Research Spotlight

Packer, M. (2018). “Do Most Obese People with Exercise Intolerance and a Normal Ejection Fraction Have Treatable Heart Failure?” Am J Med. Feb 22. [Epub ahead of print].

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Heart failure is a syndrome of exercise intolerance that results from an abnormal elevation in left ventricular filling pressure. However, the diagnosis can be difficult to make in clinical practice, particularly in obesity. Despite reduced exercise capacity, obese people may not report exertional dyspnea to their physicians, possibly because they have a preconception that their body mass should limit effort tolerance or because they elect to restrict their activities to minimize the possibility of experiencing unpleasant symptoms. Therefore, unless a motivated practitioner asks about and confirms the presence of exercise impairment, such individuals may not undergo an echocardiographic evaluation. If performed, in many obese people, this test would demonstrate an abnormality in early diastolic mitral annular velocity, which is indicative of increased left ventricular filling pressures, and often, the additional finding of mild left atrial enlargement. However, if the left ventricular ejection fraction is normal, these abnormalities are likely to be ignored or regarded as evidence of “diastolic dysfunction” that is attributed to associated hypertension. Moreover, many physicians find it difficult to examine a morbidly obese patient for the presence of distended jugular venous pressures or fluid retention. Given the pandemic of obesity in the United States, it is appropriate to ask: Are physicians systematically ignoring the diagnosis of heart failure in obese people? Can the limitations imposed by this disorder be effectively treated? (Excerpt from text, p.2, advance text; no abstract available.)

Packer, M. (2018). “Derangements in adrenergic-adipokine signalling establish a neurohormonal basis for obesity-related heart failure with a preserved ejection fraction.” Eur J Heart Fail. Mar 1. [Epub ahead of print].

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Among patients with heart failure and a preserved ejection (HFpEF), obesity is associated with a distinct phenotype that is characterized by adiposity-driven plasma volume expansion and cardiac overfilling, which is coupled with an impairment of ventricular distensibility. These pathophysiological abnormalities may be related to the increased actions of specific adipocyte-derived signalling molecules (aldosterone, neprilysin and leptin) that work in concert with increased renal sympathetic nerve traffic and activated beta2 -adrenergic receptors to promote sodium retention, microvascular rarefaction, cardiac fibrosis and systemic inflammation. This interplay leads to striking activation of the mineralocorticoid receptor, possibly explaining why obese patients with heart failure are most likely to benefit from spironolactone and eplerenone in large-scale clinical trials. Additionally, adipocytes express and release neprilysin, which (by degrading endogenous natriuretic peptides) can further promote plasma volume expansion and cardiac fibrosis. Heightened neprilysin activity may explain the low circulating levels of natriuretic peptides in obesity, the accelerated breakdown of natriuretic peptides in HFpEF, and the cardiac decompression following neprilysin inhibition in HFpEF patients who are obese. Furthermore, as adipose tissue accumulates and becomes dysfunctional, its secretion of leptin promotes renal sodium retention, microvascular changes and fibrotic processes in the heart, and systemic inflammation; these effects may be mediated or potentiated by the activation of beta2 -adrenergic receptors. These adrenergic-adipokine interactions provide a mechanistic framework for novel therapeutic strategies to alleviate the pathophysiological abnormalities of obesity-related HFpEF. Ongoing trials are well-positioned to test this hypothesis.

Packer, M. (2018). “Data sharing in medical research.” Bmj 360: k510.

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The imperative for data sharing is now widely understood by the research community. After years of debate, there is a growing consensus that data sharing is an inseparable part of the research process. My publicly stated position is that an investigator who performs studies in people has implicitly agreed to a social contract, which includes the responsibility to make the raw data available for examination.3 It has always been delusional for researchers to imagine that the public would believe their findings and accept their conclusions without access to supporting data. If clinicians are expected to change their practice based on their reading of medical journals, they need to know that the evidence in published papers can be verified . . . Trust is the crux of the matter. Some researchers who did not provide datasets may have been sceptical of Naudet and colleagues’ motives; meanwhile, Naudet and colleagues may have harboured subconscious doubts about the researchers’ claim that their raw data would support their findings. Interestingly, in the majority of their audits (82%, 95% confidence interval 59% to 94%), the authors verified the primary conclusions of the researchers’ work. Is that reassuring? They only looked at the primary endpoint data; they did not validate secondary analyses, and they could not verify the findings from datasets that were withheld. Undoubtedly, this paper will be perceived by some as encouraging and by others as distressing. When mutual distrust is so pervasive, progress on data sharing will be slow and painful. How do we build trust? Everyone who submits research for the public good should naturally expect that they will be asked to make their data available for examination and reanalysis. This is not a new idea. Citizens who pay taxes assume that some federal agency is poised to check their calculations. In the United States, every pharmaceutical company that submits an application to the Food and Drug Administration for a new chemical entity does so with the full understanding and expectation that their raw data will be audited and that their analyses will be verified. Why should individual researchers be an exception? Perhaps, industry can put pressure on their sponsored investigators to let go. (Excerpt from text, p. 1; no abstract available.)

