Cardiology

Packer, M. (2018). “Increased Mortality in Patients With Heart Failure Who Are Taking Commonly Prescribed Antidiabetic Medications and Achieve Recommended Levels of Glycemic Control.” Diabetes Obes Metab. Feb 22. [Epub ahead of print].

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Current guidelines for diabetes recommend that physicians attain a glycated hemoglobin (HbA1c) less than or equal to 7.0%, but this target may not be applicable to those with heart failure. Fourteen studies of patients with chronic heart failure that examined the relationship between the level of glycated hemoglobin and the risk of death specified whether the HbA1c was influenced by treatment with antidiabetic medications. In patients with heart failure not receiving glucose-lowering drugs, mortality was not increased if the HbA1c was less than 7.0%. In contrast, in patients who were treated with insulin, sulfonylureas and thiazolidinediones, an inverse or U-shaped relationship between HbA1c and the risk of death was generally observed, and mortality was lowest in patients with both heart failure and diabetes if the level of HbA1c was greater than 7.0%. These studies suggest that patients with both heart failure and diabetes are at increased risk of death if they are prescribed certain glucose-lowering drugs to achieve levels of HbA1c less than 7.0%.

Packer, M. (2018). “Do Dipeptidyl Peptidase-4 Inhibitors Cause Heart Failure Events by Promoting Adrenergically-Mediated Cardiotoxicity? Clues from Laboratory Models and Clinical Trials.” Circ Res. Feb 7. [Epub ahead of print].

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Rationale: Dipeptidyl peptidase-4 (DPP-4) inhibitors have increased the risk of heart failure events in both randomized clinical trials and observational studies, but the mechanisms that underlie their deleterious effect remain to be elucidated. Previous work has implicated a role of these drugs to promote cardiac fibrosis. Objective: This paper postulates that DPP-4 inhibitors increase the risk of heart failure events by activating the sympathetic nervous system to stimulate cardiomyocyte cell death, and it crystallizes the findings from both experimental studies and clinical trials that support the hypothesis. Methods and Results: Inhibition of DPP-4 not only potentiates the actions of glucagon-like peptide-1 (which can increase myocardial cyclic AMP), but it also potentiates the actions of stromal cell-derived factor-1 (SDF-1), neuropeptide Y and substance P to activate the sympathetic nervous system and stimulate beta-adrenergic receptors to cause cardiomyocyte apoptosis, presumably through a Ca++/calmodulin-dependent protein kinase II pathway. An action of SDF-1 to interfere with cyclic AMP and protein kinase A signaling may account for the absence of a clinically overt positive chronotropic effect. This conceptual framework is supported by the apparent ability of beta-blocking drugs to attenuate the increased risk of DPP-4 inhibitors in a large-scale clinical trial. Conclusions: Sympathetic activation may explain the increased risk of heart failure produced by DPP-4 inhibitors. The proposed mechanism has major implications for clinical care, since in the treatment of patients with type 2 diabetes, DPP-4 inhibitors are widely prescribed, but beta-blockers are underutilized because of fears that they might mask hypoglycemia.

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.)