Cardiovascular disease (CVD), including myocardial infarction (MI) and peripheral or coronary artery disease (PAD, CAD), remains the number one killer of individuals in the United States and worldwide, accounting for nearly 18 million (>30%) global deaths annually. Despite considerable basic science and clinical investigation aimed at identifying key etiologic components of and potential therapeutic targets for CVD, the number of individuals afflicted with these dreaded diseases continues to rise. Of the many biochemical, molecular, and cellular elements and processes characterized to date that have potential to control foundational facets of CVD, the multifaceted cyclic nucleotide pathways continue to be of primary basic science and clinical interest. Cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP) and their plethora of downstream protein kinase effectors serve ubiquitous roles not only in cardiovascular homeostasis but also in the pathogenesis of CVD. Already a major target for clinical pharmacotherapy for CVD as well as other pathologies, novel and potentially clinically appealing actions of cyclic nucleotides and their downstream targets are still being discovered. With this in mind, this review article focuses on our current state of knowledge of the cyclic nucleotide-driven serine (Ser)/threonine (Thr) protein kinases in CVD with particular emphasis on cyclic AMP-dependent protein kinase (PKA) and cyclic GMP-dependent protein kinase (PKG). Attention is given to the regulatory interactions of these kinases with inflammatory components including interleukin 6 signals, with G protein-coupled receptor and growth factor signals, and with growth and synthetic transcriptional platforms underlying CVD pathogenesis. This article concludes with a brief discussion of potential future directions and highlights the importance for continued basic science and clinical study of cyclic nucleotide-directed protein kinases as emerging and crucial controllers of cardiac and vascular disease pathologies.

Background: Major adverse cardiac events (MACE) are a leading cause of morbidity and mortality after orthotopic liver transplantation (OLT). Cirrhotic cardiomyopathy (CCM) is relatively common and a source of MACE in patients after OLT. Initial diagnostic criteria based on transthoracic echocardiogram (TTE) were described in 2005 and revised in 2019 with echocardiographic advancements (Table 1). We sought to identify CCM related predictors of MACE at 13 months post-OLT. Methods: This is a retrospective study of adult patients who underwent OLT between 2009-2019. All patients had TTE’s within one year pre-OLT and one month to 13 months post-OLT. We excluded TTE’s within one-month post-OLT to reduce contributions from stress cardiomyopathy. Patients with a left ventricular ejection fraction less than 50% pre-OLT were excluded. MACE was defined as death, MI, CHF hospitalization, or cardiac arrest. Multivariable Cox regression was used to identify independent predictors of MACE. Results: Of 568 OLT patients screened, 131 met inclusion criteria for this study. There were 103 and 23 patients who met 2005 and 2019 criteria, respectively. During the 13 month follow up period, 42 patients had MACE. Compared to those without MACE, patients with MACE had more ascites (93 vs 70%, p 0.003), hepatorenal syndrome (HRS) (17 vs 4%, p 0.019), delayed OLT >10 days after admission (19 vs 7%, p 0.033), pre-OLT CCM per 2005 criteria (90% vs 73%, p 0.023), and lower diastolic blood pressure (60.81 vs 66.88, p 0.014). There was no difference in pre-OLT CCM per 2019 criteria (19 vs 17%, p 0.758) or MELD-Na score (21.24 vs 19.40, p 0.166). In multi-variable cox regression analysis adjusted for diastolic blood pressure, HRS, ascites, and OLT timing during admission, CCM per 2005 criteria remained significant as seen in Figure 1 (Hazard Ratio = 3, p 0.038). Conclusion: CCM per 2005 criteria is an independent predictor of MACE at 13 months post-OLT while CCM per 2019 criteria is not.