Published descriptions of the neuropathological features of COVID-19 patients have been controversial, ranging from only modest or no pathology to severe hypoxic and hemorrhagic phenotypes, thrombotic complications, acute disseminated encephalomyelitis-like changes, and encephalitis and meningitis. Here, we describe the neuropathological findings of four COVID-19-positive patients autopsied at the Helsinki University Hospital during the spring of 2020. While three of the patients (age range 63-90) exhibited merely mild to moderate hypoxia-associated changes, one 38-year-old subject with obesity, diabetes (type 2), Parkinson's disease and a very severe clinical course was found to have severe ischemic injury, abundant microhemorrhages and enlarged perivascular spaces most pronounced in the white matter and deep gray matter. The pattern of ischemic changes suggested a defect in microcirculation. In addition, a few small perivascular white matter lesions, with macrophages engulfing myelin, were found. No signs of encephalitis or meningitis were detected in any of the patients. When conducting RT-PCR and immunohistochemical analyses of brain tissue, we could not demonstrate in any of the patients marked injury or presence of SARS-CoV2 in the olfactory epithelium, olfactory bulbs or brain areas responsible for respiratory control. In conclusion, our small autopsy series demonstrates various hypoxia-associated neuropathological features in COV-ID-19 patients, but no evidence of neurotropism or meningitis/encephalitis.

Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain- and loss-of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor-B (VEGF-B) in the heart. A cardiomyocyte-specific VEGF-B transgene induced an expanded coronary arterial tree and reprogramming of cardiomyocyte metabolism. This was associated with protection against myocardial infarction and preservation of mitochondrial complex I function upon ischemia-reperfusion. VEGF-B increased VEGF signals via VEGF receptor-2 to activate Erk1/2, which resulted in vascular growth. Akt and mTORC1 pathways were upregulated and AMPK downregulated, readjusting cardiomyocyte metabolic pathways to favor glucose oxidation and macromolecular biosynthesis. However, contrasting with a previous theory, there was no difference in fatty acid uptake by the heart between the VEGF-B transgenic, gene-targeted or wildtype rats. Importantly, we also show that VEGF-B expression is reduced in human heart disease. Our data indicate that VEGF-B could be used to increase the coronary vasculature and to reprogram myocardial metabolism to improve cardiac function in ischemic heart disease.Subject Categories Cardiovascular System; MetabolismSee also: C Kupatt and R Hinkel (March 2014)

Angiotensin-converting enzyme and chymase, two Ang II-forming enzymes, are locally expressed in aortic valves, and owing to infiltration of macrophages and MCs, are further upregulated in stenotic valves. These novel findings, implicating chronic inflammation and an increased expression of local Ang II-forming systems, suggest that therapeutic interventions aiming at inhibiting these processes may slow AS progression.

No abstract

ORP8 is a previously unexplored member of the family of oxysterol-binding protein-related proteins (ORP). We now report the expression pattern, the subcellular distribution, and data on the ligand binding properties and the physiological function of ORP8. ORP8 is localized in the endoplasmic reticulum (ER) via its C-terminal transmembrane span and binds 25-hydroxycholesterol, identifying it as a new ER oxysterolbinding protein. ORP8 is expressed at highest levels in macrophages, liver, spleen, kidney, and brain. Immunohistochemical analysis revealed ORP8 in the shoulder regions of human coronary atherosclerotic lesions, where it is present in CD68(؉) macrophages. In advanced lesions the ORP8 mRNA was up-regulated 2.7-fold as compared with healthy coronary artery wall. Silencing of ORP8 by RNA interference in THP-1 macrophages increased the expression of ATP binding cassette transporter A1 (ABCA1) and concomitantly cholesterol efflux to lipidfree apolipoprotein A-I but had no significant effect on ABCG1 expression or cholesterol efflux to spherical high density lipoprotein HDL 2 . Experiments employing an ABCA1 promoter-luciferase reporter confirmed that ORP8 silencing enhances ABCA1 transcription. The silencing effect was partially attenuated by mutation of the DR4 element in the ABCA1 promoter and synergized with that of the liver X receptor agonist T0901317. Furthermore, inactivation of the E-box in the promoter synergized with ORP8 silencing, suggesting that the suppressive effect of ORP8 involves both the liver X receptor and the E-box functions. Our data identify ORP8 as a negative regulator of ABCA1 expression and macrophage cholesterol efflux. ORP8 may, thus, modulate the development of atherosclerosis.

