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Diabetes, Heart Failure and Beyond: Elucidating the Cardioprotective Mechanisms of Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors

Ojha, Utkarsh; Reyes, Lenisse; Eyenga, Florence; Oumbe, Diane; Watkowska, Justyna; Saint-Jacques, Henock
Approximately 5 million individuals in the US are living with congestive heart failure (CHF), with 650,000 new cases being diagnosed every year. CHF has a multifactorial etiology, ranging from coronary artery disease, hypertension, valvular abnormalities and diabetes mellitus. Currently, guidelines by the American College of Cardiology advocate the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, β-blockers, diuretics, aldosterone antagonists, and inotropes for the medical management of heart failure. The sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of drug that have been widely used in the management of type 2 diabetes mellitus that work by inhibiting the reabsorption of glucose in the proximal convoluted tubule. Since the EMPA-REG OUTCOME trial, several studies have demonstrated the benefits of SGLT2 inhibitors in reducing cardiovascular risk related to heart failure. While the cardiovascular benefits could be explained by their ability to reduce weight, improve glycemic index and lower blood pressure, several recent trials have suggested that SGLT2 inhibitors exhibit pleiotropic effects that underlie their cardioprotective properties. These findings have led to an expansion in preclinical and clinical research aiming to understand the mechanisms by which SGLT2 inhibitors improve heart failure outcomes.
PMID: 34189716
ISSN: 1179-187x
CID: 4926572

Exercise-Induced Sustained Ventricular Tachycardia without Structural Heart Disease: A Case Report

Darmadi, Michelle Audrey; Duval, Axel; Khadraoui, Hanaa; Romero, Alberto N; Simon, Blanca; Watkowska, Justyna; Saint-Jacques, Henock
BACKGROUND Exercise-induced ventricular tachycardia (VT) has been widely reported in patients with preexisting structural heart disease or underlying ischemia and is attributed to reentry tachycardia and abnormal automaticity. However, studies regarding exercise-induced VT in individuals without evident structural heart disease are still limited. CASE REPORT A 51-year-old woman came to our practice for a treadmill stress echocardiogram. The patient experienced only mild chest discomfort and was otherwise asymptomatic. Cardiovascular risk factors were significant only for obesity and positive family history of coronary artery disease in the mother. During the exercise stress test, the patient developed wide complex VT with multiple capture beats accompanied by nausea and dizziness, which lasted approximately 2 minutes before resolving spontaneously. Subsequent evaluation with magnetic resonance imaging, transthoracic echocardiography, and coronary angiography revealed an absence of apparent structural heart disease. CONCLUSIONS Exercise-induced VT in the absence of structural heart disease, although rare, can pose a life-threatening event and requires different considerations for management. The benefits of currently available therapeutic options have yet to be elucidated for this subset of patients. Thus, we assert that there is a need for further investigation on the approach of exercise-induced VT in patients without structural heart disease.
PMID: 33298825
ISSN: 1941-5923
CID: 4709042

A Late Case of Ischemic Cerebral Event after Resection of a Left Atrial Myxoma

Lafleur, Reginald; Watkowska, Justyna; Zhou, Guoping; Alcide, Phenix; Saint-Jacques, Henock
Atrial myxoma is one of the most common primary cardiac tumors reported in the literature. In very rare instances, stroke has been the sequelae after a myxomatous tumor resection. We report this unique case of late ischemic cerebral event in a 46-year-old female some days after resection of a left atrial myxoma.
PMID: 27403129
ISSN: 1662-680x
CID: 2179092

Effect of the novel direct factor Xa inhibitor DX-9065a on thrombin generation and inhibition among patients with stable atherosclerotic coronary artery disease

