Marfan syndrome (MFS) is a systemic connective tissue disorder that is caused by mutations in the extracellular matrix protein fibrillin-1. While MFS patients are considered to be at high risk of dental disorders and cardiovascular complications, little causal relationship has been provided to date. It is well known that an elevated level of active TGF-β in the plasma is a major manifestation of MFS. TGF-β is known to play a critical role in the development of cardiovascular diseases and its levels were also elevated in the serum and saliva of periodontitis patients. These findings may suggest an association between periodontitis and the cardiovascular complications of MFS. In this article, we review the influence of periodontitis in MFS patients with cardiovascular complications in order to identify critical therapeutic targets of TGF-β.
In 1986, endothelial function was measured for the first time in patients with atherosclerotic coronary arteries. Since then, several methods for assessment of endothelial function, such as endothelium-dependent vasodilation induced by intra-arterial infusion of vasoactive agents using coronary angiography, Doppler flow guide wire, mercury-filled Silastic strain-gauge plethysmography, flow-mediated vasodilation, reactive hyperemia-peripheral arterial tonometry, and vascular response using an oscillometric method have been performed in humans. This review focuses on the assessment of endothelial function, including measurement history, methodological issues, and clinical perspectives.
The vasopressin receptor 2 (V2) receptor antagonist tolvaptan is an aquaretic agent that has been found to improve symptoms in patients with congestive heart failure. In this study (SMILE study), we administered tolvaptan to patients aged ≥ 80 years with heart failure accompanied by congestive symptoms and compared its effectiveness and safety profiles in this group with those in patients < 80 years (U-80). The results showed that the effectiveness of tolvaptan in the aged patients was similar to that in U-80 patients. In the safety profile, the incidence rate of thirst was lower in the aged patients than that in U-80 patients (9.6% versus 11.6%, P = 0.0023). Furthermore, the incidence of hypernatremia, defined as ≥ 150 mEq/L in aged patients, was comparable with that in U-80 patients (2.9% versus 3.6%, respectively, P = 0.3657). Based on these findings, tolvaptan has similar effectiveness and safety profiles in aged patients compared with U-80 patients. In addition, we found that a higher starting dose of tolvaptan was markedly associated with the occurrence of hypernatremia exclusively in the aged population; therefore, we recommend that tolvaptan should be started at lower doses in aged patients.
Low cardiac output syndrome (LCOS) is one of the most important complications following coronary artery bypass grafting (CABG) and results in higher morbidity and mortality. However, few reports have focused on the predictors of LCOS following CABG. This study aimed to evaluate the predictors of LCOS following isolated CABG through the review of 1524 consecutive well-documented patients in a single center, retrospective trial. The relevant preoperative and intraoperative data of patients with complete information from medical records undergoing isolated CABG from January 2010 to December 2013 in our center were investigated and retrospectively analyzed. LCOS was considered when the following criteria were met: signs of impairment of body perfusion and need for inotropic support with vasoactive drugs or mechanical circulatory support with an intra-aortic balloon pump to maintain systolic blood pressure greater than 90 mmHg. LCOS developed in 205 patients following CABG, accounting for 13.5% of the total population. The in-hospital mortality in the LCOS group was significantly higher than that in the non-LCOS group (25.4% versus 1.8%, P < 0.0001). In addition to the length of ICU stay and postoperative hospital stay, LCOS was correlated with negative cerebral, respiratory and renal outcomes. Through univariate analysis and then logistic regression analysis, the predictors of LCOS following CABG included older age (age > 65 years) (OR = 1.85, 95%CI 1.27-3.76), impaired left ventricular function (OR = 2.05, 95%CI 1.53-4.54), on-pump CABG (OR = 2.16, 95%CI 1.53-4.86), emergent CPB (OR = 9.15, 95%CI 3.84-16.49), and incomplete revascularization (OR = 2.62, 95%CI 1.79-5.15). LCOS following isolated CABG caused higher mortality, higher rates of morbidity, and longer ICU and postoperative hospital stays. Older age, impaired left ventricular function, on-pump CABG, emergent CPB, and incomplete revascularization were identified as 5 predictors of LCOS following isolated CABG surgery.
