Inflammation as an exacerbation marker and target for prophylaxis against Coronavirus Disease 2019-related thrombosis.

Objectives: There are currently no appropriate markers and target for prophylaxis against COVID-19-related thrombosis, especially in the not-severe cases. We tested the hypothesis that inflammation is a suitable marker and target for prophylaxis against COVID-19-related thrombosis. Methods: Data of all 32 COVID-19 patients admitted to Saitama Medical Center between January 1 and March 30, 2021, were analyzed. Patients were divided into severe (requiring oxygen, n=12) and non-severe (no requirement for oxygen, n=20), and also those with high C-reactive protein (CRP) level (cutoff value: 30 mg/L, n=21) and low-CRP (n=11). We also compared the clinical and laboratory data of a 46-year-old post-liver transplant male patient, who was treated with a combination of immunosuppressants (methylprednisolone, fludrocortisone, cyclosporine, and everolimus) with those of other COVID-19 patients, using the Smirnoff-Grubbs and Box plots tests. Results: The levels of CRP, ferritin, lactate dehydrogenase, aspartate aminotransferase, and thrombin-antithrombin complex (TAT) were significantly higher in the high-severity group than the low-severity group; while other coagulation parameters were comparable. The time between onset of illness and blood levels of lactate dehydrogenase, fibrinogen, D-dimer, TAT, and plasmin alpha2-plasmin inhibitor complex (PIC) were significantly higher whereas lymphocyte count was significantly lower in the high-CRP group. Extremely low levels of TAT, PIC, and plasminogen activator inhibitor-1 (PAI-1) were recorded in the liver transplant patient treated with immunosuppressants. The TAT, PIC, and PAI-1 levels were deemed outliers. Conclusions: Inflammation is a potentially suitable marker and target for prophylaxis against COVID-19-related thrombosis.

Indoxyl Sulfate-induced Vascular Calcification is mediated through Altered Notch Signaling Pathway in Vascular Smooth Muscle Cells.

Introduction: The aim of this study was to determine the role of Notch in indoxyl sulfate (IS)-induced vascular calcification (VC). Materials and methods: VC and expression of Notch-related and osteogenic molecules were examined in Dahl salt-sensitive (DS), DS hypertensive (DH), and DH IS-treated rats (DH+IS). The effects of IS on expression of Notch receptors, apoptotic activity, and calcification were examined in cultured aortic smooth muscle cells (SMCs). Results: Medial calcification was noted only in aortas and coronary arteries of DH+IS rats. Notch1, Notch3, and Hes-1 were expressed in aortic SMCs of all rats, but only weakly in the central areas of the media and around the calcified lesions in DH+IS rats. RT-PCR and western blotting of DH+IS rat aortas showed downregulation of Notch ligands, Notch1 and Notch3, downstream transcriptional factors, and SM22, and conversely, overexpression of osteogenic markers. Expression of Notch1 and Notch3 in aortic SMCs was highest in incubation under 500 µM IS for 24hrs, and then decreased time- and dose-dependently. Coupled with this decrease, IS increased caspase 3/7 activity and TUNEL-positive aortic SMCs. In addition, pharmacological Notch signal inhibition with DAPT induced apoptosis in aortic SMCs. ZVAD, a caspase inhibitor abrogated IS-induced and DAPT-induced in vitro vascular calcification. Knockdown of Notch1 and Notch3 cooperatively increased expression of osteogenic transcriptional factors and decreased expression of SM22. Conclusion: Our results suggested that IS-induced VC is mediated through suppression of Notch activity in aortic SMCs, induction of osteogenic differentiation and apoptosis.

Assessment of abdominal aortic calcification by computed tomography for prediction of latent left ventricular stiffness and future cardiovascular risk in pre-dialysis patients with chronic kidney disease: A single center cross-sectional study.

