy. Of 286 patients 240 (84%) had CCs compacted into clusters that were large enough to be measured and analyzed. Moderate to extensive CC content was present in 172 cases (60%). Totally occluded arteries had significantly larger CC clusters than partially occluded arteries (p <0.05). Patients with CC cluster area >12,000 µm2 had significantly elevated interleukin-1 beta (IL-1β) levels (p <0.01), were less likely to have TIMI blush grade of 3 (p <0.01), and more likely to have TIMI flow grade of 1 (p <0.01). Patients with recurrent AMI had smaller CC cluster area (p <0.04), lower troponin (p <0.02), and IL-1β levels (p <0.04). Women had smaller CC clusters (p <0.04). Macrophages in the aspirates were found to be attached to CCs. Coronary artery aspirates had extensive deposits of CCs during AMI. In conclusion, presence of large CC clusters was associated with increased inflammation (IL-1β), increased arterial narrowing, and diminished reflow following percutaneous coronary intervention.