Coronary intraplaque hemorrhage up-regulates hemoglobin scavenger receptor CD163 expression on macrophages, and has an association with vulnerable plaque development. During percutaneous coronary intervention, mechanical plaque disruption exposes potentially embolic atheromatous contents from culprit plaque. In 37 patients with stable angina pectoris (SAP, n = 20) or acute coronary syndrome (ACS, n = 17), atherothrombotic debris was collected using a filter-based distal embolic protection device. We immunohistochemically determined CD14-positive macrophages and CD163-positive macrophages in filtered debris. We also examined the relation of CD14- and CD163-positive macrophages with culprit plaque volume and components evaluated with ultrasonic tissue characterization (VH-IVUS). The only significant difference in clinical characteristics between the two groups was in hs-CRP. In ACS, the percentage of CD14- and CD163-positive macrophages to the whole cells (%CD14 and %CD163, respectively) was significantly higher than that in SAP (20.1 ± 8.2 versus 8.8 ± 6.8%, P < 0.001 and 32.6 ± 18.9 versus 9.0 ± 3.8%, P < 0.001, respectively). In IVUS indices of culprit plaque, the remodeling index was significantly higher in ACS than in SAP. However, necrotic core component (%NC) in ACS was significantly higher than that in SAP. Furthermore, fibrotic component (%Fibrous) in ACS was significantly lower than that in SAP (56.1 ± 4.7 versus 60.1 ± 3.3%, P = 0.03). %CD14 and %CD163 had a significant positive correlation with %NC (%CD14: r = 0.40, P = 0.01 and %CD163: r = 0.45, P = 0.01), but only %CD163 was negatively correlated with %Fibrous (%CD163: r = −0.48, P = 0.01). These findings suggest that the presence of CD14- and CD163-positive macrophages may reflect plaque inflammation, NC expansion, and plaque vulnerability in patients with coronary heart disease.
Virtual histology intravascular ultrasound (VH-IVUS) was employed to compare coronary plaque characteristics between acute coronary syndrome (ACS) patients with and without subsequent coronary events. It is critical to predict subsequent coronary events in patients treated for ACS. Coronary artery events sometimes occur in lesions that do not receive intervention. VH-IVUS was performed in 57 patients with ACS to analyze 83 non-culprit lesions. Characteristics of plaques in the non-culprit lesions were determined. Patients were followed-up for 4.8 ± 1.8 years. During the follow-up period, ACS and stable angina pectoris occurred in 7 patients in whom 13 non-culprit lesions had been analyzed. Seventy non-culprit lesions in 50 patients who did not experience subsequent coronary events were also analyzed. Plaque area was greater in 7 patients who had subsequent coronary events than in those who did not (11.5 ± 3.1 versus 9.1 ± 3.6 mm3/mm, P = 0.03). However, there was no significant difference in plaque burden between the two groups (57.1 ± 8.9 versus 55.6 ± 8.7%, P = 0.18). Areas of dense calcium (DC) and necrotic core (NC) were greater in patients who had subsequent coronary events than in those who did not (0.6 ± 0.5 versus 0.2 ± 0.3 mm3/mm, P < 0.001, and 1.8 ± 1.0 versus 1.0 ± 0.8 mm3/mm, P < 0.01, respectively). When DC area was larger (≥ 3.4% of the plaque area), the cumulative coronary event rate increased significantly (28.6 versus 6.5%, P < 0.01). This was also true for NC area (≥ 20.9%, 31.4 versus 5.1%, P < 0.01). Area size of DC or NC in non-culprit plaques may be associated with subsequent coronary events in patients with ACS.