Introduction: There is general interest in finding clinical markers for left ventricular diastolic dysfunction (LVDD), a major cause of cardiorenal syndrome leading to heart failure in chronic kidney disease (CKD) patients. The aim was to assess the utility of computed tomography (CT)-based abdominal aortic calcification (AAC) for the prediction of LVDD and prognosis of asymptomatic pre-dialysis CKD patients. Materials and methods: We prospectively evaluated 218 pre-dialysis CKD patients [median estimated glomerular filtration rate (eGFR); 40.9 mL/min/1.73m²]. Non-contrast CT scan and echocardiography were performed to determine the aortic calcification index (ACI) as a semi-quantitative measure of AAC. Results: The median ACI was 11.4. AAC and LVDD were diagnosed in 193 patients (89%) and 75 patients (34%), respectively. Using receiver operating characteristic curve analysis for the estimation of LVDD, ACI of 20 showed optimal sensitivity (52.0%) and specificity (62.8 %) (AUC = 0.664, p < .001). High ACI group included more patients with LVDD-related factors, such as old age, hypertension, diabetes, and more severe CKD. LVDD was significantly more common in patients with high ACI group [39 (50%) and 36 (26%), respectively, p<0.001]. Multivariate analysis showed that ACI correlated significantly with E/A (ß=-0.993, p=0.003), E/e' (ß=0.077, p<0.001), and cardio-ankle vascular index (ß=0.209, p=0.001). Correspondingly, E/e' correlated with logBNP and log(ACI+1), and increased proportionately and significantly with the quartiles of ACI values. Cox proportional hazard models showed that ACI was an independent predictor of CV outcome (hazard ratio 1.03, 95% confidence interval 1.00-1.06, p=0.029). Conclusion: The results would suggest the usefulness of AAC assessment by CT to predict latent LVDD and future CV risk in asymptomatic pre-dialysis CKD patients.

Angiotensin receptor blocker irbesartan reduces stress-induced intestinal inflammation via AT1a signaling and ACE2-dependent mechanism in mice.

Stress is associated with pathophysiology of both irritable bowel syndrome (IBS) and hypertension. Angiotensin receptor blockers (ARB) have anti-inflammatory properties via inhibition of angiotensin II (Ang II)/Ang II type I receptor axis (AT1). Inhibition of the classical RAS pathway is also involved in upregulation of angiotensin converting enzyme-2 (ACE2), which activates the Ang-(1-7)/Mas pathway to counteract inflammatory signaling and acts as a partner of the amino acid transporter, B0AT-1, to absorb tryptophan for regulation of microbiota-gut-brain axis. In this study, we determined the effects of ARB irbesartan on stress-induced intestinal inflammation. C57BL/6J mice were subjected to 2-week intermittent restraint stress. They were orally treated during the stress with either vehicle, 3 or 10 mg/kg/day irbesartan. Restraint stress resulted in colon inflammation with higher histological damage scores, increased expression of Nox4, TLR-4 and IL1-ß, accumulation of reactive oxygen species (ROS), and activation of the ACE-angiotensin II-AT1 receptor axis. Stress also downregulated intestinal amino acid transporter, ACE2/B0AT-1, and activity of intestinal mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K), resulting in decrease in α-defensins, changes in intestinal microbial contents, and perturbation of tryptophan metabolism with activation of the kynurenine pathway. Administration of irbesartan inhibited activation of stress-induced AT1 pathway to reduce intestinal ROS accumulation and inflammation, restored expression of ACE2/B0AT-1, activity of mTOR and p70S6K, dysbiosis and tryptophan metabolism. Our results suggest that AT1 is a potentially suitable therapeutic target in stress-induced intestinal inflammation, and that irbesartan could be beneficially suitable for the treatment of stressed patients with IBS.

Measurements of renal shear wave velocities in chronic kidney disease patients.

