Ticagrelor and Rosuvastatin Have Additive Cardioprotective Effects via Adenosine.

BACKGROUND: Ticagrelor inhibits the equilibrative-nucleoside-transporter-1 and thereby, adenosine cell re-uptake. Ticagrelor limits infarct size (IS) in non-diabetic rats and the effect is adenosine-dependent. Statins, via ecto-5'-nucleotidase activation, also increase adenosine levels and limit IS. HYPOTHESIS: Ticagrelor and rosuvastatin have additive effects on myocardial adenosine levels, and therefore, on IS and post-reperfusion activation of the NLRP3-inflammasome. METHODS: Diabetic ZDF rats received via oral gavage; water (control), ticagrelor (150 mg/kg/d), prasugrel (7.5 mg/kg/d), rosuvastatin (5 mg/kg/d), ticagrelor + rosuvastatin and prasugrel + rosuvastatin for 3d. On day 4, rats underwent 30 min coronary artery occlusion and 24 h of reperfusion. Two additional groups received, ticagrelor + rosuvastatin or water in combination with CGS15943 (CGS, an adenosine receptor antagonist, 10 mg/kg i.p. 1 h before ischemia). RESULTS: Both ticagrelor and rosuvastatin increased myocardial adenosine levels with an additive effect of the combination whereas prasugrel had no effect. Similarly, both ticagrelor and rosuvastatin significantly reduced IS with an additive effect of the combination whereas prasugrel had no effect. The effect on IS was adenosine dependent as CGS15943 reversed the effect of ticagrelor + rosuvastatin. The ischemia-reperfusion injury increased myocardial mRNA levels of NLRP3, ASC, IL-1ß and IL-6. Ticagrelor and rosuvastatin, but not prasugrel, significantly decreased these pro-inflammatory mediators with a trend to an additive effect of the combination. The combination also increased the levels of anti-inflammatory 15-epilipoxin A4. CONCLUSIONS: Ticagrelor and rosuvastatin when given in combination have an additive effect on local myocardial adenosine levels in the setting of ischemia reperfusion. This translates into an additive cardioprotective effect mediated by adenosine-induced effects including downregulation of pro- but upregulation of anti-inflammatory mediators.

Statin-Induced Cardioprotection Against Ischemia-Reperfusion Injury: Potential Drug-Drug Interactions. Lesson to be Learnt by Translating Results from Animal Models to the Clinical Settings.

Numerous interventions have been shown to limit myocardial infarct size in animal models; however, most of these interventions have failed to have a significant effect in clinical trials. One potential explanation for the lack of efficacy in the clinical setting is that in bench models, a single intervention is studied without the background of other interventions or modalities. This is in contrast to the clinical setting in which new medications are added to the "standard of care" treatment that by now includes a growing number of medications. Drug-drug interaction may lead to alteration, dampening, augmenting or masking the effects of the intended intervention. We use the well described model of statin-induced myocardial protection to demonstrate potential interactions with agents which are commonly concomitantly used in patients with stable coronary artery disease and/or acute coronary syndromes. These interactions could potentially explain the reduced efficacy of statins in the clinical trials compared to the animal models. In particular, caffeine and aspirin could attenuate the infarct size limiting effects of statins; morphine could delay the onset of protection or mask the protective effect in patients with ST elevation myocardial infarction, whereas other anti-platelet agents (dipyridamole, cilostazol and ticagrelor) may augment (or mask) the effect due to their favorable effects on adenosine cell reuptake and intracellular cAMP levels. We recommend that after characterizing the effects of new modalities in single intervention bench research, studies should be repeated in the background of standard-of-care medications to assure that the magnitude of the effect is not altered before proceeding with clinical trials.

Heart Failure in Thyrotoxic Cardiomopathy: Extracorporeal Membrane Oxygenation Treatment for Graves' Disease.

Thyrotoxicosis-induced cardiomyopathy and consequent heart failure is one of the most grave complications of uncontrolled hyperthyroidism. In such patients, early recognition of thyrotoxicosis, and directed antithyroid therapy can lead to rapid normalization of left ventricular function. Herein, we present a case of a 29-year-old male with Graves' disease who developed heart failure with severe deterioration of left ventricular function and eventually, circulatory collapse. Height and weight of the patient were 1.8 m and 84 kg, respectively. The patient was placed on venoarterial extracorporeal membrane oxygenation for immediate circulatory support, with restoration of cardiac function after 6 days.

Twenty years of ECG grading of the severity of ischemia.