To determine the number and function of naturally occurring CD4+CD25+FOXP3+ regulatory T cells (nTregs) in patients with acute coronary syndrome (ACS) and to determine the effects of a low dose of atorvastatin treatment (20 mg/day) on nTregs. Patients with ACS were randomly divided into a group receiving conventional therapy (n = 60) or conventional therapy supplemented with atorvastatin (20 mg/day) (n = 60). A group of healthy volunteers that did not suffer from ACS was used as controls (n = 60). T lymphocytes were isolated from ACS patients, both before and 4 weeks after treatment, or control patients and the percentage of nTregs was determined by flow cytometry. Serum levels of cytokines were determined by enzyme-linked immunosorbent assays. A mixed lymphocyte reaction was used to determine the ability of nTregs to inhibit proliferation of effector T cells. Quantitative PCR and Western blot were used to analyze (forkhead box P3) FOXP3 mRNA transcript levels and the expression of FOXP3 protein. In ACS patients, the percentage and inhibitory properties of nTregs were reduced, IFN-γ and hsCRP levels were increased, and IL-10 and TGF-β1 levels were lowered. Atorvastatin treatment increased the percentage and inhibitory ability of nTregs, decreased serum IFN-γ and hsCRP levels, and decreased IL-10 and TGF-β1 levels, as compared with the non-atorvastatin group. Our findings suggest that nTregs play an atheroprotective role in atherosclerosis. The inhibitory effects of atorvastatin on inflammation in ACS may be due to its beneficial effects on nTregs and restoration of immune homeostasis.
Early reperfusion by percutaneous coronary intervention (PCI) is the current standard therapy for ST-elevation myocardial infarction (STEMI). To achieve better prognoses for these patients, reducing the door-to-balloon time is essential. As we reported previously, the Kitasato University Hospital Doctor Car (DC), an ambulance with a physician on board, is equipped with a novel mobile cloud 12-lead ECG system. Between September 2011 and August 2013, there were 260 emergency dispatches of our Doctor Car, of which 55 were for suspected acute myocardial infarction with chest pain and cold sweat. Among these 55 calls, 32 patients received emergent PCI due to STEMI (DC Group). We compared their data with those of 76 STEMI patients who were transported directly to our hospital by ambulance around the same period (Non-DC Group). There were no differences in patient age, gender, underlying diseases, or Killip classification between the two groups. The door-to-balloon time in the DC group was 56.1 ± 13.7 minutes and 74.0 ± 14.1 minutes in the Non-DC Group (P < 0.0001). Maximum levels of CPK were 2899 ± 308 and 2876 ± 269 IU/L (P = 0.703), and those of CK-MB were 292 ± 360 and 295 ± 284 ng/mL (P = 0.423), respectively, in the 2 groups. The Doctor Car system with the Mobile Cloud ECG was useful for reducing the door-to-balloon time.
Serial endomyocardial biopsies (EMBs) are scheduled even several years after heart transplantation (HTx) to monitor for late rejection (LR). However, repeated EMBs are associated with an increased risk for fatal complications and decrease the quality of life of the recipient. We retrospectively analyzed clinical data from 42 adult recipients who had received HTx and were followed > 1 year at the University of Tokyo Hospital. Five recipients experienced LR at 1130 ± 157 days after HTx, and all 5 had experienced acute cellular rejection (ACR) with ISHLT grade ≥ 2R within the first year, which was treated with methylprednisolone pulse therapy (sensitivity, 1.000; specificity, 0.7027). Logistic regression analyses demonstrated that positive panel reactive antibody (PRA) was the only significant predictor for LR among all parameters at 1 year after HTx (P = 0.020, odds ratio 24.00). Among the 5 recipients with LR, LR occurred earlier in the two PRA positive recipients than in those with a negative PRA (981 ± 12 versus 1230 ± 110 days, P = 0.042). Among the perioperative parameters, gender mismatch [n = 13 (31%)] was the only significant predictor for ACR within the first year in logistic regression analyses (P = 0.042, odds ratio 4.200). In conclusion, the current schedule of serial EMBs should perhaps be reconsidered for recipients without any history of ACR within the first year due to their lower risk of LR.
Although sympathetic reinnervation is accompanied by the improvement of exercise tolerability during the first years after heart transplantation (HTx), little is known about parasympathetic reinnervation and its clinical impact. We enrolled 21 recipients (40 ± 16 years, 71% male) who had received successive cardiopulmonary exercise testing at 6 months, and 1 and 2 years after HTx. Exercise parameters such as peak oxygen consumption or achieved maximum load remained unchanged, whereas recovery parameters including heart rate (HR) recovery during 2 minutes and the delay of peak HR, which are influenced by parasympathetic activity, improved significantly during post-HTx 2 years (P < 0.05 for both). HR variability was analysed at post-HTx 6 months in 18 recipients, and high frequency power, representing parasympathetic activity, was significantly associated with the 2 recovery parameters (P < 0.05 for all). We also assessed quality of life using the Minnesota Living with Heart Failure (HF) Questionnaire at post-HTx 6 months and 2 years in the same 18 recipients, and those with improved recovery parameters enjoyed a better HF-specific quality of life (P < 0.05 for both). In conclusion, parasympathetic reinnervation emerges along with improved post-exercise recovery ability of HR and quality of life during post-HTx 2 years.