Background Chronic kidney disease (CKD) patients have advanced glomerulosclerosis and renal interstitial fibrosis. Shear wave elastography (SWE) is useful to diagnose liver fibrosis. However, there are few data available regarding evaluation of kidney function on the use of SWE. Purpose To assess the utility of SWE by evaluating the correlation between renal function and renal elasticity using SWE. Material and Methods A total of 187 participants who had available serum creatinine levels and also underwent SWE of the kidney using a transabdominal ultrasonography were recruited at Nagoya University Hospital. We measured the depth of the shear wave (SW) in the right and left kidneys and calculated the measurement success rates. The glomerular filtration rate (GFR) classification and shear wave value (SWV) were compared. Results The success rates of the right and left kidneys were 93.6% and 71.6%, respectively. Based on these results, the correlation between GFR classification and SWV were analyzed in only the right kidneys because the success rates and the number of enrolled patients were low for the left kidney. There were significant differences found between G1 and G3a, G2 and G3a, G3a and G3b, G3a and G4, and G3a and G5. SWV significantly negatively and positively correlated with the G2-G3a and G3a-G3b classifications. Conclusion There is no correlation between renal function and SW. However, we can diagnose the progression to the CKD stages G3a and G3b by observing the changes over time using the SWV.

Left ventricular hypertrophy and proteinuria in patients with essential hypertension in Andkhoy, Afghanistan.

Left ventricular hypertrophy (LVH) and proteinuria are known as independent predictors of cardiovascular death in hypertension. However, LVH and its association with proteinuria have not been investigated in adult hypertensive patients in Afghanistan. The objective of this research was to determine the prevalence of LVH and the correlation between LVH and proteinuria among the Afghan adult hypertensive population visiting an outpatient clinic in Afghanistan. We retrospectively evaluated 789 hypertensive patients (mean age is 56 years and 46% were men) who visited the clinic between December 2014 and August 2016. Patient characteristics and laboratory and clinical findings were recorded. The rate of LVH among hypertensive patients was 54.4%. Patients with proteinuria had a significantly higher LVH percentage compared to those without proteinuria (73.2% versus 55.8%; P<0.001). There was a significant correlation between LVH and proteinuria among hypertensive patients (r=0.182, P<0.001). Based on a multivariate regression analysis, age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02-1.05), proteinuria (OR, 1.69; 95% CI, 1.19-2.41), and female sex (OR, 0.09; 95% CI, 0.06-0.13) were significant factors. In conclusion, the prevalence of LVH was more than 50% in the Afghan adult hypertensive population. This study indicates that there is a significant relationship between LVH detected by ECG and the presence of proteinuria among such subjects.

Cathepsin S Activity Controls Injury-Related Vascular Repair in Mice via the TLR2-Mediated p38MAPK and PI3K-Akt/p-HDAC6 Signaling Pathway.

OBJECTIVE: Cathepsin S (CatS) participates in atherogenesis through several putative mechanisms. The ability of cathepsins to modify histone tail is likely to contribute to stem cell development. Histone deacetylase 6 (HDAC6) is required in modulating the proliferation and migration of various types of cancer cells. Here, we investigated the cross talk between CatS and HADC6 in injury-related vascular repair in mice. APPROACH AND RESULTS: Ligation injury to the carotid artery in mice increased the CatS expression, and CatS-deficient mice showed reduced neointimal formation in injured arteries. CatS deficiency decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and toll-like receptor 2 expression in ligated arteries. The genetic or pharmacological inhibition of CatS also alleviated the increased phosphorylation of p38 mitogen-activated protein kinase, Akt, and HDAC6 induced by platelet-derived growth factor BB in cultured vascular smooth muscle cells (VSMCs), and p38 mitogen-activated protein kinase inhibition and Akt inhibition decreased the phospho-HDAC6 levels. Moreover, CatS inhibition caused decrease in the levels of the HDAC6 activity in VSMCs in response to platelet-derived growth factor BB. The HDAC6 inhibitor tubastatin A downregulated platelet-derived growth factor-induced VSMC proliferation and migration, whereas HDAC6 overexpression exerted the opposite effect. Tubastatin A also decreased the intimal VSMC proliferation and neointimal hyperplasia in response to injury. Toll-like receptor 2 silencing decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and VSMC migration and proliferation. CONCLUSIONS: This is the first report detailing cross-interaction between toll-like receptor 2-mediated CatS and HDAC6 during injury-related vascular repair. These data suggest that CatS/HDAC6 could be a potential therapeutic target for the control of vascular diseases that are involved in neointimal lesion formation.

