Cardiology

Lewis, E. F., B. L. Claggett, J. J. V. McMurray, M. Packer, M. P. Lefkowitz, J. L. Rouleau, J. Liu, V. C. Shi, M. R. Zile, A. S. Desai, S. D. Solomon and K. Swedberg (2017). “Health-related quality of life outcomes in paradigm-hf.” Circ Heart Fail 10(8): 1-16.

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BACKGROUND: Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only. METHODS AND RESULTS: Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29; P=0.008) and KCCQ overall summary score (+1.13 versus -0.14; P<0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (>/=5 points decrease) of both KCCQ scores (27% versus 31%; P=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months. CONCLUSIONS: Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure.

Rosenthal, R. L. (2017). “Revisiting the historical origins of clinically meaningful coronary artery obstruction.” Mayo Clin Proc 92(8): 1312.

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As part of a recent informative editorial on the significance of nonobstructive coronary artery disease, Rumberger1 reviewed the historical origins of the 50% coronary stenosis standard for the definition of myocardial ischemia and the relationship of percentage stenosis to coronary flow reserve and fractional flow reserve. I believe some corrections are warranted.

Packer, M. (2017). “Who should deliver medical therapy for patients with chronic heart failure? An immediate call for action to implement a community-based collaborative solution.” Circ Heart Fail 10(8): 1-4.

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When we communicate with our colleagues in primary care medicine, why do we convey only a broad philosophical directive rather than a detailed list of specific actionable recommendations? The management of chronic heart failure is not simple. Optimal treatment requires the skillful orchestration of as many as 7 different classes of drugs, together with the appropriate application of different types of devices.2 Heart failure is generally more disabling and lethal than cancer,3 and its comprehensive management is frequently far more challenging. When chemotherapy is given to patients with cancer, its administration is tightly controlled by medical oncologists, who prescribe antineoplastic drugs aggressively and under close supervision, generally at doses and durations that closely resemble those used in randomized clinical trials. Serious adverse effects are expected, but patient compliance and provider enthusiasm is enhanced by societally reinforced fears about the need for aggressive therapy to prevent the silent spread of malignantcells. In contrast, although heart failure with a reduced ejection fraction also progresses silently and requires complex multidrug regimens over long periods of time, specialists are generally not involved, and intensive pharmacological strategies and doses are rarely achieved in clinical practice.4 Continued pursuit of optimal regimens often ceases at the first hint of patient intolerance or reluctance. As in the management of cancer, the treatment of patients with heart failure requires knowledge, experience, and perseverance, which necessitates a multidisciplinary team of healthcare providers that can deal effectively with each patient’s individual circumstances. Those who care for patients with cancer are richly rewarded for creating these conditions; those who care for patients with heart failure are not.5

Tecson, K. M., E. Erhardtsen, P. M. Eriksen, A. O. Gaber, M. Germain, L. Golestaneh, M. L. A. Lavoria, L. W. Moore and P. A. McCullough (2017). “Optimal cut points of plasma and urine neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury among critically ill adults: Retrospective determination and clinical validation of a prospective multicentre study.” BMJ Open 7(7): 1-9.