Cardiovascular complications are the main cause of morbidity and mortality in peritoneal dialysis (PD) patients. Left ventricular hypertrophy (LVH) is a major predictor of the development of cardiovascular events. This study aimed to identify risk factors that contribute to the development of LVH and to determine their cutoffs in patients on maintenance peritoneal dialysis. In this cross sectional study we evaluated the association of 23 variables including age, PD vintage, ultrafiltration, urine volume, residual renal function, mean daily SBP, mean daily DBP, fasting glucose, HbA1c, peritoneal glucose load index (PGLI), fluid overload (FO), plasma brain natriuretic peptide (BNP), plasma hsCRP and IL-6, serum albumin, white blood cell (WBC) count, hemoglobin, hematocrit, triglycerides, LDL-C (low density lipoprotein cholesterol), HDL-C (high density lipoprotein cholesterol), and PTH with LVH in 38 stable patients on maintenance PD ≥ 24 months. LVH was detected in 57.9% of patients. Logistic regression and receiver operating characteristics (ROC) analysis revealed that HbA1c, PGLI, FO, plasma BNP, hsCRP and IL-6 seem to be possible predictors of LVH. The cutoffs associated with the presence of LVH were: 7.5%, 3.2 g/kg/day, 1.7 L, 330 pg/mL, 7.5 mg/dL and 3.3 pg/mL for HbA1c, PGLI, FO, plasma BNP, hsCRP and IL-6, respectively (sensitivity 72.8 to 81.8% and specificity 75.0 to 93.8%). The results suggest that efforts should be made to reduce the peritoneal glucose load (PGL), to improve the hydration status, and to attenuate the inflammatory process in order to reduce the risk of the development of LVH among PD patients.
Restrictive fluid intake is recommended, in addition to standard pharmacologic treatment, in the treatment of patients with chronic heart failure (CHF). However, this recommendation lacks firm scientific evidence. We conducted a systematic review and meta-analysis of published randomized controlled trials to estimate the effect of fluid restriction in patients with heart failure. Randomized controlled trials were identified in the MEDLINE, EMBASE, and Cochrane databases using the search-keywords “fluid” and “heart failure”. Outcomes were compared in heart failure patients with liberal and restricted fluid intake. Pooled risk ratios (RR) and weighted mean differences (WMD) were calculated using random effects models. Studies focusing on decompensated heart failure were analyzed separately. Six small randomized trials comparing liberal and restricted fluid intake met the inclusion criteria. Significant heterogeneity was noted in the reported studies for several outcomes. There were no differences in readmission rate (5 studies, pooled RR = 1.32; 95% CI: 0.86 to 2.01; P = 0.2), mortality rate (5 studies, pooled RR = 1.50; 95% CI: 0.87 to 2.57; P = 0.14), perceived thirst (4 studies, WMD = -0.7; 95% CI: -2.58 to 1.17; P = 0.46), duration of intravenous diuretics (2 studies, WMD = 0.17; 95% CI: -1.26 to 1.6; P = 0.81) or serum sodium levels (WMD = -1.61; 95% CI: -3.28 to 0.07; P = 0.06) between the liberal fluid intake group and the restrictive fluid intake group. Mean serum creatinine and BNP levels were significantly higher in the liberal fluid group: WMD 0.20 (95% CI: 0.15 to 0.25; P < 0.00001) and 172.59 (95% CI: 67.38 to 277.8; P = 0.001), respectively. There was no difference in any of the outcomes after correcting for heterogeneity. While studies to date are limited by heterogeneity and small sample sizes, the combined data suggest similar clinical outcomes in patients with CHF managed with liberal and restrictive fluid intake. Larger studies are needed to confirm our findings.