Midkine Promotes Atherosclerotic Plaque Formation Through Its Pro-Inflammatory, Angiogenic and Anti-Apoptotic Functions in Apolipoprotein E-Knockout Mice.

BACKGROUND: A recent study suggested that midkine (MK), a heparin-binding growth factor, is associated with atherosclerosis progression in patients with artery disease. It has previously been reported that MK plays a critical role in neointima formation in a restenosis model, whereas the role of MK in the development of atherosclerosis has not been investigated. The present study assessed the effect of MK administration on the process of atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE-/-) mice.Methods and Results:Using an osmotic pump, human recombinant MK protein was intraperitoneally administered for 12 weeks in C57BL/6 ApoE-/-(ApoE-/--MK) and ApoE+/+mice fed a high-fat diet. Saline was administered to the control groups of ApoE-/-(ApoE-/--saline) and ApoE+/+mice. The atherosclerotic lesion areas in longitudinal aortic sections were significantly larger in ApoE-/--MK mice than in ApoE-/--saline mice. The aortic mRNA levels of pro-inflammatory and angiogenic factors, and the percentage of macrophages in aortic root lesions, were significantly higher in ApoE-/--MK mice than in ApoE-/--saline mice, whereas the percentage of apoptotic cells was significantly lower in ApoE-/--MK mice than in ApoE-/--saline mice. CONCLUSIONS: The systemic administration of MK in ApoE-/-mice promoted atherosclerotic plaque formation through pro-inflammatory, angiogenic, and anti-apoptotic effects. MK may serve as a potential therapeutic target for the prevention of atherosclerosis under atherogenic conditions.

Biphasic Force-Frequency Relation Predicts Primary Cardiac Events in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: The force-frequency relation (FFR) is a hemodynamic index of the chronotropic relationship between left ventricular (LV) systolic function (percent change in dP/dtmax) and elevation of heart rate. FFR is a marker of myocardial contractile reserve and follows an upward slope in healthy myocardium [monophasic FFR (MoF)], a pattern that becomes biphasic (BiF) under pathological conditions. However, it remains uncertain whether the FFR determines a patient's prognosis. We investigated the promising role of the FFR as a predictor of cardiac events in the setting of hypertrophic cardiomyopathy (HCM).Methods and Results:A total of 113 consecutive patients with HCM (New York Heart Association (NYHA) class I-II) were retrospectively evaluated; 27 (23.9%) had a BiF pattern and they experienced a higher incidence of cardiac events compared with those showing an MoF pattern (median follow-up, 4.7 years; P<0.001). Furthermore, Cox proportional hazard regression analysis revealed that the LV end-diastolic volume index (hazard ratio: 1.051, P=0.014) and BiF pattern (hazard ratio: 15.260, P=0.001) were independent predictors of primary cardiac events. Interestingly, abnormal reductions in myocardial regulatory molecules related to contractility (SERCA2α) were observed exclusively in the patients exhibiting a BiF pattern. CONCLUSIONS: The FFR reflects latent myocardial abnormalities and predicts cardiac events in the setting of HCM, even during the asymptomatic stages of the disease.

Abnormal Circadian Blood Pressure Profile as a Prognostic Marker in Patients with Nonischemic Dilated Cardiomyopathy.

