A Modern History RAAS Inhibition and Beta Blockade for Heart Failure to Underscore the Non-equivalency of ACEIs and ARBs.

Beta blockers and renin-angiotensin-aldosterone-inhibitors (RAAS-i) including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been a mainstay of guideline-based medical therapy for heart failure with reduced ejection fraction (HFrEF) for decades. However, initial evidence supporting each of the aforenoted class of drug for heart failure indications was largely found independently of the other two classes with the exception of the addition of BBs to ACEIs. In the initial ACEI trials for HFrEF, few participants were on BBs as BBs were seen as contraindicated in HFrEF at the time. The seminal BB in HFrEF trials had high prevalence of ACEIs use as ACEIs for HF were standard of care by then, but ARBs as a class were still in their infancy. We closely examine the evidence for combinations of BB and ACEIs versus ARBs in HFrEF. In doing so, we demonstrate the lack of evidence for consideration of ARBs to be interchangeable with ACEIs when used in combination with BB and provide evidence that calls in to question the validity of assuming benefits from each drug class are independently cumulative, widening the gap between ACEIs and ARBs when used with BBs. Modern guidelines should emphasize this lack of evidence for the combination use of ARB and BB in HFrEF, except for candesartan. Even as practice moves towards the widespread uptake of angiotensin receptor-neprilysin inhibitors (which contain the ARB valsartan) in heart failure, the distinction has important implications for the ongoing role of combination therapy with BB, which thus far has been assumed, but not proven.

Various Manifestations of 5-Fluorouracil Cardiotoxicity: A Multicenter Case Series and Review of Literature.

5-Fluorouracil is a key element to the treatment of colon cancer. But it is also one of the most cardiotoxic chemotherapies, and the management of those that experience cardiotoxicity can be challenging. We present three cases of 5-FU cardiac toxicity that manifested as myocardial infarction, cardiogenic shock, and ventricular fibrillation. Additionally, we discuss the current literature regarding 5-fluorouracil cardiotoxicity mechanisms as well as management.

Multivessel Traumatic Coronary Artery Dissection After a Motor Vehicle Accident With Successful Percutaneous Coronary Intervention.

Coronary artery dissection is a rare complication of blunt chest wall trauma. We report a case of acute left anterior descending and right coronary artery dissections after a motor vehicle accident. The musculoskeletal injuries obscured the cardiac symptoms. Electrocardiogram and bedside echocardiogram revealed cardiac pathology, which prompted urgent coronary angiography and intervention. (Level of Difficulty: Advanced.).

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.

Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction.

OBJECTIVE: In addition to P2Y12 receptor antagonism, ticagrelor inhibits adenosine cell uptake. Prior data show that 7-day pretreatment with ticagrelor limits infarct size. We explored the acute effects of ticagrelor and clopidogrel on infarct size and potential long-term effects on heart function. APPROACH AND RESULTS: Rats underwent 30-minute ischemia per 24-hour reperfusion. (1) Ticagrelor (10 or 30 mg/kg) or clopidogrel (12.5 mg/kg) was given via intraperitoneal injection 5 minutes before reperfusion. (2) Rats received ticagrelor acute (intraperitoneal; 30 mg/kg), chronic (oral; 300 mg/kg per day) for 4 weeks starting 1 day after reperfusion or the combination (acute+chronic). Another group received clopidogrel (intraperitoneal [12.5 mg/kg]+oral [62.5 mg/kg per day]) for 4 weeks. (1) Ticagrelor dose-dependently reduced infarct size, 10 mg/kg (31.5%±1.8%; P<0.001) and 30 mg/kg (21.4%±2.6%; P<0.001) versus control (45.3±1.7%), whereas clopidogrel had no effect (42.4%±2.6%). Ticagrelor, but not clopidogrel, increased myocardial adenosine levels, increased phosphorylation of Akt, endothelial NO synthase, and extracellular-signal-regulated kinase 1/2 4 hours after reperfusion and decreased apoptosis. (2) After 4 weeks, left ventricular ejection fraction was reduced in the vehicle-treated group (44.8%±3.5%) versus sham (77.6%±0.9%). All ticagrelor treatments improved left ventricular ejection fraction, acute (69.5%±1.6%), chronic (69.2%±1.0%), and acute+chronic (76.3%±1.2%), whereas clopidogrel had no effect (37.4%±3.7%). Ticagrelor, but not clopidogrel, attenuated fibrosis and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor, but not clopidogrel, attenuated the increase in proinflammatory tumor necrosis factor-α, interleukin-1ß, and interleukin-18, and increased anti-inflammatory 15-epi-lipoxin-A4 levels. CONCLUSIONS: Ticagrelor, but not clopidogrel, administered just before reperfusion protects against reperfusion injury. This acute treatment or chronic ticagrelor for 4 weeks or their combination improved heart function, whereas clopidogrel, despite achieving a similar degree of platelet inhibition, had no effect.