Aims The present study was done to assess the role of sudden cardiac death (SCD) among the presenting manifestations of and fatalities from cardiac sarcoidosis (CS). Methods and results We analysed altogether 351 cases of CS presenting from year 1998 through 2015 in Finland. There were 262 patients with a clinical diagnosis and treatment of CS, 27 patients with an initial lifetime diagnosis of giant cell myocarditis that was later converted to CS, and 62 cases detected at autopsy and identified by screening >820 000 death certificates from the national cause-of-death registry. The total case series comprised 253 females and 98 males aged on average 52 years at presentation. High-grade atrioventricular block was the most common first sign of CS (n = 147, 42%) followed by heart failure (n = 58, 17%), unexpected fatal (n = 38) or aborted (n = 12) SCD (14%), and sustained ventricular tachycardia (n = 48, 14%). Severe coronary artery disease was found at autopsy concomitant with CS in four of the 38 cases presenting with fatal SCD. Of all deaths recorded till the end of 2015, 64% (n = 54/84) were unexpected SCDs from CS that had either been silent during life or defied all attempts at diagnosis. The Kaplan–Meier estimate (95% CI) of survival from symptom onset was 85% (80–90%) at 5 years and 76% (68–84%) at 10 years. Conclusion Together fatal and aborted SCD constitute 14% of the presenting manifestations of CS. Nearly two-thirds of all fatalities from CS are caused by undiagnosed granulomas in the heart.

In stenotic aortic valves, mast cell-derived cathepsin G may cause adverse valve remodelling and AS progression.

Background: Symptomatic high-grade atrioventricular block (AVB) is the most common and often the only presenting manifestation (lone AVB) of cardiac sarcoidosis. Implantation of an intracardiac cardioverter defibrillator instead of a pacemaker is recommended, but the true risk of fatal arrhythmia, one incident to lone AVB in particular, remains poorly known. Methods: We used Myocardial Inflammatory Diseases in Finland Study Group Registry to analyze the presentations, left ventricular (LV) function, pacemaker therapy, and ventricular arrhythmias in cardiac sarcoidosis. From year 1988 to 2015, altogether 325 cases of cardiac sarcoidosis were diagnosed in Finland. Of them, 143 patients (112 women, mean age 52 years) presented with Mobitz II second degree or third degree AVB in the absence of other explanatory cardiac disease. Results: Concomitant with AVB at presentation, 20 patients had either ventricular tachycardia or severe LV dysfunction with ejection fraction <35% and 29 patients had nonsevere LV dysfunction (ejection fraction, 35%–50%) while 90 patients presented with AVB alone. During a median of 2.8 years’ follow-up, 23 sudden cardiac deaths (fatal or aborted) and 19 ventricular tachycardias were recorded as arrhythmic end point events. Their composite 5-year incidence (95% confidence interval) was 56% (36%–88%) in the AVB subgroup with ventricular tachycardia or severe LV dysfunction versus 24% (12%–49%) in the subgroup with nonsevere LV dysfunction and 24% (15%–38%) with lone AVB ( P =0.019). The 5-year incidence of sudden cardiac death was 34% (16%–71%), 14% (6%–35%), and 9% (4%–22%) in the respective subgroups ( P =0.060). Conclusions: The risk of sudden cardiac death is significant in cardiac sarcoidosis presenting with high-grade AVB with or without ventricular tachycardia or LV dysfunction. The consensus recommendation to implant an intracardiac cardioverter defibrillator whenever permanent pacing is needed seems well-founded.