OBJECTIVES: An abnormal circadian blood pressure (BP) profile is considered a risk factor for cardiovascular disease. However, its significance in heart failure patients with nonischemic etiology is unknown. Herein, we investigated the prognostic value of a circadian BP profile in patients with nonischemic dilated cardiomyopathy (NIDCM). METHODS: We enrolled 114 NIDCM patients (76 males, mean age 53.1 years). The percent nighttime BP fall (%NBPF) was defined using ambulatory BP monitoring as a percent decrease in mean systolic BP in nighttime from daytime. All patients were divided into three groups: dipper (%NBPF ≥10), non-dipper (0 ≤ %NBPF < 10), and riser (%NBPF <0). RESULTS: Riser patients had the highest serum creatinine levels (dipper, 0.78 ± 0.20 mg/dl; non-dipper, 0.85 ± 0.21 mg/dl; riser, 0.99 ± 0.23 mg/dl; p = 0.006). In survival analysis, riser patients had the highest cumulative cardiac-related deaths (log-rank, p = 0.001), which was an independent predictor of cardiac-related deaths (hazard ratio, 12.6; 95% confidence interval, 1.76-253; p = 0.01). Multivariate analysis revealed that the norepinephrine level at 24-hour collected urine (24 h U-NE) and the serum creatinine level were independent determinants of %NBPF (adjusted R2 = 0.20; 24 h U-NE, p = 0.0001; serum creatinine, p = 0.04). CONCLUSIONS: The riser profile was associated with poor prognosis of NIDCM, which may reflect impaired sympathetic nervous system activity. Evaluating the circadian BP profile may be useful for risk stratification in NIDCM patients.

Sokolow-Lyon voltage is suitable for monitoring improvement in cardiac function and prognosis of patients with idiopathic dilated cardiomyopathy.

BACKGROUND: The clinical significance of electrocardiogram in the assessment of patients with idiopathic dilated cardiomyopathy (IDCM) is currently unknown. The aim of this study was to determine the feasibility of recording serial changes in Sokolow-Lyon voltage (∆%QRS-voltage) in one year to estimate left ventricular reverse remodeling (LVRR) and predict a prognosis of IDCM patients under tailored medical therapy. METHODS: Sixty-eight consecutive patients with mild symptoms (52.1 ± 13 years old; 69% men; NYHA I/II/III/IV; 33/29/6/0) underwent electrocardiography and echocardiography at baseline and 12 month follow-up (follow-up period: 3.9 years). RESULTS: LVRR was observed in 30 patients (44.1%). The ∆%QRS-voltage was significantly lower in the LVRR group (LVRR; -26.9%, non-LVRR: -9.2%, p < .001). Univariate analysis showed that ∆%QRS-voltage correlated with ∆%LV end-diastolic diameter (r = .634, p < .001), and with ∆%LV ejection fraction and ∆%LV mass index (r = -.412, p < .001; r = .429, p < .001 respectively). Using receiver operating characteristic curve analysis for the estimation of LVRR, ∆%QRS of -14.7% showed optimal sensitivity (63.2%) and specificity (83.3%) (AUC = 0.775, p < .001). The composite endpoints of cardiac death (n = 0), hospitalization for advanced heart failure (n = 11) and fatal arrhythmia (n = 2) were observed in 13 patients during the follow-up period. Kaplan-Meier analysis showed significantly higher event-free rate in patients of the low ∆%QRS-voltage group (<-14.7%) (83%) than those of the high group (66%, p = .022). CONCLUSIONS: The present study showed that decrease in Sokolow-Lyon voltage is associated with improvement in cardiac function and favorable prognosis in IDCM patients on medical therapy, suggesting that this index is a feasible marker for response to treatment of IDCM.

Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells.