Becker, Richard C; Alexander, John H; Dyke, Christopher; Huang, Yao; Saint-Jacques, Henock; Hasselblad, Vic; Harrington, Robert A; Bovill, Edwin G
INTRODUCTION: Thrombin, a pluripotential effector enzyme with prothrombotic, proinflammatory, and mitogenic properties, plays a pivotal role in the pathobiology and clinical expression of atherothrombotic coronary artery disease. Existing anticoagulant drugs have not been shown to attenuate thrombin generation or activity consistently. We sought to investigate the effect of DX-9065a on thrombin generation and inhibition in patients with stable CAD. DX-9065a is a small-molecule, synthetic, direct inhibitor of factor Xa. MATERIALS AND METHODS: Peripheral venous blood samples were collected serially during and after administration of either placebo or 1 of 4 weight-adjusted regimens of DX-9065a, in 73 patients with stable CAD participating in the XaNADU-1B study. RESULTS AND CONCLUSIONS: At baseline, the median (25th, 75th) prothrombin activation fragment 1.2 (F1.2) level was 2.56 (2.05, 3.20) nmol/L, and the median d-dimer level was 0.26 (0.19, 0.38) microg FEU/L. There were significant relationships between measured plasma DX-9065a concentrations and both F1.2 (4.9% decrease for each doubling of DX-9065a) (P<0.0001) and d-dimer (5.5% decrease for each doubling of DX-9065a) (P=0.001). F1.2 was suppressed (below baseline) at 96 h after administration of DX-9065a. Coronary thrombotic events did not occur during or after study drug administration. DX-9065a, the first in a class of small-molecule, direct, selective and reversible factor Xa inhibitors, reduces thrombin generation and fibrin formation among patients with stable CAD. The effect is concentration-dependent and persists for at least 96 h following drug cessation, without biochemical or clinical evidence of rebound
PMID: 15882894
ISSN: 0049-3848
CID: 110197

Acute coronary syndrome critical pathway: chest PAIN caremap: a qualitative research study--provider-level intervention

Saint-Jacques, Henock; Burroughs, Valentine J; Watkowska, Justyna; Valcarcel, Michelle; Moreno, Pedro; Maw, Myo
Recently published data on healthcare performance continue to show a substantial gap between evidence-based guidelines and management of patients in real-world settings. This article describes an operational model that will be used to test whether a critical pathway applied in a secondary care-level institution may improve the process of care related to acute coronary syndromes (ACS). We have developed the pathway for management of all patients who present to our emergency department with a chief complaint of acute chest pain. Based on individual immediate ischemic event risk, patients are categorized according to a prespecified algorithm under the acronym of 'PAIN' (P-Priority risk, A-Advanced risk, I-Intermediate risk, and N-Negative/low risk) as prespecified in an algorithm. Along with the algorithm come 2 detailed order sets, 1 for ST-elevation ACS and another for non ST-elevation ACS. The pathway, together with the 2 order sets, are color-coded with the 'PAIN' acronym (P-red, A-yellow, I-yellow, N-green) that will guide patient management according to his or her risk stratification. These colors, similar to the road traffic light code, have been chosen as an easy reference for the provider about the sequential risk level of patients with ACS. This experimental model intends, with its unique structured approach, to increase awareness and improve adherence to the published American Heart Association/American College of Cardiology guidelines for the management of ACS
PMID: 18340201
ISSN: 1535-2811
CID: 110214

The PAIN pathway as a tool to bridge the gap between evidence and management of acute coronary syndrome

Herzog, Eyal; Saint-Jacques, Henock; Rozanski, Alan
Clinical guidelines on the management of Acute Coronary Syndrome (ACS) have consistently shown a major gap between the guidelines and their application in the actual management of ACS. In an attempt to achieve the goal of bridging the gap between these evidence-based guidelines and patient management, we have reorganized the pathway for the management of ACS at our institution. The pathway has been designated with the acronym of PAIN (Priority risk, Advanced risk, Intermediate risk, and Negative/Low risk), to reflect patients risk stratification upon admission. Along with the pathway comes a single detailed order sheet and a single discharge form which are color-coded according to the patient's risk stratification.This model is designed to mandate and, thus, markedly improve adherence to the published American Heart Association/American College of Cardiology guidelines for the management of ACS
PMID: 18340134
ISSN: 1535-2811
CID: 110213

