Research Spotlight

Pollifrone, M., S. Sikka and R. Hamilton (2020). “Takotsubo cardiomyopathy in a chronic spinal cord injury patient with autonomic dysreflexia: A case report.” J Spinal Cord Med Feb 11:1-4. [Epub ahead of print].

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Context: Takotsubo cardiomyopathy (TC) is a transient stress-induced cardiomyopathy with left ventricular dysfunction of unknown etiology. A well accepted theory for the pathophysiology of TC is attributed to a massive catecholamine release [1]. This case report will review a chronic tetraplegia patient who was diagnosed with TC after a severe episode of autonomic dysreflexia (AD). He experiences mild episodes of AD several times a day; however, he had never experienced the severity of symptoms that was associated with this episode which led to his hospitalization. Autonomic dysreflexia is a syndrome of imbalanced sympathetic input secondary to loss of descending central sympathetic control in spinal cord injury due to noxious stimuli below the level of the injury, which occurs when the injury level is at thoracic level 6 (T6) or above [2].Findings: In this specific case, it is presumed that the massive catecholamine release associated with this severe AD episode resulted in TC. Although TC has been diagnosed after other instances of acute stress, it is unknown for it to be diagnosed after AD in a chronic setting.Clinical Relevance: The long-term effects of AD have not been well studied, and this case illustrates the importance of education to recognize and manage AD in the spinal cord patient who frequently has episodes of AD.

Pineda, R., D. Prince, J. Reynolds, M. Grabill and J. Smith (2020). “Preterm infant feeding performance at term equivalent age differs from that of full-term infants.” J Perinatol Feb 17. [Epub ahead of print].

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OBJECTIVE: To identify differences in feeding skill performance among preterm infants at term equivalent age compared with full-term infants. STUDY DESIGN: Ninety-two infants (44 preterm infants born less-than-or-equal-to 32 weeks gestation at term equivalent age and 48 full-term infants within 4 days of birth) had a standardized oral feeding assessment. RESULT: Preterm infants at term equivalent age had lower Neonatal Eating Outcome Assessment scores (67.8 +/- 13.6 compared with 82.2 +/- 8.1; p < 0.001) and were more likely to have poor arousal (p = 0.04), poor tongue positioning (p = 0.04), suck-swallow-breathe discoordination (p < 0.001), inadequate sucking bursts (p = 0.01), tonal abnormalities (p < 0.001), discoordination of the jaw and tongue during sucking (p < 0.001), lack of positive engagement with the feeder and/or discomfort (p < 0.001), signs of aspiration (p < 0.001), difficulty regulating breathing (p < 0.001), and have an inability to maintain an appropriate state (p < 0.001), and complete the feeding (<0.001). CONCLUSION: A broad range of feeding-related difficulties appear to remain evident in preterm infants at term equivalent age.

Peng, X. V., R. Ayyagari, R. Lubwama, L. Shi, E. G. Price-Haywood, P. Hollander and V. Fonseca (2020). “Impact of Simultaneous Versus Sequential Initiation of Basal Insulin and Glucagon-like Peptide-1 Receptor Agonists on HbA1c in Type 2 Diabetes: A Retrospective Observational Study.” Diabetes Ther Feb 28. [Epub ahead of print].

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INTRODUCTION: When and how to intensify treatment in patients with type 2 diabetes (T2D) not achieving glycated hemoglobin (HbA1c) targets with oral antidiabetic drugs (OADs) in clinical practice remains a matter of clinical preference. This pilot study was conducted using the retrospective observational data from such patients to evaluate the impact on HbA1c of three treatment sequences: simultaneous initiation of basal insulin (BI) and a glucagon-like peptide-1 receptor agonist (GLP-1 RA; Cohort 1); BI followed by GLP-1 RA initiation within a 90-day timeframe (Cohort 2); or BI followed by GLP-1 RA initiation beyond 90 days (Cohort 3). METHODS: Data from the regional US electronic medical records database, Research Action for Health Network (REACHnet), were extracted for all patients with T2D aged >/= 18 years who had encounter dates between January 2011 and August 2017 and >/= 1 HbA1c laboratory value(s) < 90 days before BI initiation and >/= 2 HbA1c laboratory values within 1 year after BI initiation and who met the inclusion criteria for GLP-1 RA initiation set for Cohorts 1, 2, or 3. The primary endpoints were the proportion of patients achieving HbA1c < 7.0%, which was estimated via Kaplan-Meier analysis, and change in HbA1c within 12 months. RESULTS: Overall, 869 patients were analyzed, of whom 109 were in Cohort 1, 301 in Cohort 2, and 459 in Cohort 3. Baseline HbA1c was 10.3 +/- 2.1, 10.3 +/- 2.0, and 10.2 +/- 2.1% for these three cohorts, respectively. Statistically significantly more patients in Cohort 1 than in Cohort 3 achieved HbA1c < 7.0% (33.4 vs. 20.9%, respectively; p = 0.0186). Mean observed reductions in HbA1c at 12 months were - 1.7% (Cohort 1), - 1.5% (Cohort 2), and - 1.3% (Cohort 3). CONCLUSIONS: Simultaneous initiation of BI and GLP-1 RA achieves glycemic control more effectively than sequential initiation of BI with GLP-1 RA added beyond 90 days.

Packer, M. and P. A. Grayburn (2020). “New Evidence Supporting a Novel Conceptual Framework for Distinguishing Proportionate and Disproportionate Functional Mitral Regurgitation.” JAMA Cardiol Feb 19. [Epub ahead of print].