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OBJECTIVES: To determine the optimal threshold of blood and urine neutrophil gelatinase-associated lipocalin (NGAL) to predict moderate to severe acute kidney injury (AKI) and persistent moderate to severe AKI lasting at least 48 consecutive hours, as defined by an adjudication panel. METHODS: A multicentre prospective observational study enrolled intensive care unit (ICU) patients and recorded daily ethylenediaminetetraacetic acid (EDTA) plasma, heparin plasma and urine NGAL. We used natural log-transformed NGAL in a logistic regression model to predict stage 2/3 AKI (defined by Kidney Disease International Global Organization). We performed the same analysis using the NGAL value at the start of persistent stage 2/3 AKI. RESULTS: Of 245 subjects, 33 (13.5%) developed stage 2/3 AKI and 25 (10.2%) developed persistent stage 2/3 AKI. Predicting stage 2/3 AKI revealed the optimal NGAL cutoffs in EDTA plasma (142.0 ng/mL), heparin plasma (148.3 ng/mL) and urine (78.0 ng/mL) and yielded the following decision statistics: sensitivity (SN)=78.8%, specificity (SP)=73.0%, positive predictive value (PPV)=31.3%, negative predictive value (NPV)=95.7%, diagnostic accuracy (DA)=73.8% (EDTA plasma); SN=72.7%, SP=73.8%, PPV=30.4%, NPV=94.5%, DA=73.7% (heparin plasma); SN=69.7%, SP=76.8%, PPV=32.9%, NPV=94%, DA=75.8% (urine). The optimal NGAL cutoffs to predict persistent stage 2/3 AKI were similar: 148.3 ng/mL (EDTA plasma), 169.6 ng/mL (heparin plasma) and 79.0 ng/mL (urine) yielding: SN=84.0%, SP=73.5%, PPV=26.6%, NPV=97.6, DA=74.6% (EDTA plasma), SN=84%, SP=76.1%, PPV=26.8%, NPV=96.5%, DA=76.1% (heparin plasma) and SN=75%, SP=75.8%, PPV=26.1, NPV=96.4%, DA=75.7% (urine). CONCLUSION: Blood and urine NGAL predicted stage 2/3 AKI, as well as persistent 2/3 AKI in the ICU with acceptable decision statistics using a single cut point in each type of specimen.

Bastarrachea, R. A., J. Chen, J. W. Kent, Jr., E. J. Nava-Gonzalez, E. Rodriguez-Ayala, M. M. Daadi, B. Jorge, H. Laviada-Molina, A. G. Comuzzie, S. Chen and P. A. Grayburn (2017). “Engineering brown fat into skeletal muscle using ultrasound-targeted microbubble destruction gene delivery in obese zucker rats: Proof of concept design.” IUBMB Life: 2017 Jul [Epub ahead of print].

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Ultrasound-targeted microbubble destruction (UTMD) is a novel means of tissue-specific gene delivery. This approach systemically infuses transgenes precoupled to gas-filled lipid microbubbles that are burst within the microvasculature of target tissues via an ultrasound signal resulting in release of DNA and transfection of neighboring cells within the tissue. Previous work has shown that adenovirus containing cDNA of UCP-1, injected into the epididymal fat pads in mice, induced localized fat depletion, improving glucose tolerance, and decreasing food intake in obese diabetic mice. Our group recently demonstrated that gene therapy by UTMD achieved beta cell regeneration in streptozotocin (STZ)-treated mice and baboons. We hypothesized that gene therapy with BMP7/PRDM16/PPARGC1A in skeletal muscle (SKM) of obese Zucker diabetic fatty (fa/fa) rats using UTMD technology would produce a brown adipose tissue (BAT) phenotype with UCP-1 overexpression. This study was designed as a proof of concept (POC) project. Obese Zucker rats were administered plasmid cDNA contructs encoding a gene cocktail with BMP7/PRDM16/PPARGC1A incorporated within microbubbles and intravenously delivered into their left thigh. Controls received UTMD with plasmids driving a DsRed reporter gene. An ultrasound transducer was directed to the thigh to disrupt the microbubbles within the microcirculation. Blood samples were drawn at baseline, and after treatment to measure glucose, insulin, and free fatty acids levels. SKM was harvested for immunohistochemistry (IHC). Our IHC results showed a reliable pattern of effective UTMD-based gene delivery in enhancing SKM overexpression of the UCP-1 gene. This clearly indicates that our plasmid DNA construct encoding the gene combination of PRDM16, PPARGC1A, and BMP7 reprogrammed adult SKM tissue into brown adipose cells in vivo. Our pilot established POC showing that the administration of the gene cocktail to SKM in this rat model of genetic obesity using UTMD gene therapy, engineered a BAT phenotype with UCP-1 over-expression.