Research Spotlight

Pollock, B. D., E. W. Harville, K. T. Mills, W. Tang, W. Chen and L. A. Bazzano (2018). “Cardiovascular Risk and the American Dream: Life Course Observations From the BHS (Bogalusa Heart Study).” J Am Heart Assoc 7(3).

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BACKGROUND: Economic literature shows that a child’s future earnings are predictably influenced by parental income, providing an index of “socioeconomic mobility,” or the ability of a person to move towards a higher socioeconomic status from childhood to adulthood. We adapted this economic paradigm to examine cardiovascular risk mobility (CRM), or whether there is life course mobility in relative cardiovascular risk. METHODS AND RESULTS: Participants from the BHS (Bogalusa Heart Study) with 1 childhood and 1 adult visit from 1973 to 2016 (n=7624) were considered. We defined population-level CRM as the rank-rank slope (beta) from the regression of adult cardiovascular disease (CVD) risk percentile ranking onto childhood CVD risk percentile ranking (beta=0 represents complete mobility; beta=1 represents no mobility). After defining and measuring relative CRM, we assessed its correlation with absolute cardiovascular health using the American Heart Association’s Ideal Cardiovascular Health metrics. Overall, there was substantial mobility, with black participants having marginally better CRM than whites (betablack=0.10 [95% confidence interval, 0.05-0.15]; betawhite=0.18 [95% confidence interval, 0.14-0.22]; P=0.01). Having high relative CVD risk at an earlier age significantly reduced CRM (betaagexslope=-0.02; 95% confidence interval, -0.03 to -0.01; P<0.001). Relative CRM was strongly correlated with life course changes in Ideal Cardiovascular Health sum (r=0.62; 95% confidence interval, 0.60-0.65). CONCLUSIONS: Results from this novel application of an economic mobility index to cardiovascular epidemiology indicated substantial CRM, supporting the paradigm that life course CVD risk is highly modifiable. High CRM implies that the children with the best relative CVD profiles may only maintain a slim advantage over their peers into adulthood.

Poehling, K. A., H. Caspard, T. R. Peters, E. A. Belongia, B. Congeni, M. Gaglani, M. R. Griffin, S. A. Irving, P. K. Kavathekar, H. Q. McLean, A. L. Naleway, K. Ryan, H. K. Talbot and C. S. Ambrose (2018). “2015-2016 Vaccine Effectiveness of Live Attenuated and Inactivated Influenza Vaccines in Children in the United States.” Clin Infect Dis 66(5): 665-672.

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Background: In the 2015-2016 season, quadrivalent live attenuated influenza vaccine (LAIV) and both trivalent and quadrivalent inactivated influenza vaccine (IIV) were available in the United States. Methods: This study, conducted according to a test-negative case-control design, enrolled children aged 2-17 years presenting to outpatient settings with fever and respiratory symptoms for <5 days at 8 sites across the United States between 30 November 2015 and 15 April 2016. A nasal swab was obtained for reverse-transcriptase polymerase chain reaction (RT-PCR) testing for influenza, and influenza vaccination was verified in the medical record or vaccine registry. Influenza vaccine effectiveness (VE) was estimated using a logistic regression model. Results: Of 1012 children retained for analysis, most children (59%) were unvaccinated, 10% received LAIV, and 31% received IIV. Influenza A (predominantly antigenically similar to the A/California/7/2009 strain) was detected in 14% and influenza B (predominantly a B/Victoria lineage) in 10%. For all influenza, VE was 46% (95% confidence interval [CI], 7%-69%) for LAIV and 65% (48%-76%) for IIV. VE against influenza A(H1N1)pdm09 was 50% (95% CI, -2% to 75%) for LAIV and 71% (51%-82%) for IIV. The odds ratio for vaccine failure with RT-PCR-confirmed A(H1N1)pdm09 was 1.71 (95% CI, 0.78-3.73) in LAIV versus IIV recipients. Conclusions: LAIV and IIV demonstrated effectiveness against any influenza among children aged 2-17 years in 2015-2016. When compared to all unvaccinated children, VE against influenza A(H1N1)pdm09 was significant for IIV but not LAIV. Clinical Trials Registration: NCT01997450.

Packer, M. (2018). “Worsening Heart Failure During the Use of DPP-4 Inhibitors: Pathophysiological Mechanisms, Clinical Risks, and Potential Influence of Concomitant Antidiabetic Medications.” JACC Heart Fail. Mar 1. [Epub ahead of print].

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Although dipeptidyl peptidase (DPP)-4 inhibitors have been reported to have a neutral effect on thromboembolic vaso-occlusive events in large-scale trials, they act to potentiate several endogenous peptides that can exert deleterious cardiovascular effects. Experimentally, DPP-4 inhibitors may augment the ability of glucagon-like peptide-1 to stimulate cyclic adenosine monophosphate in cardiomyocytes, and potentiation of the effects of stromal cell-derived factor-1 by DPP-4 inhibitors may aggravate cardiac fibrosis. These potentially deleterious actions of DPP-4 inhibitors might not become clinically apparent if these drugs were to promote sodium excretion. However, the natriuretic effect of DPP-4 inhibitors is modest, because they act on the distal (rather than proximal) renal tubules. Accordingly, both clinical trials and observational studies have reported an increase in the risk of heart failure in patients with type 2 diabetes who were receiving DPP-4 inhibitors. This risk may be muted in trials with a high prevalence of metformin use or with low and declining background use of insulin and thiazolidinediones. Still, the most vulnerable patients (i.e., those with established heart failure) were not well represented in these studies. The only trial that specifically evaluated patients with pre-existing left ventricular dysfunction observed important drug-related adverse structural and clinical effects. In conclusion, an increased risk of worsening heart failure appears to be a class effect of DPP-4 inhibitors, even in patients without a history of heart failure. Additional clinical trials are urgently needed to elucidate the benefits and risks of DPP-4 inhibitors in patients with established left ventricular dysfunction.

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.