Mechanobiology of Microvascular Function and Structure in Health and Disease: Focus on the Coronary Circulation

The coronary microvasculature plays a key role in regulating the tight coupling between myocardial perfusion and myocardial oxygen demand across a wide range of cardiac activity. Short-term regulation of coronary blood flow in response to metabolic stimuli is achieved via adjustment of vascular diameter in different segments of the microvasculature in conjunction with mechanical forces eliciting myogenic and flow-mediated vasodilation. In contrast, chronic adjustments in flow regulation also involve microvascular structural modifications, termed remodeling. Vascular remodeling encompasses changes in microvascular diameter and/or density being largely modulated by mechanical forces acting on the endothelium and vascular smooth muscle cells. Whereas in recent years, substantial knowledge has been gathered regarding the molecular mechanisms controlling microvascular tone and how these are altered in various diseases, the structural adaptations in response to pathologic situations are less well understood. In this article, we review the factors involved in coronary microvascular functional and structural alterations in obstructive and non-obstructive coronary artery disease and the molecular mechanisms involved therein with a focus on mechanobiology. Cardiovascular risk factors including metabolic dysregulation, hypercholesterolemia, hypertension and aging have been shown to induce microvascular (endothelial) dysfunction and vascular remodeling. Additionally, alterations in biomechanical forces produced by a coronary artery stenosis are associated with microvascular functional and structural alterations. Future studies should be directed at further unraveling the mechanisms underlying the coronary microvascular functional and structural alterations in disease; a deeper understanding of these mechanisms is critical for the identification of potential new targets for the treatment of ischemic heart disease.

Correlating biological activity to thermo-structural analysis of the interaction of CTX with synthetic models of macrophage membranes

The important pharmacological actions of Crotoxin (CTX) on macrophages, the main toxin in the venom of Crotalus durissus terrificus, and its important participation in the control of different pathophysiological processes, have been demonstrated. The biological activities performed by macrophages are related to signaling mediated by receptors expressed on the membrane surface of these cells or opening and closing of ion channels, generation of membrane curvature and pore formation. In the present work, the interaction of the CTX complex with the cell membrane of macrophages is studied, both using biological cells and synthetic lipid membranes to monitor structural alterations induced by the protein. Here we show that CTX can penetrate THP-1 cells and induce pores only in anionic lipid model membranes, suggesting that a possible access pathway for CTX to the cell is via lipids with anionic polar heads. Considering that the selectivity of the lipid composition varies in different tissues and organs of the human body, the thermostructural studies presented here are extremely important to open new investigations on the biological activities of CTX in different biological systems.

522 A strange case of bradycardia in a 38-year-old woman postpartum

Methods and results A 38-year-old woman at her 4th day postpartum from a twin pregnancy, presented to the Emergency Room with general malaise, headache, and dyspnoea. Her symptoms had started to show 2 days prior to her ER admission and were worsened by bilateral pitting oedema. In particular they had started when she was administered cabergoline to suppress lactation. Her blood pressure was elevated (160/80 mmHg) and her heart rate was 40 b.p.m. On examination she was oriented in time and space. Her laboratory exams showed anaemia (Hb 8.8 g/dl), with negative D-dimer and troponin. She had no urine proteinuria, which allowed pre-eclampsia to be excluded from the diagnostic hypotheses. A 12-lead ECG was performed and showed junctional rhythm with isorhythmic dissociation at 40 b.p.m. She was admitted to the cardiology ward for diagnostic workup. Her echocardiogram showed no structural alteration and preserved ejection fraction. A cardiac magnetic resonance confirmed the absence of structural alterations or late gadolinium enhancement. During her hospital stay, sinus rhythm was spontaneously restored at 42 b.p.m.; in addition to this, restoration of sinus rhythm, although bradycardic, was associated to the resolution on both her symptoms and of her pitting oedema. She was discharged with a diagnosis of bradycardia secondary to carbegoline use. Her Holter ECG, performed 7 days after discharge, showed sinus bradycardia with occasional isorhythmic dissociation. Conclusions Cabergoline is an ergot-derived dopamine agonist usually used in the treatment of Parkinson’s disease. It acts selectively on D2 receptors. It can be associated to orthostatic hypotension, cardiac valvular fibrosis, and angina pectoris. No cases of cabergoline-induced bradycardia can be currently found in literature; however, a similar effect was seen with the use of methylergometrine in a women during her post-partum period. Furthermore, studies on mice have shown that ergot derivatives may cause reduction of heart rate. It therefore seems possible that in our case, the use of cabergoline induced the patient’s bradyarrhythmia.

Mbnl1 and Mbnl2 regulate brain structural integrity in mice

Myotonic Dystrophy Type I (DM1) patients demonstrate widespread and variable brain structural alterations whose etiology is unclear. We demonstrate that inactivation of the Muscleblind-like proteins, Mbnl1 and Mbnl2, initiates brain structural defects. 2D FSE T2w MRIs on 4-month-old Mbnl1+/−/Mbnl2−/− mice demonstrate whole-brain volume reductions, ventriculomegaly and regional gray and white matter volume reductions. Comparative MRIs on 2-month-old Mbnl1−/−, Mbnl2−/− and Mbnl1−/−/Mbnl2+/− brains show genotype-specific reductions in white and gray matter volumes. In both cohorts, white matter volume reductions predominate, with Mbnl2 loss leading to more widespread alterations than Mbnl1 loss. Hippocampal volumes are susceptible to changes in either Mbnl1 or Mbnl2 levels, where both single gene and dual depletions result in comparable volume losses. In contrast, the cortex, inter/midbrain, cerebellum and hindbrain regions show both gene and dose-specific volume decreases. Our results provide a molecular explanation for phenotype intensification in congenital DM1 and the variability in the brain structural alterations reported in DM1.