Obesity and the metabolic syndrome (MetS) are risk factors for left ventricular diastolic dysfunction (LVDD). However, little is known about the impact of successful weight reduction (WR) on diastolic function and physical performance. Obese subjects (øBMI 40.2 ± 8.6 kg/m2) underwent a 1-year WR program comprising diet and lifestyle components. Echocardiography and exercise capacity (6-minute walk) were performed at baseline and after 1 year. The distribution of weight reduction was split at the sample median and subjects were dichotomized in “successful WR” (% WR ≥ median, corresponding to a weight loss of 8%) and “failed-WR” (% WR < median). From a total of 188 obese subjects, 71 had LVDD at baseline. Obese patients with successful WR improved their MetS alterations, including fasting glucose, insulin, lipids, adipokines, blood pressure levels, and epicardial fat thickness. The same was not true for obesity with failed WR. Subjects with successful WR demonstrated significant improvement in echocardiographic LVDD parameters (median [interquartile range]): Δe’ (2,5 [-1.0, 4.7], P < 0.01), Δe’/a’ (0.34 [0.07, 079], P < 0.01), ΔE/e’ (-1.14 [-2.72, -0.54], P < 0.05), ΔE/A (0.08 [-0.04, 0.26], P < 0.05), ΔArd-Ad (-28 [-54, -4], P < 0.01), and 6-minute walk distance (65 [19, 135], P < 0.01). Improvement of ≥ 2 LVDD criteria was accomplished in 30% of subjects with WR versus 10% without (P = 0.009). Using multivariable regression analysis, reduction of epicardial fat thickness was particularly predictive for the improvement of diastolic function. In summary, in severe obesity, successful long-term WR was associated with improved LV diastolic function and exercise capacity.
Waon therapy (WT), which in Japanese means soothing warmth, is a repeated sauna therapy that improves cardiac and vascular endothelial function in patients with chronic heart failure (CHF). We investigated whether WT could improve the quality of life (QOL) of CHF patients in addition to improving cardiac function and exercise capacity. A total of 49 CHF patients (69 ± 14 years old) were treated with a 60°C far infrared-ray dry sauna bath for 15 minutes and then kept in a bed covered with blankets for 30 minutes once a day for 3 weeks. At baseline and 3 weeks after starting WT, cardiac function, 6-minute walk distance (6MWD), flow mediated dilation (FMD) of the brachial artery, and SF36-QOL scores were determined. WT significantly improved left ventricular ejection fraction (LVEF), B-type natriuretic peptide (BNP), 6MWD, and FMD (3.6 ± 2.3 to 5.1 ± 2.8%, P < 0.01). Moreover, WT significantly improved not only the physical (PC) but also mental component (MC) of the QOL scores. WT-induced improvement of PC was negatively correlated with changes in BNP (r = -0.327, P < 0.05), but MC improvement was not related directly to changes in BNP, LVEF, or 6MWD. WT-induced changes in MC were not parallel to PC improvement. WT improved QOL as well as cardiac function and exercise capacity in patients with CHF. Mental QOL improved independently of WT-induced improvement of cardiac function and exercise capacity.
Coronary artery disease (CAD) is a major determinant of long-term prognosis in patients with peripheral artery disease (PAD). We investigated the predictors of CAD in patients with lower extremity PAD. A total of 107 patients with PAD who underwent peripheral and simultaneous coronary angiography were reviewed. PAD was defined as (≥ 50%) stenosis associated with claudication or critical limb ischemia. PAD was divided into proximal and distal lesions. CAD was defined as angiographically significant (≥ 50%) stenosis of coronary arteries. The prevalence of CAD in patients with PAD was 62% (67/107), and of this 62%, only 13% (9/67) had angina and 72% (48/67) had multi-vessel disease. Diabetes significantly increased the risk of CAD in patients with PAD and the odds ratio of having multi-vessel CAD was 2.5 (1.1-5.9, P = 0.037) in multivariate regression analysis. The patients with multi-vessel CAD had more cardiovascular risk factors than those with normal, minimal and single CAD (P = 0.032). Interestingly, the prevalence of proximal PAD was higher in the normal or single CAD group than the multi-vessel CAD group, whereas both proximal and distal involvement of PAD was higher in the multi-vessel CAD group. Diabetes, multi-cardiovascular risk factors, and involvement of both proximal and distal lesions significantly increased the risk of multi-vessel CAD. Therefore, simultaneous CAD evaluation should be considered in patients with lower extremity PAD having diabetes, multi-cardiovascular risk factors, or multi-level disease.
