Baylor Heart and Vascular Institute

Packer, M. (2016). “Cobalt cardiomyopathy: A critical reappraisal in light of a recent resurgence.” Circ Heart Fail 9(12).

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Cobalt can cause a distinctive, rapidly progressive and reversible depression of cardiac systolic function, which is readily distinguished from other causes of cardiomyopathy. Patients present with the subacute onset of severe heart failure, which is accompanied by hypotension and cyanosis, pericardial effusion, low voltage on the electrocardiogram, marked elevation of serum enzymes, and lactic acidosis. They typically have a history of lethargy, anorexia, and weight loss in the months preceding the illness and exhibit other evidence of cobalt’s effects on the body (eg, polycythemia and goiter). The course of cobalt-related cardiomyopathy may be progressive and fatal, but those who survive and cease exposure generally demonstrate complete resolution of symptoms and recovery of cardiac function. Patients presenting with rapid onset of cardiomyopathy, who also exhibit polycythemia, pericardial effusion, or goiter should be evaluated for cobalt exposure. Exposure can be confirmed by the measurement of cobalt in the serum, but serum levels of the ion are not reliably predictive of clinical cardiotoxicity. The clinical emergence of cobalt cardiomyopathy seems to require the coexistence of one or more cofactors, particularly a low-protein diet, thiamine deficiency, alcoholism, and hypothyroidism. As the medicinal use of cobalt has waned and measures to reduce industrial exposure have been implemented, subacute cobalt-related cardiomyopathy had become rare. However, reports describing classical features of the disease have recently surged among patients with a malfunctioning cobalt-alloy hip prosthesis.

Desai, A. S., O. Vardeny, B. Claggett, J. J. McMurray, M. Packer, K. Swedberg, J. L. Rouleau, M. R. Zile, M. Lefkowitz, V. Shi and S. D. Solomon (2016). “Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: A secondary analysis of the paradigm-hf trial.” JAMA Cardiol: 2016 Nov [Epub ahead of print].

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Importance: Consensus guidelines recommend the use of mineralocorticoid receptor antagonists (MRAs) for selected patients with symptomatic heart failure and reduced ejection fraction (HFrEF) to reduce morbidity and mortality; however, the use of MRAs in combination with other inhibitors of the renin-angiotensin-aldosterone system increases the risk of hyperkalemia. Objective: To determine whether the risk of hyperkalemia associated with use of MRAs for patients with HFrEF is reduced by sacubitril/valsartan in comparison with enalapril. Design, Setting, and Participants: The PARADIGM-HF (Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial randomly assigned 8399 patients with chronic HF, New York Heart Association class II to IV symptoms, and a left ventricular EF of 40% or less to treatment with enalapril 10 mg twice daily or sacubitril/valsartan 97/103 mg twice daily (previously known as LCZ696 [200 mg twice daily]) in addition to guideline-directed medical therapy. Use of MRAs was encouraged but left to the discretion of study investigators. Serum potassium level was measured at every study visit. The incidence of hyperkalemia (potassium level >5.5 mEq/L) and severe hyperkalemia (potassium level >6.0 mEq/L) among patients treated or not treated with an MRA at baseline and the risk of subsequent hyperkalemia for those newly treated with an MRA during study follow-up were defined in time-updated Cox proportional hazards models. Analyses were conducted between August 1 and October 15, 2016. Main Outcomes and Measures: Incident hyperkalemia and severe hyperkalemia. Results: In comparison with the 3728 patients (44.4% of enrolled participants [21.6% female]) not taking an MRA at baseline, the 4671 patients (55.6% [22.0% female]) taking an MRA tended to be younger, with a lower EF, lower systolic blood pressure, and more advanced HF symptoms. Among those taking an MRA at baseline, the overall rates of hyperkalemia were similar between treatment groups, but severe hyperkalemia was more common in patients randomly assigned to enalapril than to sacubitril/valsartan (3.1 vs 2.2 per 100 patient-years; HR, 1.37 [95% CI, 1.06-1.76]; P = .02). In analyses including patients who newly started taking MRAs during the PARADIGM-HF trial, severe hyperkalemia remained more common in those randomly assigned to enalapril than to those randomly assigned to sacubitril/valsartan (3.3 vs 2.3 per 100 patient-years; HR, 1.43 [95% CI, 1.13-1.81]; P = .003). Conclusions and Relevance: Among MRA-treated patients with symptomatic HFrEF, severe hyperkalemia is more likely during treatment with enalapril than with sacubitril/valsartan. These data suggest that neprilysin inhibition attenuates the risk of hyperkalemia when MRAs are combined with other inhibitors of the renin-angiotensin-aldosterone system in patients with HF.

