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MiD49 and MiD51: New mediators of mitochondrial fission and novel targets for cardioprotection

Samangouei P, Crespo-Avilan GE, Cabrera-Fuentes H, Hernández-Reséndiz S, Ismail NI, Katwadi KB, et al.

Cond Med, 2018 Aug;1(5):239-246.
PMID: 30338314

Acute myocardial infarction (AMI) and the heart failure (HF) that often follows are among the leading causes of death and disability worldwide. As such novel therapies are needed to reduce myocardial infarct (MI) size, and preserve left ventricular (LV) systolic function in order to reduce the propensity for HF following AMI. Mitochondria are dynamic organelles that can undergo morphological changes by two opposing processes, mitochondrial fusion and fission. Changes in mitochondrial morphology and turnover are a vital part of maintaining mitochondrial health, DNA stability, energy production, calcium homeostasis, cellular division, and differentiation, and disturbances in the balance of fusion and fission can predispose to mitochondrial dysfunction and cell death. Changes in mitochondrial morphology are governed by mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1) and mitochondrial fission proteins (Drp1, hFis1, and Mff). Recent experimental data suggest that mitochondria undergo fission during acute ischemia/reperfusion injury (IRI), generating fragmented dysfunctional mitochondrial and predisposing to cell death. We and others have shown that genetic and pharmacological inhibition of the mitochondrial fission protein Drp1 can protect cardiomyocytes from acute IRI and reduce MI size. Novel components of the mitochondrial fission machinery, mitochondrial dynamics proteins of 49 kDa (MiD49) and mitochondrial dynamics proteins of 51 kDa (MiD51), have been recently described, which have been shown to mediating mitochondrial fission by targeting Drp1 to the mitochondrial surface. In this review article, we provide an overview of MiD49 and MiD51, and highlight their potential as novel therapeutic targets for treating cardiovascular diseases such as AMI, anthracycline cardiomyopathy, and pulmonary arterial hypertension.
Fulltext Verifying Death Reports in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

Serebruany V, Tanguay JF, Benavides MA, Cabrera-Fuentes H, Eisert W, Kim MH, et al.

Am J Ther, 2020 10 29;27(6):e563-e572.
PMID: 33109913 DOI: 10.1097/MJT.0000000000001286

BACKGROUND: Excess vascular deaths in the PLATO trial comparing ticagrelor to clopidogrel have been repeatedly challenged by the Food and Drug Administration (FDA) reviewers and academia. Based on the Freedom of Information Act, BuzzFeed won a court order and shared with us the complete list of reported deaths for the ticagrelor FDA New Drug Application (NDA) 22-433. This dataset was matched against local patient-level records from PLATO sites monitored by the sponsor.
STUDY QUESTION: Whether FDA death data in the PLATO trial matched the local site records.
STUDY DESIGN: The NDA spreadsheet contains 938 precisely detailed PLATO deaths. We obtained and validated local evidence for 52 deaths among 861 PLATO patients from 14 enrolling sites in 8 countries and matched those with the official NDA dataset submitted to the FDA.
MEASURES AND OUTCOMES: Existence, precise time, and primary cause of deaths in PLATO.
RESULTS: Discrepant to the NDA document, sites confirmed 2 extra unreported deaths (Poland and Korea) and failed to confirm 4 deaths (Malaysia). Of the remaining 46 deaths, dates were reported correctly for 42 patients, earlier (2 clopidogrel), or later (2 ticagrelor) than the actual occurrence of death. In 12 clopidogrel patients, cause of death was changed to "vascular," whereas 6 NDA ticagrelor "nonvascular" or "unknown" deaths were site-reported as of "vascular" origin. Sudden death was incorrectly reported in 4 clopidogrel patients, but omitted in 4 ticagrelor patients directly affecting the primary efficacy PLATO endpoint.
CONCLUSIONS: Many deaths were inaccurately reported in PLATO favoring ticagrelor. The full extent of mortality misreporting is currently unclear, while especially worrisome is a mismatch in identifying primary death cause. Because all PLATO events are kept in the cloud electronic Medidata Rave capture system, securing the database content, examining the dataset changes or/and repeated entries, identifying potential interference origin, and assessing full magnitude of the problem are warranted.

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