Impact of Diastolic Dysfunction on the Development of Heart Failure in Diabetic Patients After Acute Myocardial Infarction

Aronson, Doron; Musallam, Anees; Lessick, Jonathan; Dabbah, Saleem; Carasso, Shemy; Hammerman, Haim; Reisner, Shimon A.; Agmon, Yoram; Mutlak, Diab

doi:10.1161/circheartfailure.109.877340

Cited by 27 publications

(28 citation statements)

References 42 publications

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“…Differences in the population might explain some of the prevalence of diastolic dysfunction. In our study, patients with known diabetes were excluded and diabetes is associated with diastolic dysfunction [38]. Also the prevalence of insulin resistance and the metabolic syndrome, which are closely related to diastolic dysfunction, was low in the GIPS-III trial.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Metformin on Diastolic Function in Patients Presenting with ST-Elevation Myocardial Infarction

et al. 2016

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IntroductionDiastolic dysfunction is an important predictor of poor outcome after myocardial infarction. Metformin treatment improved diastolic function in animal models and patients with diabetes. Whether metformin improves diastolic function in patients presenting with ST-segment elevation myocardial infarction (STEMI) is unknown.MethodsThe GIPS-III trial randomized STEMI patients, without known diabetes, to metformin or placebo initiated directly after PCI. The previously reported primary endpoint was left ventricular ejection fraction at 4 months, which was unaffected by metformin treatment. This is a predefined substudy to determine an effect of metformin on diastolic function. For this substudy trans-thoracic echocardiography was performed during hospitalization and after 4 months. Diastolic dysfunction was defined as having the combination of a functional alteration (i.e. decreased tissue velocity: mean of septal e’ and lateral e’) and a structural alteration (i.e. increased left atrial volume index (LAVI)). In addition, left ventricular mass index and transmitral flow velocity (E) to mean e' ratio (E/e’) were measured to determine an effect of metformin on individual echocardiographic markers of diastolic function.ResultsIn 237 (63%) patients included in the GIPS-III trial diastolic function was measured during hospitalization as well as at 4 months. Diastolic dysfunction was present in 11 (9%) of patients on metformin and 11 (9%) patients on placebo treatment (P = 0.98) during hospitalization. After 4 months 22 (19%) of patients with metformin and 18 (15%) patients with placebo (P = 0.47) had diastolic dysfunction. In addition, metformin did not improve any of the individual echocardiographic markers of diastolic function.ConclusionsIn contrast to experimental and observational data, our randomized placebo controlled trial did not suggest a beneficial effect of short-term metformin treatment on diastolic function in STEMI patients.

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Section: Discussionmentioning

confidence: 99%

The Effect of Metformin on Diastolic Function in Patients Presenting with ST-Elevation Myocardial Infarction

et al. 2016

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“…This type of adverse remodeling is particularly common in diabetics and may be associated with an overactive TGF-β system. 264, 265, 266 Identification of patient subpopulations with distinct pathophysiologic perturbations, using suitable biomarkers or molecular imaging modalities, is needed in order to design effective therapies to attenuate adverse remodeling in patients with MI.…”

Section: Targeting the Inflammatory Response In Myocardial Infarctionmentioning

confidence: 99%

The Biological Basis for Cardiac Repair After Myocardial Infarction

Prabhu

Frangogiannis

2016

Circulation Research

1,651

1,396

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In adult mammals, massive sudden loss of cardiomyocytes following infarction overwhelms the limited regenerative capacity of the myocardium, resulting in formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of pro-inflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/CCL2). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response following myocardial infarction. Dysregulation of immune pathways, impaired suppression of post-infarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for prevention of post-infarction heart failure.

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“…However, certain patient subpopulations (such as those with diabetes mellitus) have post-infarction heart failure in the absence of significant dilation 118 . In patients with diabetes mellitus, post-infarction heart failure is often linked with diastolic dysfunction 119 and might reflect enhanced excessive activation of the pro-fibrotic TGF-β/Smad axis 120 . Different therapeutic strategies are, therefore, needed for these pathophysiologically distinct patient subpopulations.…”

Section: Targeting the Infarcted Heartmentioning

confidence: 99%

The inflammatory response in myocardial injury, repair, and remodelling

2014

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Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of post-infarction remodeling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited remove dead cells and matrix debris by phagocytosis, while setting the stage for scar formation. Timely repression of the inflammatory response is critical for effective healing and followed by activation of infarct myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor-β family are critically involved in suppression of inflammation and activation of a pro-fibrotic program. Translation of these concepts in the clinic requires understanding of the pathophysiologic complexity and heterogeneity of post-infarction remodeling in human patients with myocardial infarction. Individuals with overactive and prolonged post-infarction inflammation might exhibit dilation and systolic dysfunction and benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with exaggerated fibrogenic reactions can develop diastolic heart failure and might require inhibition of the smad3 cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.

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Impact of Diastolic Dysfunction on the Development of Heart Failure in Diabetic Patients After Acute Myocardial Infarction

Cited by 27 publications

References 42 publications

The Effect of Metformin on Diastolic Function in Patients Presenting with ST-Elevation Myocardial Infarction

The Effect of Metformin on Diastolic Function in Patients Presenting with ST-Elevation Myocardial Infarction

The Biological Basis for Cardiac Repair After Myocardial Infarction

The inflammatory response in myocardial injury, repair, and remodelling

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