Shortly following an occlusion of an epicardial coronary artery, changes in the surface electrocardiogram (ECG) can be detected. Initially, T waves in leads with their positive poles facing the ischemic zone become positive, tall and symmetrical. Later, ST segment elevation (STE) becomes apparent. If ischemia continues, changes in the terminal portion of the QRS may also be detected. The changes in the terminal portion of the QRS are believed to be caused by prolongation of the electrical conduction in the ischemic zone and reflect severe ischemia due to lack of protection by preconditioning or collateral circulation. Several groups have shown that patients with the QRS changes of grade 3 ischemia have higher mortality, higher incidence of reinfarction and heart failure than patients presenting with only the T and ST changes of grade 2 ischemia, despite equal success in recanalizing the epicardial coronary artery by either thrombolytic therapy or primary percutaneous coronary intervention. Grade 3 ischemia is associated with more rapid progression of necrosis and larger final infarct size. Further studies are needed to better understand the underlying mechanisms that determine the severity of ischemia and how we should use this method based on the standard 12 lead ECG to implement clinical therapeutic decisions.

High-risk ECG patterns in ACS--need for guideline revision.

The current guidelines advocate distinct approaches (urgent reperfusion therapy) to patients with suspected acute coronary syndromes (ACS) presenting with ST elevation (STE) versus patients without STE on their electrocardiogram (ECG). This is based on the paradigm that STE represents ongoing transmural ischemia due to an acute occlusion of an epicardial coronary artery whereas the significance of other ECG findings is more contentious. The role of urgent coronary angiography in patients without STE is less clear and initial stabilization with conservative treatment is recommended. However, in some cases the distinction between STEMI and non-STE-ACS is difficult. Acute occlusion of a coronary artery may cause less than the current recommended threshold STE. On the other hand, many patients may have STE secondary to nonischemic etiology. In many patients with non-STE-ACS the coronary artery is not completely occluded at the time of presentation and there are rapid fluctuations in the severity of ischemia and hence, dynamic changes are observed in the ECG. Several ECG patterns associated with particular coronary anatomy and high-risk prognosis have been identified. Patients with ACS presenting with these high-risk patterns should probably be referred for coronary angiography with the possibility of urgent intervention with the goal of prevention of ischemic complications, rather than for immediate myocardial salvage, as in classic STEMI.

Robot-assisted stenting of a high-grade anastomotic pulmonary artery stenosis following single lung transplantation.

PURPOSE: To report robot-assisted stenting of a stenosis at the pulmonary artery anastomosis following lung transplantation, a rare complication that conveys poor prognosis even after surgical correction. TECHNIQUE: The technique is illustrated in a 72-year-old man with end-stage lung disease who received a left single lung transplant. On postoperative day 54, he was evaluated for recurrent dyspnea on exertion that was due to a severe stenosis at the site of the pulmonary artery anastomosis. Balloon angioplasty was performed, and a 10-mm stent was deployed, with marked clinical improvement. Fourteen months later, he presented with recurrent symptoms due to in-stent restenosis. Multiple attempts at catheterization and balloon angioplasty of the stent failed. Due to the technical difficulty involved in maneuvering the balloon while maintaining stability, it was decided to repeat the angioplasty with the assistance of a Hansen Sensei remote robotic navigation system. The robotic arm markedly enhanced stability and facilitated successful navigation of the stented site. A 16-mm-diameter Wallstent was placed through the previously placed balloon-expandable stent and postdilated. CONCLUSION: A remote robotic catheter navigation system was able to assist stenting of an anastomotic pulmonary artery stenosis following failure of conventional interventional techniques.

A Double Whammy: Severe Aortic Stenosis and Cocaine Overwhelm the Mitral Valve.

A 50-year-old man presented with acute onset dyspnea following cocaine use. He had severe aortic stenosis (AS), mild mitral regurgitation (MR) due to mitral valve prolapse, and no coronary artery disease on recent coronary angiography. He was in acute heart failure with signs of impending cardiogenic shock. Urgent bedside echocardiography revealed hyperdynamic left ventricular systolic function with acute severe MR from a ruptured chordae tendineae. The acute cocaine-induced spike of his already elevated left ventricular systolic pressure from severe AS likely precipitated chordal rupture of his vulnerable mitral valve. This patient underwent emergent mitral and aortic valve replacements. Although cocaine use has been associated with a myriad of cardiovascular complications, acute MR due to chordal rupture has not, to our knowledge, been previously reported in this setting. Prompt diagnosis with echocardiography and surgical intervention are of paramount importance in the management of acute MR.