Zhang, J., M. K. Fallahzadeh and P. A. McCullough (2016). “Aging male spontaneously hypertensive rat as an animal model for the evaluation of the interplay between contrast-induced acute kidney injury and cardiorenal syndrome in humans.” Cardiorenal Med 7(1): 1-10.

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BACKGROUND: Although there are some animal models for biomarkers of contrast-induced acute kidney injury (CI-AKI), for cardiorenal syndrome (CRS) and for acute renal failure, the interplay between CI-AKI and CRS has yet to be evaluated. Insight into the pathogenesis of CRS is urgently needed from animal models in order to foster the discovery and implementation of novel biomarkers for this disease. Specially designed animal models for type 1 and 3 CRS, particularly CI-AKI, have not yet emerged. SUMMARY: We hypothesize that the aging male spontaneously hypertensive rat (SHR) is likely to be a suitable model. The SHR model is able to mimic risk factors for preclinical CRS that appears in the clinical setting, specifically hypertension, age, preexisting damage and dysfunction of the heart and kidney, endothelial dysfunction, increased level of reactive oxygen species, decreased level and bioavailability of nitric oxide (NO), impairment of the L-arginine-NO pathway, and insulin resistance. In the SHR, CI-AKI results in a different profile of AKI biomarkers than is seen with preexisting chronic kidney injury. KEY MESSAGES: The SHR model can be used to evaluate the interaction between CI-AKI and CRS type 1 and 3 and to verify neutrophil gelatinase-associated lipocalin (NGAL) as a reliable CI-AKI biomarker for clinical application. Further research is warranted with a large number of aging male SHRs to prove NGAL as a sensitive, specific, highly predictive, early biomarker for CI-AKI.

Packer, M. (2016). “Angiotensin neprilysin inhibition for patients with heart failure: What if sacubitril/valsartan were a treatment for cancer?” JAMA Cardiol.

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Oncologists would adopt the new drug as the standard of care in a heartbeat, but US physicians who treat patients with heart failure often do little. Heart failure is a fatal disorder, and current drugs achieve only a brief clinical remission. Twoyears ago, sacubitril/valsartanwas shown to be superior to a conventional inhibitor of the renin-angiotensin system in reducing the risk of cardiovascular death,1 and it received expedited US Food and Drug Administration approval for treatment of chronic heart failure. Owing to cost, third-party payors discouraged the use of the drug by requiring high patient copays and administrative preapprovals. Oncologists are accustomed to overcoming these distractions, but other physicians are not. Consequently, uptake of sacubitril/ valsartan by US practitioners has been slow.

Packer, M. (2016). “Data sharing: Lessons from copernicus and kepler.” Bmj 354: i4911.

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To understand the workings of science, pick up a copy of De Revolutionibus Orbium Coelestium. Published with great reluctance by the astronomer Nicolaus Copernicus in 1543, the book puts forth a compelling argument for a heliocentric universe. Turn the pages and you will see the book is filled with data. Whose data? Copernicus relied on the data collected by others in addition to his own to formulate his revolutionary theory. Publication of these data subsequently allowed Johannes Kepler to identify discrepancies, which led to his innovative proposal in 1605 that the planets moved in an ellipse (rather than in a circle), an idea that he had previously assumed to be too simple for earlier astronomers to have overlooked. Of course, Kepler presented his data at the same time that he published his conclusions. In contrast, Tycho Brahe (who opposed Copernicus) famously withheld his astronomical data from Kepler because he knew they could be used to confirm Copernicus’s heliocentric model.