Diuresis is a major therapy for the reduction of congestive symptoms in acute decompensated heart failure (ADHF) patients. Carperitide has natriuretic and vasodilatory effects, and tolvaptan produces water excretion without electrolyte excretion. We previously reported the usefulness of tolvaptan compared to carperitide in ADHF patients with fluid volume retention. The purpose of this study was to examine whether the efficacy of tolvaptan was altered in ADHF patients with reduced left ventricular systolic function and in those with hypotension. A total of 109 hospitalized ADHF patients were randomly assigned to either a tolvaptan or a carperitide treatment group. Baseline clinical characteristics were not different between the two groups. We divided these patients based on the left ventricular ejection fraction (EF) by echocardiography, and blood pressure (BP) at the time of admission. Daily urine volume between the tolvaptan and carperitide groups in patients with preserved EF (≥ 50%) was not different, however, in those with reduced EF (< 50%), the urine volume was significantly higher in the tolvaptan group than in the carperitide group (day 2, 3, 4, P < 0.05 for all). Daily urine volume did not differ between these two groups in the high blood pressure group (BP ≥ 140 mmHg), but was significantly higher in the tolvaptan group than in the carperitide group (day 1, P = 0.021; day 3, P = 0.017) in the low blood pressure group (BP < 140 mmHg). The present study reveals that tolvaptan is more effective than carperitide, especially in ADHF patients with reduced left ventricular systolic function and without hypertension.
Repeated hospitalization due to acute decompensated heart failure (HF) is a pandemic health problem in Japan. However, it is difficult to predict rehospitalization after discharge for acute decompensated HF. We used a single hospital-based cohort from the Shinken Database 2004–2012, comprising all new patients (n = 19,994) who visited the Cardiovascular Institute Hospital. A total of 282 patients discharged after their first acute HF admission were included in the analysis. The median follow-up period was 908 ± 865 days. Of these patients, rehospitalization due to worsening HF occurred in 55 patients. The cumulative rate of rehospitalization was 17.5% at 1 year, 21.4% at 2 years, and 25.5% at 3 years. Patients with rehospitalization were older than those without rehospitalization. Prevalence of diabetes mellitus (DM) was more common in patients with rehospitalization. Average heart rate (HR) tended to be higher in patients with rehospitalization. Loop diuretics were more commonly used at hospital discharge in patients with rehospitalization. Multivariate Cox regression analysis revealed that age ≥ 75 years, DM, HR ≥ 75 bpm at discharge, and use of loop diuretics at discharge were independent predictors for rehospitalization. The number of these independent risk factors could be used to clearly discriminate between the HF rehospitalization low-, middle- and high-risk patients. HF rehospitalization commonly occurred in patients who were discharged after their first acute HF admission. Older age, DM, increased HR, and loop diuretics use at discharge were independently associated with HF rehospitalization. By simply counting these risk factors, we might be able to predict the risk of HF rehospitalization after discharge.
Decreased Transthyretin (TTR) can be observed in heart failure patients with malnutrition evaluated by the Mini Nutritional Assessment (MNA). This study investigated whether a combination of different nutritional assessment methods would be useful for assessing prognosis in patients with acute decompensated heart failure (ADHF). This prospective study included 52 patients with ADHF (mean age, 71.1 ± 14.7 years; men 55.8%) who were admitted to our hospital between June 2012 and August 2013. On admission, nutritional status was evaluated according to levels of TTR and the MNA. Of 52 patients, 28 (53.8%) had TTR < 15 mg/dL, 39 (75.0%) had malnutrition or were at risk of malnutrition (MNA score ≤ 23.5), and 21 (40.4%) were categorized into group L (MNA score ≤ 23.5 and TTR < 15 mg/dL). Readmission due to worsening heart failure occurred in 12 patients (23.1%), and there were 4 (7.7%) allcause deaths. The 1-year event-free survival rates in group L and the remaining patients (group O) were 27.7% and 85.6%, respectively (P = 0.001). Using Cox multivariate analysis, group L also had a poorer prognosis (hazard ratio 4.35, 95% confidence interval 1.26–17.74, P = 0.020). MNA revealed that 75% of patients with ADHF had malnutrition or were at risk of malnutrition. The combination of low MNA and low TTR on admission can predict the prognosis of patients with ADHF.