Indoxyl sulfate (IS) induces fibrosis and inflammation in kidneys via oxidative stress through the induction of transforming growth factor-ß1 (TGF-ß1) and monocyte chemotactic protein-1 (MCP-1). Furthermore, IS is a potent endogenous agonist for aryl hydrocarbon receptor (AHR), which regulates the transcription of genes such as cytochrome P450 (CYP) 1A1. Indole-3-propionic acid (IPA) is an antioxidant and has been reported to be neuroprotective. We determined whether IPA suppresses IS-induced expression of AHR, CYP1A1, TGF-ß1, and MCP-1 in proximal tubular cells. The effects of IS on the expression of AHR, CYP1A1, TGF-ß1, and MCP-1 were studied using normotensive rats and hypertensive rats. The effects of IPA on IS-induced expression of AHR, CYP1A1, TGF-ß1, and MCP-1 were studied using proximal tubular cells (HK-2). Furthermore, the effects of IPA on IS-induced expression and phosphorylation of signal transducer and activator of transcription 3 (Stat3) were studied in HK-2 cells. Administration of IS induced the expression of AHR, CYP1A1, TGF-ß1, and MCP-1 in the tubular cells of rat kidneys. IPA significantly suppressed IS-induced mRNA and protein expression of AHR, CYP1A1, TGF-ß1, and MCP-1 in HK-2 cells. IPA suppressed the IS-induced expression and phosphorylation of Stat3 in HK-2 cells. Furthermore, knockdown of Stat3 inhibited the IS-induced mRNA and protein expression of AHR, CYP1A1, TGF-ß1, and MCP-1 in HK-2 cells. In conclusion, IPA suppressed the IS-induced expression of AHR, CYP1A1, TGF-ß1, and MCP-1 through suppression of Stat3 in proximal tubular cells. Thus, IPA suppresses IS-induced expression of fibrotic and inflammatory genes in proximal tubular cells.

Cardiopulmonary Exercise Testing as a Tool for Diagnosing Pulmonary Hypertension in Patients with Dilated Cardiomyopathy.

BACKGROUND: Recently, it has become increasingly recognized that pulmonary hypertension (PH) is a particularly threatening result of left-sided heart disease. However, there have been few investigations of the impact of cardiopulmonary exercise testing (CPX) variables on PH in dilated cardiomyopathy (DCM). We evaluated the usefulness of crucial CPX variables for detecting elevated pulmonary arterial pressure (PAP) in patients with DCM. METHODS: Ninety subjects with DCM underwent cardiac catheterization and CPX at our hospital. Receiver operator characteristic (ROC) analysis was performed to assess the ability of CPX variables to distinguish between the presence and absence of PH. RESULTS: Overall mean values were: mean PAP (mPAP), 18.0 ± 9.6 mmHg; plasma brain natriuretic peptide, 233 ± 295 pg/mL; and left ventricular ejection fraction, 30.2 ± 11.0%. Patients were allocated to one of two groups on the basis of mean PAP, namely DCM without PH [mean PAP (mPAP) <25 mmHg; n = 75] and DCM with PH (mPAP ≥25 mmHg; n = 15). A cutoff achieved percentage of predicted peak VO2 (%PPeak VO2 ) of 52.5% was the best predictor of an mPAP ≥25 mmHg in the ROC analysis (area under curve: 0.911). In the multivariate analysis, %PPeak VO2 was the only significant independent predictor of PH (Wald 6.52, odds ratio 0.892, 95% CI 0.818-0.974; P = 0.011). CONCLUSIONS: %PPeak VO2 was strongly associated with the presence of PH in patients with DCM. Taken together, these findings indicate that CPX variables could be important for diagnosing PH in patients with DCM.

Associations between proteinuria and cardiovascular risk factors among hypertensive patients in Andkhoy, Afghanistan.

Proteinuria in hypertension is an early marker of renal disease and a predictor for the progression of end stage renal disease, and cardiovascular diseases. This study was designed to determine the prevalence of proteinuria and its association with cardiovascular risk factors among adult hypertensive patients in Afghanistan. Five hundred fifty-five patients with a high blood pressure recorded in an outpatient clinic in Andkhoy, Afghanistan from December 2014 to May 2015, were included in this study. Data obtained from each patient, included demographic characteristics, body mass index, blood pressure patterns, cardiovascular history, cardiovascular risk factors, comorbidity, and current drug-therapy. Dipstick screening for proteinuria was performed with reagent test strips. The mean age of the patients was 57.9 ± 13.3 years, and a female predominance was observed (n = 333, 60%). The prevalence of proteinuria was 67.2%. The predictors of proteinuria were found to be age ≥65 years (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00-1.04), smoking (OR 1.88, 95% CI 1.17-3.02), heart failure (OR 2.23, 95% CI 1.13-4.41), and diabetes mellitus (OR 3.41, 95% CI 1.49-7.81). In conclusion, this study shows that proteinuria is highly prevalent among hypertensive outpatients in an outpatient clinic in Andkhoy, Afghanistan, especially in those with high cardiovascular risk.