Initial experience with factor-Xa inhibition in percutaneous coronary intervention: the XaNADU-PCI Pilot

Alexander, J H; Dyke, C K; Yang, H; Becker, R C; Hasselblad, V; Zillman, L A; Kleiman, N S; Hochman, J S; Berger, P B; Cohen, E A; Lincoff, A M; Saint-Jacques, H; Chetcuti, S; Burton, J R; Buergler, J M; Spence, F P; Shimoto, Y; Robertson, T L; Kunitada, S; Bovill, E G; Armstrong, P W; Harrington, R A
BACKGROUND: Direct factor (F)Xa inhibition is an attractive method to limit thrombotic complications during percutaneous coronary intervention (PCI). OBJECTIVES: To investigate drug levels achieved, effect on coagulation markers, and preliminary efficacy and safety of several doses of DX-9065a, an intravenous, small molecule, direct, reversible FXa inhibitor during PCI. PATIENTS AND METHODS: Patients undergoing elective, native-vessel PCI (n = 175) were randomized 4 : 1 to open-label DX-9065a or heparin in one of four sequential stages. DX-9065a regimens in stages I-III were designed to achieve concentrations of > 100 ng mL-1, > 75 ng mL-1, and > 150 ng mL-1. Stage IV used the stage III regimen but included patients recently given heparin. RESULTS: At 15 min median (minimum) DX-9065a plasma levels were 192 (176), 122 (117), 334 (221), and 429 (231) ng mL-1 in stages I-IV, respectively. Median whole-blood international normalized ratios (INRs) were 2.6 (interquartile range 2.5, 2.7), 1.9 (1.8, 2.0), 3.2 (3.0, 4.1), and 3.8 (3.4, 4.6), and anti-FXa levels were 0.36 (0.32, 0.38), 0.33 (0.26, 0.39), 0.45 (0.41, 0.51), and 0.62 (0.52, 0.65) U mL-1, respectively. Stage II enrollment was stopped (n = 7) after one serious thrombotic event. Ischemic and bleeding events were rare and, in this small population, showed no clear relation to DX-9065a dose. CONCLUSIONS: Elective PCI is feasible using a direct FXa inhibitor for anticoagulation. Predictable plasma drug levels can be rapidly obtained with double-bolus and infusion DX-9065a dosing. Monitoring of DX-9065a may be possible using whole-blood INR. Direct FXa inhibition is a novel and potentially promising approach to anticoagulation during PCI that deserves further study
PMID: 14995984
ISSN: 1538-7933
CID: 43522

Glycoprotein receptor inhibitors in the management of acute coronary syndromes

Saint-Jacques, Henock; Harrington, And Robert A
Coronary thrombosis and the risk of clinical adverse events remains high despite considerable advances in the management of acute coronary syndromes (ACS) with the combined use of aspirin, heparin, fibrinolytic therapy, and percutaneous coronary intervention (PCI). Platelet aggregation and thrombosis play a key role in the pathogenesis of unstable coronary syndromes. Over the past several years, multiple placebo-controlled trials involving more than 50,000 ACS patients have shown that blockade of the platelet receptor glycoprotein (GP) IIb/IIIa, the final pathway in platelet aggregation, reduces the incidence of ischemic complications among patients with ACS. Three agents (abciximab, eptifibatide, and tirofiban) are currently approved for use with aspirin and heparin in the management of ACS or during percutaneous coronary intervention. They have consistently been shown to reduce the incidence of death or myocardial infarction in the ACS population including the patients not routinely scheduled for early revascularization. They provide an augmented treatment effect among high-risk ACS patients, particularly those who have a baseline troponin-t-positive status. Recently published practice guidelines have recommended their use in high-risk patients with ACS and all those undergoing PCI
PMID: 12052269
ISSN: 1523-3782
CID: 110187