As the mechanisms underlying PKC activation induced arrhythmias are not yet fully verified, we investigated the role of gap junctions in arrhythmias induced by PKC activation. Arterially-perfused rabbit left ventricular preparations were randomly assigned to perfusion with phorbol ester (PMA) or in combination with AAP10. Transmural ECG as well as action potentials from both endocardium and epicardium were simultaneously recorded throughout all experiments. Changes in connexin43 (Cx43) and nonphosphorylated Cx43 on S368 were measured by Western blot analysis. In the PMA group, the QT interval was shortened, the interval from the peak to the end of the electrocardiographic T wave (Tp-e) and induced nonsustained ventricular tachycardia (VT) were increased, and the expressions of Cx43 and nonphosphorylated Cx43 on S368 were decreased compared with the control group. Compared with the PMA group, without significant changes in the QT interval and the expression of nonphosphorylated connexin43 on S368, Tp-e and induced VT decreased and the expression of Cx43 increased in the AAP10 group. AAP10 can prevent PMA-induced rabbit ventricular arrhythmias by attenuating the increase of Tp-e and the decrease of expression of Cx43. These data suggest that increasing gap junction coupling prevents arrhythmias induced by protein kinase C activation.
A 35-year-old Japanese woman was admitted with coma following flu-like symptoms. She was diagnosed with diabetic ketoacidosis and fulminant type 1 diabetes (FT1D) and received intravenous infusion of insulin and saline. The next day, the ketoacidosis disappeared, and she recovered consciousness. However, extensive ST-segment elevations in the electrocardiogram appeared with a positive troponin test, and the patient developed pulmonary edema on day 3. An echocardiogram showed globally reduced wall motion of the left ventricle and mild pericardial effusion. Despite medical therapy with intravenous furosemide, carperitide, and catecholamines, her cardiac function deteriorated rapidly, with the left ventricular ejection fraction decreasing to 26% within 7 hours, and progressed to cardiogenic shock that afternoon. The patient received mechanical circulatory support for 4 days with intra-aortic balloon pumping and percutaneous cardiopulmonary support, and recovered fully from circulatory failure. A paired serum antibody test showed a significantly elevated titer against parainfluenza-3 virus, indicating a diagnosis of fulminant viral myocarditis. She was discharged on multiple daily insulin injection therapy, and her subsequent clinical course has been uneventful. In summary, we present a case of concurrent FT1D and fulminant viral myocarditis. Parainfluenza-3 viral infection was confirmed serologically and was considered to be a cause of both the FT1D and fulminant myocarditis.
Pulmonary hypertension (PH) induced by pulmonary tumor thrombotic microangiopathy (PTTM) can be fatal because its rapid progression confounds diagnosis, and it is difficult to control with therapy. Here we describe a woman with symptomatic PTTM-PH accompanying gastric cancer that was suspected from perfusion scintigraphy. PTTM-PH was diagnosed by gastroesophageal endoscopy and lung biopsy after partial control of PH using the platelet-derived growth factor (PDGF) receptor (PDGFR) tyrosine kinase inhibitor, imatinib. Treatment with sildenafil and ambrisentan further decreased PH, and she underwent total gastrectomy followed by adjuvant TS-1 chemotherapy. PH did not recur before her death from metastasis. Postmortem histopathology showed recanalized pulmonary arteries where the embolized cancer masses disappeared. PDGF-A, -B, and PDGFR-α, β expression was detected in cancer cells and proliferating pulmonary vascular endothelial cells. Thus, PTTM-PH was successfully controlled using a combination of imatinib, drugs to treat pulmonary arterial hypertension, and cancer management.