Impact of airflow limitation on carotid atherosclerosis in coronary artery disease patients.

BACKGROUND: Both airflow limitation and smoking are established cardiovascular risk factors. However, their interaction as risk factors for the development of atherosclerosis in coronary artery disease patients remains unclear. OBJECTIVES: To evaluate the effect of the interaction between airflow limitation and smoking status on the severity of carotid atherosclerosis. METHODS: We categorized the 234 enrolled patients with coronary artery disease into four groups: never-smokers with normal pulmonary function (group A), never-smokers with airflow limitation (group B), ever-smokers with normal pulmonary function (group C), and ever-smokers with airflow limitation (group D). RESULTS: The prevalence of airflow limitation in the enrolled patients was 23.1% (ever-smokers: 15.8%, never-smokers: 7.3%). The prevalence of severe carotid atherosclerosis was 28.2, 29.4, 41.3, and 45.9%, respectively, in the four groups (group D vs. group A, p = 0.035). Even after multivariate adjusting for confounding factors, ever-smokers with airflow limitation were independently associated with severe carotid atherosclerosis (odds ratio 2.89, 95% confidence interval, 1.19-7.00, p = 0.019). CONCLUSIONS: Ever-smokers with airflow limitation were significantly associated with severe carotid atherosclerosis among patients with coronary artery disease. These findings also provide additional insight into the correlation between airflow limitation and poor cardiovascular clinical outcomes.

Impact of Admission Anemia on Coronary Microcirculation and Clinical Outcomes in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Microvascular dysfunction after primary percutaneous coronary intervention (PCI) augments myocardial damage and prognosis in acute myocardial infarction. However, the relationship between baseline anemia and coronary microcirculation in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. We performed primary PCI in 337 consecutive patients with STEMI. Anemia was defined as a hemoglobin level < 13 g/dL in men and < 12 g/dL in women. Admission anemia was present in 17.5% of the patients enrolled. Data on epicardial coronary flow, STsegment resolution (STR) on electrocardiography, myocardial injury, and the incidence of adverse cardiac events defined as cardiac death or hospitalization for congestive heart failure were analyzed. The median follow-up period was 54.8 months. Despite comparable epicardial coronary flow, the rate of STR ≥ 50% was lower in anemic patients compared with non-anemic patients (55.9% versus 71.2%, P = 0.02). On multivariate logistic regression analysis, baseline anemia was an independent negative predictor of STR ≥ 50% (odds ratio, 0.53; 95% confidence interval: 0.31-0.92, P = 0.03). Moreover, anemic patients had higher maximum creatine kinase levels normalized for body surface area (2,215 ± 1,318 IU/L/m(2) versus 1,797 ± 1,199 IU/L/m(2), P = 0.047). Anemia remained an independent significant predictor of adverse events on multivariate Cox proportional hazard analysis (hazard ratio, 2.34; 95% confidence interval: 1.01-5.64, P = 0.048). In conclusion, admission anemia was related to microcirculatory dysfunction and poor prognosis in patients with STEMI. The decreased oxygen delivery might exacerbate microvascular function.

Plasminogen activator inhibitor-1 in aging.

