A Case of Chronic Active Antibody-Mediated Rejection Caused by a Pre-Existing Anti-DQ Donor-Specific Antibody in a Systemic Lupus Erythematosus Recipient Without History of Sensitization: A Case Report.

BACKGROUND: Systemic lupus erythematosus (SLE) is reported to produce anti-HLA antibodies. We report a case of chronic active antibody-mediated rejection caused by pre-existing donor-specific antibody (DSA) in a patient with SLE without a history of sensitization. CASE REPORT: The case was a 29-year-old man with end-stage renal disease due to lupus nephritis. Cross-match with the mother was negative, but low titer anti-DQ DSA was detected, although he had no prior history of sensitization. After desensitization with rituximab and mycophenolate mofetil, a living donor kidney transplant was undergone, and his early postoperative period was uneventful. However, his renal function started to decline at 2 years post-transplant. Although there was no rejection on the biopsy at 2.5 years post-transplant, his renal function continued to decline after that. At 7 years, he had failed his graft due to chronic active antibody-mediated rejection. Retrospective analysis of human leukocyte antigen antibody tests revealed that anti-DQ DSA had disappeared at 1 year post-transplant, but high titer DSA was detected again with complement-binding capacity at 2 years and after that. CONCLUSION: Careful monitoring might be warranted in an SLE patient with pre-existing DSA, even though the titer was low and without any prior histories of sensitization events.

Hyperglycemia and Thrombocytopenia　- Combinatorially Increase the Risk of Mortality in Patients With Acute Myocardial Infarction Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation.

Background: Patients with cardiogenic shock due to acute myocardial infarction (AMI) can rapidly undergo veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy to recover cardiac output and decrease mortality. However, the clinical indicators predictive of mortality in these patients remain unknown. Methods and Results: We conducted a single-center retrospective cohort study targeting AMI patients undergoing VA-ECMO. All 63 patients undergoing VA-ECMO for AMI at the Japanese Red Cross Kumamoto Hospital between January 1, 2010 and June 30, 2020 were enrolled. An exploratory analysis was conducted using a survival tree model and variables selected in a univariate Cox proportional hazard model. The median survival time from the start of VA-ECMO was 6.3 days, and 77.8% (n=49) of patients died. Survival analysis divided patients into 3 groups based on 2 parameters at the initial medical examination: Group 1, patients with neither hyperglycemia (blood glucose ≥213 mg/dL) nor thrombocytopenia (platelets ≤145,100/µL); Group 2, patients with hyperglycemia; and Group 3, patients with hyperglycemia plus thrombocytopenia. Relative to Group 1, the risk of in-hospital mortality was significantly increased in Group 2 (hazard ratio [HR] 2.25; 95% confidence interval [CI] 1.13-4.46), and that risk further increased in Group 3 (HR 7.60; 95% CI 3.21-17.95). Conclusions: Hyperglycemia plus thrombocytopenia on initial medical examination combinatorially increase the risk of mortality in patients with cardiogenic shock due to AMI undergoing VA-ECMO.

High incidence of provoked coronary spasm in the presence of a stent after myocardial infarction: therapeutic and prognostic implications.

OBJECTIVES: Coronary spasm is implicated in the pathogenesis of acute coronary syndromes including acute myocardial infarction (AMI). Stent implantation in the primary percutaneous coronary intervention is the first choice of treatment for patients with AMI. However, the relationship between coronary spasm and stent implantation after AMI and its clinical implications remain unknown. We examined the incidence and clinical implications of provoked coronary spasm after stent implantation in patients with AMI. METHODS: Fifty-seven patients (43 men and 14 women with a mean age of 65.1±12.5 years) with ST elevation AMI who had undergone a stent implantation were the participants of this study. They underwent a provocation test for coronary spasm by intracoronary injection of acetylcholine 2-5 weeks after the attack. The patients with provoked spasms were given calcium channel blockers, and all the participants of the study were followed up for an average of 35.0±26.9 months. RESULTS: Coronary spasm was induced in 40 (70.2%) and multivessel spasm in 17 (29.8%) of the 57 patients. Spasms occurred in 31 (55.4%) of the infarct-related arteries (IRAs) and 33 (30.6%) of the non-IRAs. There was no significant difference (χ=1.01, P=0.314) in the major cardiac events between the spasm group and nonspasm group during the follow-up. CONCLUSION: Coronary spasm was provoked with a high frequency in both the IRAs and non-IRAs after stent implantation in patients with AMI. Calcium channel blockers may be useful to improve the prognosis in patients with AMI after stent implantation by suppressing coronary spasm.

