Aims To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs). Methods and Results We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019. We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P < 0.001). The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7–32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3–70.3; P < 0.001). Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191). A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%). The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7–6.6; P < 0.001]. A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1–2.8; P = 0.009). Conclusion Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates. This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies.

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We examined the mechanism of atrial natriuretic factor (ANF) transcription by isoproterenol (ISO), an agonist for the ␤-adrenergic receptor (␤AR), in cardiac myocytes. ISO only modestly activated members of the mitogen-activated protein kinase family. ISO-induced ANF transcription was not affected by inhibition of mitogen-activated protein kinases, whereas it was significantly inhibited by KN93, an inhibitor of Ca 2؉ /calmodulin-dependent kinase (CaM kinase II). Production of 3-phosphorylated phosphatidylinositides (3 phosphoinositides) was also required for ISO-induced ANF transcription. ISO caused phosphorylation (Ser-473) and activation of Akt through CaM kinase II-and 3 phosphoinositides-dependent mechanisms. Constitutively active Akt increased myocyte surface area, total protein content, and ANF expression, whereas dominant negative Akt blocked ISO-stimulated ANF transcription. ISO caused Ser-9 phosphorylation and decreased activities of GSK3␤. Overexpression of GSK3␤ inhibited ANF transcription, which was reversed by ISO. ISO failed to reverse the inhibitory effect of GSK3␤(S9A), an Akt-insensitive mutant. Kinase-inactive GSK3␤ increased ANF transcription. Cyclosporin A partially inhibited ISOstimulated ANF transcription, indicating that calcineurin only partially mediates ANF transcription. These results suggest that both CaM kinase II and 3 phosphoinositides mediate ␤AR-induced Akt activation and ANF transcription in cardiac myocytes. Furthermore, ␤AR-stimulated ANF transcription is predominantly mediated by activation of Akt and subsequent phosphorylation/inhibition of GSK3␤.The development of cardiac hypertrophy is a complex process mediated by mechanical forces, neurotransmitters, and hormonal factors (1, 2). In vivo and in vitro studies have shown that stimulation of myocardial ␤-adrenergic receptors (␤ARs) 1 results in cardiac hypertrophy characterized by increases in the cell size, reexpression of the "fetal gene" program (atrial natriuretic factor (ANF) and skeletal ␣-actin), and organization of actin cytoskeleton (3-8). 2 The phenotype of cardiac hypertrophy stimulated by Gs-coupled ␤AR is similar, if not identical, to that by agonists for Gq␣-coupled receptors, such as angiotensin II, phenylephrine (PE), and endothelin-1, 2 despite the fact that the intracellular signaling mechanism activated by Gs␣ and that by Gq␣ are substantially different. We have shown that increases in the protein content and transcription of ANF induced by ␤AR stimulation are predominantly mediated by the ␤1AR subtype and that both Gs␣ and G␤␥ in concert mediate ␤AR-stimulated ANF transcription.2 The intracellular signaling mechanism remains unclear, however, as to how stimulation of the ␤1AR causes cardiac hypertrophy.Many protein kinases and protein phosphatases are activated by hypertrophic stimuli in the heart, and a series of protein phosphorylation and de-phosphorylation events are responsible for induction of specific phenotypes in cardiac hypertrophy. Among them, growing lines of evidence suggest that members of t...

These data suggest that in response to chronic pressure overload, cardiomyocyte-specific apoptosis contributed to the transition from LVH to LVD. LVH and LVD were accompanied by a dramatic cardiomyocyte upregulation of the proapoptotic gene bax and reduced bcl-2/bax ratio, predisposing cardiomyocytes to apoptosis.

Inactivation of glycogen synthase kinase 3␤ (GSK3␤)is critical for transcription of atrial natriuretic factor (ANF) by ␤-adrenergic receptors in cardiac myocytes. We examined the mechanism by which GSK3␤ regulates ANF transcription. Stimulation of ␤-adrenergic receptors induced nuclear accumulation of GATA4, whereas ␤-adrenergic ANF transcription was suppressed by dominant negative GATA4, suggesting that GATA4 plays an important role in ␤-adrenergic ANF transcription. Interestingly, GATA4-mediated transcription was markedly attenuated by GSK3␤. GSK3␤ physically associates with GATA4 and phosphorylates GATA4 in vitro. Overexpression of GSK3␤ suppressed both basal and ␤-adrenergic increases in nuclear expression of GATA4, whereas inhibition of GSK3␤ by LiCl caused nuclear accumulation of GATA4, suggesting that GSK3␤ negatively regulates nuclear expression of GATA4. The nuclear exportin Crm1 reduced nuclear expression of GATA4, and the reduction was enhanced by GSK3␤ but not by kinase-inactive GSK3␤. Leptomycin B, an inhibitor for Crm1, increased basal nuclear GATA4 and suppressed GSK3␤-induced decreases in nuclear GATA4. These results suggest that GSK3␤ negatively regulates nuclear expression of GATA4 by stimulating Crm1-dependent nuclear export. Inhibition of GSK3␤ by ␤-adrenergic stimulation abrogates GSK3␤-induced nuclear export of GATA4, causing nuclear accumulation of GATA4, which may represent an important signaling mechanism mediating cardiac hypertrophy.