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Importance: Traditionally, physicians distinguished between mitral regurgitation (MR) as a determinant of outcomes and MR as a biomarker of left-ventricular (LV) dysfunction by designating the lesions as primary or secondary, respectively. In primary MR, leaflet abnormalities cause the MR, resulting in modest increases in LV end-diastolic volume over time, whereas in patients with classic secondary MR, LV dysfunction and dilatation lead to MR without structural leaflet abnormalities. However, certain patients with global LV disease (eg, those with left bundle branch block or regional wall motion abnormalities) have the features of primary MR and might respond favorably to interventions that aim to restore the proper functioning of the mitral valve apparatus. Observations: A novel conceptual framework is proposed, which classifies patients with meaningful LV disease based on whether the severity of MR is proportionate or disproportionate to the LV end-diastolic volume. Treatments that reduce LV volumes (eg, neurohormonal antagonists) are effective in proportionate MR but not disproportionate MR. Conversely, procedures that restore mitral valve function (eg, cardiac resynchronization and mitral valve repair) are effective in patients with disproportionate MR but not in those with proportionate MR. The proposed framework explains the discordant findings in the Multicentre Randomized Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) and the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trials; differences in procedural success and medical therapy in the 2 studies cannot explain the different results. In addition, the small group of patients in the COAPT trial who had the features of proportionate MR and were similar to those enrolled in the MITRA-FR trial did not respond favorably to transcatheter mitral valve repair. Conclusions and Relevance: The characterization of patients with functional MR into proportionate and disproportionate subtypes may explain the diverse range of responses to drug and device interventions that have been observed.

Packer, M. (2020). “SGLT2 Inhibitors Produce Cardiorenal Benefits by Promoting Adaptive Cellular Reprogramming to Induce a State of Fasting Mimicry: A Paradigm Shift in Understanding Their Mechanism of Action.” Diabetes Care 43(3): 508-511.

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There is compelling evidence that sodium–glucose cotransporter 2 (SGLT2) inhibitors exert cardioprotective and renoprotective effects that are far greater than expected based on their effects on glycemia or glycosuria. In large-scale randomized controlled trials, SGLT2 inhibitors reduce the risk of hospitalizations for heart failure by ∼30% and often decrease the risk of cardiovascular death. This benefit is particularly striking in patients who have the most marked impairment of systolic function prior to treatment. In parallel, SGLT2 inhibitors also reduce the risk of end-stage renal events, including the occurrence of renal death and the need for dialysis or renal transplantation by ∼30%. This benefit is seen even when glomerular filtration rates are sufficiently low to abolish the glycosuric effect of these drugs. These cardiorenal benefits cannot be explained by an action of SGLT2 inhibitors to lower blood glucose, since similar effects are not seen with antidiabetes drugs that have greater antihyperglycemic actions. Additionally, they cannot be ascribed to a natriuretic action, since these drugs exert only a modest effect on plasma volume or on circulating natriuretic peptides . . . Three lines of clinical evidence support the hypothesis that SGLT2 inhibitors exert their effects by the activation of low-energy sensors, which are responsible for mimicking a fasting transcriptional paradigm. First, SGLT2 inhibitors induce a loss of calories in the urine, and glycosuria is accompanied by a decrease of glucagon synthesis (often with the promotion of glycolysis), increased fatty acid oxidation, and the shrinkage of adipose tissue depots, including the alleviation of organ steatosis. Viewed from this perspective, the ketonemia seen with these drugs is not the source of an efficient fuel but instead is a biomarker of a fasting-like transcriptional state. Second, SGLT2 inhibitors may not only deceive cells into believing that they are fasting but also that they are hypoxic. Oxygen deprivation (like nutrient deprivation) stimulates AMPK and SIRT1. The latter activates hypoxia-inducible factor-2α (HIF-2α) and possibly also hypoxia-inducible factor-1α (HIF-1α) under certain conditions; these represent the principal stimuli for erythropoietin synthesis. Thus, the erythrocytosis that is seen with SGLT2 inhibitors may represent a biomarker for enhanced SIRT1 signaling and its organ-protective effects. Such a relationship may explain why, in statistical mediation analyses, erythrocytosis has been the most powerful predictor of the action of SGLT2 inhibitors to reduce heart failure events in large-scale trials. Third, metformin also stimulates autophagy, primarily by activating AMPK and SIRT1 and suppressing Akt/mTOR. Metformin exerts both cardioprotective and renoprotective effects in experimental models, and it favorably influences the evolution of heart failure and nephropathy in cohort studies. The overlap in the mechanism of action between metformin and SGLT2 inhibitors (with respect to AMPK/SIRT1 activation and autophagy) may explain why the magnitude of the benefit of SGLT2 inhibitors in large-scale trials may be attenuated in patients receiving metformin. However, metformin suppresses HIF-1α, thus distinguishing its action from that of SGLT2 inhibitors; this effect may explain why metformin modestly decreases hematocrit, whereas SGLT2 inhibitors induce erythrocytosis. However, since both HIF-1α and HIF-2α appear to induce autophagy in a manner than is independent of AMPK, it is possible that enhanced HIF-1α/HIF-2α signaling by SGLT2 inhibitors may amplify the autophagic flux that is already augmented by AMPK/SIRT1, thereby contributing importantly to the striking cardiorenal benefits of these drugs, which are not seen with other glucose-lowering agents. (Excerpts from text, p. 508, 510; no abstract available.)