假屋 太郎

BACKGROUND: Vasoplegia is a life-threatening intraoperative condition. Methylene blue (MB), a potent inhibitor of nitric oxide (NO) synthase and soluble guanylyl cyclase (sGC), can treat vasoplegia but may antagonize pulmonary arterial hypertension (PAH) drugs that enhance the NO-sGC-cyclic guanosine monophosphate (cGMP) pathway. Although reports on the use of MB for vasoplegia during liver transplantation (LT) have often been published, managing vasoplegia during LT in a patient with cardiopulmonary disease, including portopulmonary hypertension (PoPH) - a subgroup of PAH - with intracardiac shunt, is challenging and has not been reported. CASE PRESENTATION: We report a 57-year-old woman with PoPH, on anti-PAH selexipag with concomitant atrial septal defect (ASD) undergoing deceased donor LT. After portal reperfusion, she developed refractory hypotension, in which mean arterial blood pressure (ABP) was less than 50 mmHg and the cardiac index (CI) was maintained at 5.0 L·min-1·m-2, despite high dose of vasopressin of 4 unit·h-1. Diagnosed with vasoplegia, she received 100 mg of MB. Mean ABP promptly improved from 45 to above 60 mmHg, systolic ABP from around 60 to above 95 mmHg, allowing immediate reduction of vasopressin to 0.5 unit·h-1. She was transferred to ICU with stable hemodynamics. CONCLUSION: MB can be lifesaving for intraoperative vasoplegia even in patients with PoPH on PAH drug therapy with an ASD, though potential drug interactions with anti-PAH drugs warrant caution.

Pharmacologic beta-blockade is a well-established therapy for reducing adverse effects from sympathetic overactivity in cardiovascular diseases, such as heart failure. Despite decades of research efforts, in vivo cardiac functional studies utilizing genetic animal models remain scant. We generated a mouse model of cardiomyocyte-specific deletion of beta-1 adrenergic receptor (ADRB1) , the primary subtype expressed in cardiac myocytes, and demonstrated the role for ADRB1 in the maintenance of cardiac function at baseline and during exposure to increase in cardiac afterload by transient aortic occlusion and increasing heart rates (HRs) via atrial pacing. cKO hearts showed mildly depressed baseline left ventricular (LV) function, including slower HR, decreased contractility (dP/dtmax/IP) and prolonged relaxation (Tau) at baseline in both sexes. Exposure to increased LV afterload depressed LV function in either genotype similarly; however, the functional recovery following the removal of the afterload was severely impaired in cKO hearts, while cardiac function was immediately normalized in WT hearts. When HR was altered from 400 to 700bpm, cKO hearts were deficient in HR-dependent improvement of cardiac contractility and relaxation, known as positive force frequency relationship, that was evident in WT hearts. Enhanced phosphorylation of phospholamban by the HR increase was markedly blunted in cKO myocardium vs wild types, while CaMKII phosphorylation was comparable between the genotypes, suggesting the critical involvement of PKA. These results provide the first experimental evidence for the role of ADRB1 in cardiomyocytes for maintaining cardiac function at baseline and during acute stress, providing clinical perspective relating to the management of patients on beta-blockers.

BACKGROUND: Chronic kidney disease (CKD) is on the rise, and over 50% of patients die from cardiac causes. Patients develop heart failure due to unelucidated reno-cardiac interactions, termed type 4 cardiorenal syndrome (CRS4). The aim of this study is to establish and characterize a reliable model of CRS4 in swine with marked cardiac diastolic dysfunction. METHODS: Yorkshire pigs (19.9±1.7 kg, 4 females and 5 males) underwent staged renal artery embolization using autologous clot. Echocardiogram, aortic pressure (AoP), renal angiogram, and blood samples were assessed monthly. At 4 months, animals were sacrificed after measuring glomerular filtration rate (GFR) and left ventricular (LV) pressure-volume parameters. Heart and kidneys were collected for post-mortem analyses. Size-matched swine (n=5; 43.7±9.8 kg) served as controls. RESULTS: After three dose-titrated renal embolization, serum creatinine (SCr) and AoP increased by week 10. At 4 months, SCr (2.03±0.45 vs 1.34±0.17 mg/dL, p=0.013) and AoP (158±16 vs 121±8 mmHg, p=0.001) were higher, and GFR was lower (12±3 vs 131±7 mL/min, p<0.001) than size-matched controls. While LV ejection fraction was similar, the slope of end-diastolic pressure-volume relationship was steeper in pigs after renal embolization (0.36±0.09 vs 0.17±0.06, p=0.003), indicating increased LV stiffness. LV mass index (2.73±0.19 vs 2.50±0.13 g/kg, p=0.043) and wall-thickness (11.4±0.8 vs 8.9±1.2 mm, p=0.003) increased. These were accompanied by histologically increased fibrosis, cardiomyocyte hypertrophy, and vascular rarefaction. CONCLUSIONS: Repeat titrated renal embolization resulted in a model that exhibits advanced CKD and cardiac abnormalities consistent with CRS4.

AIM: Estrogen exerts beneficial cardiovascular effects by binding to specific receptors on various cells to activate nuclear and non-nuclear actions. Estrogen receptor α (ERα) non-nuclear signaling confers protection against heart failure remodeling, involving myocardial cyclic guanosine monophosphate (cGMP) - cGMP-dependent protein kinase G (PKG) activation; however, its tissue-specific role remains elusive. Herein, we examined the cell type-specific role of ERα non-nuclear signaling in estrogen-conferred protection against heart failure. METHODS AND RESULTS: We first assessed the tissue-specific impacts of ERα in estrogen's cardiac benefits, utilizing endothelial ERα deletion (ERαf/f/Tie2Cre+) and myocyte ERα deletion (ERαf/f/αMHCCre+) female mice. Female mice were ovariectomized and the effect of estradiol (E2) was assessed in hearts exposed to 3week pressure-overload (TAC). E2 failed to improve cardiac function in ERαf/f/Tie2Cre+ TAC hearts but provided benefits in ERαf/f/αMHCCre+ TAC hearts, indicating that endothelial ERα is essential. We next assessed the role of non-nuclear signaling in endothelial cells, employing animals with endothelial-specific inactivation of ERα non-nuclear signaling (ERαKI/KI/Tie2Cre+). Female OVX mice were supplemented with E2 and subjected to 3-week TAC. ERαKI/KI/Tie2Cre+ TAC hearts revealed exacerbated cardiac dysfunction and reduced myocardial PKG activity as compared to littermate TAC hearts, which was associated with attenuated myocardial induction of vascular endothelial growth factor (VEGF) and angiogenesis as assessed with CD31-stained capillary density. This phenotype of ERαKI/KI/Tie2Cre+ was rescued by myocardial PKG activation from chronic treatment with soluble guanylate cyclase (sGC) stimulator. We performed co-culture experiments to determine endothelial-cardiomyocyte interactions. VEGF induction by E2 in cardiac myocytes required co-existence of intact endothelial ERα signaling in a NOS-dependent manner. On the other hand, VEGF was induced in myocytes directly with an sGC stimulator in the absence of endothelial cells. CONCLUSIONS: An endothelial estrogen - myocardial cGMP axis stimulates angiogenic response and improves cardiac performance during pressure-overload.