Cocaine Induces Cytoskeletal Changes in Cardiac Myocytes: Implications for Cardiac Morphology

Abstract

Cocaine is one of the most widely abused illicit drugs worldwide and has long been recognised as an agent of cardiac dysfunction in numerous cases of drug overdose. Cocaine has previously been shown to up-regulate cytoskeletal rearrangements and morphological changes in numerous tissues; however, previous literature observes such changes primarily in clinical case reports and addiction studies. An investigation into the fundamental cytoskeletal parameters of migration, adhesion and proliferation were studied to determine the cytoskeletal and cytotoxic basis of cocaine in cardiac cells. Treatment of cardiac myocytes with cocaine increased cell migration and adhesion (p < 0.05), with no effect on cell proliferation, except with higher doses eliciting (1–10 μg/mL) its diminution and increase in cell death. Cocaine downregulated phosphorylation of cofilin, decreased expression of adhesion modulators (integrin-β3) and increased expression of ezirin within three hours of 1 μg/mL treatments. These functional responses were associated with changes in cellular morphology, including alterations in membrane stability and a stellate-like phenotype with less compaction between cells. Higher dose treatments of cocaine (5–10 μg/mL) were associated with significant cardiomyocyte cell death (p < 0.05) and loss of cellular architecture. These results highlight the importance of cocaine in mediating cardiomyocyte function and cytotoxicity associated with the possible loss of intercellular contacts required to maintain normal cell viability, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.

From Bumps to Binges: Overview of Deaths Associated with Cocaine in England, Wales and Northern Ireland (2000–2019)

“…Collectively, the presented data identify individuals with a history of cocaine abuse and cardiac pathophysiology as being at an increased risk of death following cocaine use, even at doses routinely considered non-toxic. While it is not possible to attribute the morphological alterations of the cardiac architecture solely to cocaine use or to distinguish them from underlying cardiac deficiencies, in the context of cardiac tissue remodeling, the cases in this investigation are supportive of previously proposed links between cocaine use and long-term pathological cardiac injury (8,(31)(32)(33)(34)(35)(36)(37). It should be noted that many of the morphological and structural changes of the heart identified in this study are irreversible; therefore, even after cessation of cocaine abuse, previously chronic or long-term users should still be considered a high-risk category for cardiac failure and myocardial ischemia.…”

LKB1 suppression promotes cardiomyocyte regeneration via LKB1-AMPK-YAP axis

“…In the early postnatal period, cardiomyocytes undergo limited proliferation after injury [ 28 - 30 ]. The significant obstacles of cardiomyocyte proliferation include: (1) stalled cell cycle, (2) specialized cytoskeleton, and (3) switched metabolic pathway [ 5 , 31 , 32 ]. Interestingly, AMPK is involved in all these three processes: AMPK senses energy stress and enhances catabolic metabolism [ 33 ]; AMPK mediates re-organization of the cytoskeleton [ 34 ], and AMPK inhibits cell proliferation [ 35 ].…”

Oxidative Stress and Cocaine Intoxication as Start Points in the Pathology of Cocaine-Induced Cardiotoxicity

“…Cocaine has very powerful direct effects on cell membranes by blocking sodium channel activity, so cocaine intoxication is a common cause of various cardiovascular events. Cardiotoxic effects are associated with the development of cardiac contractile dysfunction, high www.videleaf.com blood pressure [11], tachycardia, arrhythmia [12,28] and sudden cardiac death (SCD) [48,49]. Its use can lead to myocardial infarction, causing vasoconstriction of the coronary artery [50,51] Blocking sodium channels and increasing calcium flow with a subsequent vasoconstrictor reaction is thought to be one of the leading mechanisms of cocaine cardiotoxicity [58].…”

“…Cocaine-induced cardiotoxicity can cause a variety of structural and functional damage to cardiac tissue [48]. Acute ischemic heart events such as myocardial infarction, angina, SCD, etc., are life-threatening conditions with high mortality and a major reason for performing forensic autopsies [84].…”