Ostermann, M., P. A. McCullough, L. G. Forni, S. M. Bagshaw, M. Joannidis, J. Shi, K. Kashani, P. M. Honore, L. S. Chawla and J. A. Kellum (2018). “Kinetics of Urinary Cell Cycle Arrest Markers for Acute Kidney Injury Following Exposure to Potential Renal Insults.” Crit Care Med 46(3): 375-383.

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OBJECTIVES: Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 predict the development of acute kidney injury following renal insults of varied aetiology. To aid clinical interpretation, we describe the kinetics of biomarker elevations around an exposure. DESIGN: In an ancillary analysis of the multicenter SAPPHIRE study, we examined the kinetics of the urinary [tissue inhibitor of metalloproteinase-2]*[insulin-like growth factor binding protein 7] in association with exposure to common renal insults (major surgery, IV radiocontrast, vancomycin, nonsteroidal anti-inflammatory drugs, and piperacillin/tazobactam). SETTING: Thirty-five sites in North America and Europe between September 2010 and June 2012. PATIENTS: Seven hundred twenty-three critically ill adult patients admitted to the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the urinary [tissue metalloproteinase-2]*[insulin growth factor binding protein 7] kinetics from the day prior to exposure up to 5 days after exposure in patients developing acute kidney injury stage 2-3, stage 1, or no acute kidney injury by Kidney Disease Improving Global Outcome criteria. Among the 723 patients, 679 (94%) had at least one, 70% had more than one, and 35% had three or more exposures to a known renal insult. There was a significant association between cumulative number of exposures up to study day 3 and risk of acute kidney injury (p = 0.02) but no association between the specific type of exposure and acute kidney injury (p = 0.22). With the exception of radiocontrast, patients who developed acute kidney injury stage 2-3 after one of the five exposures, had a clear rise and fall of urinary [tissue inhibitor of metalloproteinase-2]*[insulin-like growth factor binding protein 7] from the day of exposure to 24-48 hours later. In patients without acute kidney injury, there was no significant elevation in urinary [tissue inhibitor of metalloproteinase-2]*[insulin-like growth factor binding protein 7]. CONCLUSIONS: Exposure to potential renal insults is common. In patients developing acute kidney injury stage 2-3, the kinetics of urinary [tissue inhibitor of metalloproteinase-2]*[insulin-like growth factor binding protein 7] matched the exposure except in the case of radiocontrast.

Odiase, E., A. Schwartz, R. F. Souza, S. J. Spechler, J. Martin and V. Konda (2018). “New Eosinophilic Esophagitis Concepts Call for Change in Proton Pump Inhibitor Management Before Diagnostic Endoscopy.” Gastroenterology. Mar 3. [Epub ahead of print].

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Irrespective of the stimulus, acid secretion by the gastric parietal cells ultimately involves H+, K+-ATPase, the enzyme that pumps hydrogen ions (protons) out of the cell and into the gastric lumen in exchange for potassium ions. Proton pump inhibitors (PPIs) bind irreversibly to H+, K+-ATPase, thereby disabling the enzyme and profoundly decreasing gastric acid secretion. It is well-established and widely appreciated that PPIs are remarkably effective agents for treating diseases mediated by gastric acid such as gastroesophageal reflux disease (GERD) and peptic ulcer disease. Far less well-known are the numerous potential anti-inflammatory effects that have been described for PPIs, including their inhibitory influence on inflammatory cells and on proinflammatory cytokine production by endothelial and epithelial cells.These anti-inflammatory PPI effects, which are independent of their effects on gastric acid secretion, might enable PPIs to heal inflammatory disorders of the upper gastrointestinal tract other than GERD and peptic ulceration. Nevertheless, physicians generally have regarded a symptomatic response to PPI therapy as de facto evidence of acid peptic disease. Physicians often prescribe PPIs empirically for patients who have symptoms that might be acid related (eg, heartburn, dyspepsia), withholding diagnostic endoscopy for those whose symptoms persist despite PPI therapy. For patients who experience partial symptom relief, the PPIs are not stopped routinely before endoscopy, and physicians generally are aware that this practice creates ≥2 potential problems: (1) PPIs can mask endoscopic evidence of early gastric cancers, and (2) PPIs can eliminate endoscopic evidence of reflux esophagitis. Although there are well-documented cases of PPIs obliterating endoscopic evidence of early gastric cancer by healing associated ulcerations,4 this phenomenon seems to be very uncommon in Western countries in which the incidence of gastric cancer is low. It is less clear why endoscopists evaluating patients with GERD symptoms so readily accept the strong possibility that PPIs will eliminate evidence of reflux esophagitis at diagnostic endoscopy. The endoscopic demonstration of reflux esophagitis for patients with GERD at baseline (off antireflux therapy) has important therapeutic implications. PPI treatment is required indefinitely for patients with severe reflux esophagitis, whereas PPI treatment might be tapered, stopped, or not needed at all for patients with no reflux esophagitis at baseline. For patients who undergo endoscopy while taking PPIs, no meaningful assessment can be made regarding the baseline presence of reflux esophagitis. (Excerpt from text, p.1; no abstract available.)