Cardiology

Vasudevan, A., K. M. Tecson, J. Bennett-Firmin, T. Bottiglieri, L. R. Lopez, M. Peterson, M. Sathyamoorthy, R. Schiffmann, J. M. Schussler, C. Swift, C. E. Velasco and P. A. McCullough (2017). “Prognostic value of urinary 11-dehydro-thromboxane b2 for mortality: A cohort study of stable coronary artery disease patients treated with aspirin.” Catheter Cardiovasc Interv: 2017 Nov [Epub ahead of print].

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AIM: There is a variable cardiovascular risk reduction attributable to aspirin because of individual differences in the suppression of thromboxane A2 and its downstream metabolite 11-dehydro-thromboxane B2 (11dhTxB2 ). The aim of this study is to evaluate the optimal cut point of urinary 11dhTxB2 for the risk of mortality in aspirin-treated coronary artery disease (CAD) patients. METHODS AND RESULTS: This was a prospective cohort study including stable CAD patients who visited the Baylor Heart and Vascular Hospital in Dallas or the Texas Heart Hospital Baylor Plano, TX between 2010 and 2013. The outcome of all-cause mortality was ascertained from chart review and automated sources. The 449 patients included in this analysis had a mean age of 66.1 +/- 10.1 years. 67 (14.9%) patients died within 5 years; 56 (87.5%) of the 64 patients with known cause of death suffered a cardiovascular related mortality. Baseline ln(urinary 11dhTxB2 /creatinine) ranged between 5.8 and 11.1 (median = 7.2) with the higher concentrations among those who died (median: 7.6) than those who survived (median = 7.2, P < 0.001). Using baseline ln(11dhTxB2 ) to predict all-cause mortality, the area under the curve was 0.70 (95% CI: 0.64-0.76). The optimal cut point was found to be ln(7.38) = 1597.8 pg/mg, which had the following decision statistics: sensitivity = 0.67, specificity = 0.62, positive predictive value = 0.24, negative predictive value = 0.92, and accuracy = 0.63. CONCLUSION: Our data indicate the optimal cut point for urine 11dhTxB2 is 1597.8 (pg/mg) for the risk prediction of mortality over five years in stable patients with CAD patients treated with aspirin.

McCullough, P. A., G. David, T. M. Todoran, E. S. Brilakis, M. P. Ryan and C. Gunnarsson (2017). “Iso-osmolar contrast media and adverse renal and cardiac events after percutaneous cardiovascular intervention.” J Comp Eff Res: 2017 Nov [Epub ahead of print].

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AIM: To assess the relationship between type of contrast media (CM), iso-osmolar contrast media (IOCM) or low-osmolar contrast media (LOCM), and major adverse renal and cardiovascular events (MARCE). MATERIALS & METHODS: Coronary or peripheral angioplasty visits were stratified into CM cohorts: IOCM or LOCM. Multivariable regression analysis used hospital fixed effects to assess the relationship between MARCE events and type of CM. RESULTS: Among 333,533 visits (357 hospitals), the incidence of MARCE was 7.41%. After controlling for observable and unobservable time invariant within-hospital characteristics, administration of IOCM versus LOCM was associated with a 0.69% absolute and 9.32% relative risk reduction in MARCE rate. CONCLUSION: Our study indicates that as compared with LOCM, IOCM may be associated with reduction of MARCE events in coronary or peripheral angioplasty patients.

Mogensen, U. M., L. Kober, P. S. Jhund, A. S. Desai, M. Senni, S. L. Kristensen, A. Dukat, C. H. Chen, F. Ramires, M. P. Lefkowitz, M. F. Prescott, V. C. Shi, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. Packer and J. J. V. McMurray (2017). “Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in paradigm-hf.” Eur J Heart Fail: 2017 Nov [Epub ahead of print].

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AIMS: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF. METHODS AND RESULTS: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1-Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA >/=8.6 mg/dL) compared with Q1 (<5.4 mg/dL) were younger (62.8 vs. 64.2 years), more often male (88.7% vs. 63.1%), had lower systolic blood pressure (119 vs. 123 mmHg), lower eGFR (57.4 vs. 76.6 mL/min/1.73 m(2) ), and greater diuretic use. Higher SUA was associated with a higher risk of the primary outcome (adjusted hazard ratios) Q5 vs. Q1 = 1.28 [95% confidence intervals (1.09-1.50), P = 0.003], cardiovascular death [1.44 (1.11-1.77), P = 0.001], HF hospitalization [1.37 (1.11-1.70), P = 0.004], and all-cause mortality [1.36 (1.13-1.64), P = 0.001]. Compared with enalapril, sacubitril/valsartan reduced SUA by 0.24 (0.17-0.32) mg/dL over 12 months (P < 0.0001). Sacubitril/valsartan improved outcomes, irrespective of SUA concentration. CONCLUSION: Serum uric acid concentration was an independent predictor of worse outcomes after multivariable adjustment in patients with HFrEF. Compared with enalapril, sacubitril/valsartan reduced SUA and improved outcomes irrespective of SUA.