Neurologic deterioration in a child undergoing treatment for tuberculosis meningitis.

Clinical deterioration while receiving antituberculosis (anti-TB) therapy can be due to a number of etiologies, including drug resistance, disease progression despite effective therapy, or alternative diagnoses. We present the case of a 22-month-old girl diagnosed with TB meningitis 4 months prior to presentation. At time of her initial diagnosis, computed tomography showed hydrocephalus and basilar meningitis with some evidence of ischemic damage. She required placement of a ventriculoperitoneal shunt and was discharged on multidrug anti-TB therapy and corticosteroids. At the time of her second emergency department presentation, she had developed new-onset seizures and hemiparesis. Her steroids had been tapered and discontinued. Differential diagnosis included shunt malfunction and/or shunt infection. Magnetic resonance imaging of the brain showed interval development of tuberculomas. Symptomatic and radiographic improvement was seen after initiation of corticosteroids for immune reconstitution inflammatory syndrome, which can be seen in immunocompetent children, with onset weeks to months after starting antituberculous therapy.

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.

Adolescents with tuberculosis: a review of 145 cases.

BACKGROUND: Adolescents comprise one-third of pediatric tuberculosis (TB) cases in the United States, but there are few specific data on the epidemiology and clinical course in this population. METHODS: This was a retrospective review of adolescents (12-18 years old) seen at a Children's Tuberculosis Clinic in Houston, TX, from 1987 to 2012. RESULTS: One hundred forty-five adolescents were identified; median age was 15.4 years: 50% female, 55% were Hispanic, 26% black, 13% Asian and 1% white; 54 were born abroad. Diagnoses were made after symptomatic presentation in 79%, during contact investigations in 14% and after screening tuberculin skin testing in the remainder. The most common symptoms were fever (63%), cough (60%) and weight loss (30%), but 21% were asymptomatic at diagnosis. Only 8% of adolescents with intrathoracic TB had hemoptysis. One hundred fourteen (78.6%) had isolated intrathoracic TB, 4 (2.8%) had intra- and extrathoracic TB and 27 (18.6%) had extrathoracic TB. The most common sites of extrathoracic TB were peripheral lymphadenopathy (10) and meningitis (6). The most common radiographic findings were infiltrates (34%), lymphadenopathy (27%), cavitary lesions (26%), pleural effusions (19%) and miliary disease (10%). Acid-fast bacillus smears and mycobacterial cultures were attempted for 97 of 118 adolescents with intrathoracic and 22 of 27 with extrathoracic disease, respectively, resulting in smear/culture positivity in 25% and 54% and 18% and 45%, respectively. Two patients died, 2 had relapse, 7 had significant sequelae and 92% recovered without complication. Seventy three percent of cases potentially were preventable. CONCLUSIONS: The clinical, radiologic and microbiologic findings in adolescents with TB have features seen in both younger children and adults; most cases were preventable.