Plasminogen activator inhibitor-1 (PAI-1), a principal inhibitor of fibrinolysis, is induced in thrombotic, fibrotic, and cardiovascular diseases, which in turn primarily afflict the older population. This induction of PAI-1 may play an important role in the pathology of these diseases as PAI-1 can regulate the dissolution of fibrin and also inhibit the degradation of the extracellular matrix by reducing plasmin generation. PAI-1 expression is elevated in aged individuals and is significantly upregulated in a variety of pathologies associated with the process of aging, including myocardial and cerebral infarction, vascular (athero) sclerosis, cardiac and lung fibrosis, metabolic syndromes (e.g., hypertension, hyperlipidemia, and insulin resistance), cancer, and inflammatory/stress responses. Thus, PAI-1 may play a critical role in the development of aging-associated pathological changes. In addition, PAI-1 is recognized as a marker of senescence and a key member of a group of proteins collectively known as the senescence-messaging secretome. In this review, we highlight the role of PAI-1 in the pathophysiology of aging and aging-associated disorders.

Prognostic impact of combined late gadolinium enhancement on cardiovascular magnetic resonance and peak oxygen consumption in ambulatory patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Peak oxygen consumption (peak VO2) and late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) are prognostic in heart failure. We investigated whether LGE-CMR and peak VO2combined had additive value in risk stratifying patients with nonischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: Fifty-seven DCM patients underwent CMR and cardiopulmonary exercise testing. Cardiac events were cardiac death, hospitalization for decompensated heart failure, or lethal arrhythmia. Twenty-five (44%) were LGE-positive. The median peak VO2was 18.5 mL·kg(-1)·min(-1). On multivariate analysis, positive LGE (P = .048) and peak VO2(P = .003) were independent cardiac event predictors. Cardiac event risk was significantly higher with positive LGE and peak VO2< 18.5 mL ·kg⁻¹ ·min⁻¹ than with negative LGE and peak VO2≥ 18.5 mL · kg⁻¹ · min⁻¹ (hazard ratio 12.5; 95% CI 1.57-100; P = .017). In 3 patient groups (group A: no LGE, peak VO2≥ 18.5 mL · kg⁻¹ · min⁻¹, n = 18; group B: positive LGE or peak VO2< 18.5 mL · kg⁻¹ · min⁻¹, n = 24; group C: positive LGE and peak VO2< 18.5 mL · kg⁻¹ · min⁻¹, n = 15) during follow-up (71 ± 32 months), group C had higher cardiac event rates than the others. CONCLUSIONS: Combined assessment of LGE-CMR and peak VO2provides additive prognostic information in ambulatory DCM.

Efficacy and safety of radiofrequency catheter ablation for atrial fibrillation in chronic hemodialysis patients.

BACKGROUND: Radiofrequency catheter ablation (RFCA) is increasingly performed for the treatment of atrial fibrillation (AF), but it is problematic because the use of anti-arrhythmic agents is largely restricted in patients undergoing hemodialysis (HD) therapy. However, little is known about the long-term clinical outcomes of AF after RFCA in HD patients. METHODS: Between 2002 and 2008, 16 HD patients (age: 63.8 ± 7.4 years, 75.0% men) underwent RFCA for AF at the Toyota Kosei Hospital. We investigated the long-term results and mortality of RFCA for AF in HD patients and compared them with those of 111 non-HD patients (age: 58.6 ± 10.0 years, 78.3% male) who received the same procedures. RESULTS: During the follow-up (64.3 ± 25.4 months in HD patients, 70.5 ± 20.2 months in non-HD patients) after the initial RFCA procedure, sinus rhythm was restored in 4 HD patients (25%) and in 45 non-HD patients (40.5%). Multiple procedures were performed in 12 HD patients and in 57 non-HD patients. After the final procedure, 13 HD patients (81.3%) and 92 non-HD patients (82.9%) were free of atrial arrhythmia and symptoms. Of importance, Kaplan-Meier analysis did not demonstrate any significant differences in the atrial arrhythmia-free rate after the last procedure between HD patients and the control group matched after propensity-score analysis despite higher all-cause mortality in HD patients than in non-HD patients. CONCLUSIONS: During 5-years of follow-up, the use of multiple RFCA procedures for AF in patients undergoing HD was favorable, whereas the use of a single procedure was disappointing. Multiple RFCA procedures can be an efficient approach to the treatment of AF in HD patients.