Moon, S. H., X. Liu, A. M. Cedars, K. Yang, M. A. Kiebish, S. M. Joseph, J. Kelley, C. M. Jenkins and R. W. Gross (2017). “Heart failure-induced activation of phospholipase ipla2gamma generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore.” J Biol Chem: 2017 Nov [Epub ahead of print].

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Congestive heart failure typically arises from cardiac myocyte necrosis/apoptosis, associated with the pathological opening of the mitochondrial permeability transition pore (mPTP). mPTP opening decreases the mitochondrial membrane potential leading to the activation of Ca(2+)-independent phospholipase A2gamma (iPLA2gamma) and the production of downstream toxic metabolites. However, the array of enzymatic mediators and the exact chemical mechanisms responsible for modulating myocardial mPTP opening remain unclear. Herein, we demonstrate that human heart failure activates specific myocardial mitochondrial phospholipases that increase Ca(2+)-dependent production of toxic hydroxyeicosatetraenoic acids (HETEs) and attenuate the activity of phospholipases that promote the synthesis of protective epoxyeicosatrienoic acids (EETs). Mechanistically, HETEs activated the Ca(2+)-induced opening of the mPTP in failing human myocardium, and highly selective pharmacological blockade of either iPLA2gamma or lipoxygenases attenuated mPTP opening in failing hearts. In contrast, pharmacological inhibition of cytochrome P450 epoxygenases opened the myocardial mPTP in human heart mitochondria. Remarkably, the major mitochondrial phospholipase responsible for Ca(2+)-activated release of arachidonic acid (AA) in mitochondria from non-failing hearts was calcium-dependent phospholipase A2zeta (cPLA2zeta) identified by sequential column chromatographies and activity-based protein profiling. In contrast, iPLA2gamma predominated in failing human myocardium. Stable isotope kinetics revealed that in non-failing human hearts, cPLA2zeta metabolically channels arachidonic acid into EETs, whereas, in failing hearts, increased iPLA2gamma activity channels AA into toxic HETEs. These results mechanistically identify the sequelae of pathological remodeling of human mitochondrial phospholipases in failing myocardium. This remodeling metabolically channels AA into toxic HETEs promoting mPTP opening, which induces necrosis/apoptosis leading to further progression of heart failure.

O’Gara, P. T., T. M. Sundt, M. A. Acker, T. E. David, R. E. Michler, M. A. Borger, G. Ailawadi, V. H. Thourani, A. M. Gillinov, R. J. Damiano, M. J. Mack, R. Lee, E. A. Rose, T. J. Gardner, M. A. Miller, R. D. Weisel and A. C. Gelijns (2017). “The cardiothoracic surgical trials network: Implications for clinical practice.” J Thorac Cardiovasc Surg 154(6): 1938-1956.

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Background: Postoperative recurrence (POR) of Crohn’s disease (CD) is common. Guidelines on POR management have recently been issued, but clinical practice may vary. Aims:To examine the current clinical practice of POR management in the USA Methods: A web-based survey was sent to all members of the American Gastroenterological Association and the American College of Gastroenterology. The survey consisted of multiple-choice questions with clinical scenarios to assess how participants manage POR. Results: A total of 189 responses were received from practices in 34 states. 44% of participants were from academic settings. The median number of CD patients seen each month was 20–30 patients per participant. The majority of participants considered smoking, prior intestinal surgery, penetrating disease, perianal fistula, early disease onset, and long extent of disease as high-risk factors for POR. To diagnose and grade endoscopic recurrence, 57% of participants used an endoscopic scoring system; 86% defined clinical recurrence using a combination of symptoms and endoscopic findings; and 79% of participants routinely performed colonoscopy after surgery. In high-risk patients, 65% offered medical prophylaxis—most often biologics and/or immunomodulators—immediately after surgery, while 34% offered medical prophylaxis regardless of the patient’s risk of POR. 64% of participants never stopped medical prophylaxis once initiated. Conclusions: Most gastroenterologists routinely perform colonoscopy to guide POR management. The majority of these providers continue medical prophylaxis indefinitely regardless of subsequent endoscopic findings. Further research is needed to determine the risks and benefits of continuing versus deescalating therapy in patients with potentially surgically induced remission.