Coronary spasm preferentially occurs at branch points: an angiographic comparison with atherosclerotic plaque.

BACKGROUND: Coronary spasm plays an important role in the pathogenesis of ischemic heart disease. However, similarities and differences between coronary spasm and atherosclerosis are not known. We examined the angiographic characteristics of coronary spasm in comparison with those of atherosclerosis. METHODS AND RESULTS: Thirty-two left anterior descending arteries, 11 left circumflex arteries, and 23 right coronary arteries with spasm and atherosclerotic plaque were analyzed for the localization of spasm in comparison with that of plaque in 47 patients (38 men and 9 women, mean age 66.8+/-10.3 yrs). Spasm predominantly occurred at the branch point as compared with plaque in each of the 3 arteries (76.7% versus 23.3%, P<0.0001; 72.7% versus 9.1%, P<0.039; and 60.0% versus 10.0%, P=0.002, in the left anterior descending, left circumflex, and right coronary arteries, respectively). Spasm involved the proximal segment less frequently as compared with plaque in each of the 3 arteries (56.7% versus 93.3%, P<0.0001; 18.2% versus 81.8%, P=0.016; and 15.0% versus 75.0%, P<0.0001 in the left anterior descending, left circumflex, and right coronary arteries, respectively). Most spasms occurred at the nonplaque site in each of the 3 arteries (73.3%, P=0.018; 100%, P<0.0001; and 75.0%, P=0.041 in the left anterior descending, left circumflex, and right coronary arteries, respectively). CONCLUSIONS: Coronary spasm preferentially occurred at branch points and nonplaque sites, whereas the atherosclerotic lesion was predominantly localized at the nonbranch points of the curved proximal segments. Coronary spasm may thus be a manifestation of a distinct type of arteriosclerosis different from the lipid-laden coronary atherosclerosis.

Metabolic derangements in an adult patient with tetralogy of Fallot: possible role of chronic systemic hypoxia.

The metabolic disorders associated with chronic hypoxemia in adult patients with tetralogy of Fallot (TOF) have not been fully appreciated. We report a 53-year-old male patient with TOF who presented with fasting hypoglycemia, hypertriglyceridemia, increased blood levels of free fatty acids, adiponectin, B-type natriuretic peptide, and uric acid. The cluster of these metabolic derangements has not been previously reported, and the possible role of chronic hypoxia in the production of these disturbances is discussed with a review of pertinent literatures.

Increase in the transcriptional activity of the endothelial nitric oxide synthase gene with fluvastatin: a relation with the -786T>C polymorphism.

HMG-CoA reductase inhibitors (statins) increase endothelial nitric oxide (NO) production, although the precise mechanism of this statin induced increase in NO production remains to be elucidated. We examined endothelial nitric oxide synthase (eNOS) mRNA levels, mRNA stability and the transcriptional activities of the eNOS gene in human umbilical vein endothelial cells treated with fluvastatin and simvastatin. We further examined whether the effects of these statins differ dependent upon the -786T>C polymorphism in the eNOS gene, and whether these statins affect gene expression of replication protein A1 (RPA1), which is known to reduce the transcriptional activity of the eNOS gene with the -786C allele. Utilizing the real-time reverse transcription-polymerase chain reaction, fluvastatin significantly increased eNOS mRNA levels and mRNA stability, and decreased RPA1 mRNA levels. Luciferase reporter gene assays revealed that fluvastatin significantly increased the transcriptional activity of the eNOS gene. The effect of fluvastatin was stronger in the -786C/C genotype than in the -786T/T genotype. Simvastatin increased eNOS mRNA levels and mRNA stability, but did not affect the transcriptional activity of the eNOS gene. Fluvastatin increased eNOS mRNA levels by enhancing both the transcriptional activity and mRNA stability. The effect of fluvastatin on the transcriptional activity was augmented in the -786C/C genotype, probably because of a decrease in RPA1 gene expression. Simvastatin increased eNOS mRNA levels only by enhancing mRNA stability. The present study suggests that fluvastatin increases endothelial NO activity and thus may be more beneficial to patients with the -786C allele.

Possible association of heart failure status with synthetic balance between aldosterone and dehydroepiandrosterone in human heart.

BACKGROUND: Aldosterone is produced not only in the adrenal gland but also in the extra-adrenal tissues, including failing human heart. This study examined the production of dehydroepiandrosterone (DHEA) in human heart and elucidated the possible physiological significance. Method and Results- Using left ventricular tissues obtained at autopsy, reverse transcription-polymerase chain reaction followed by Southern blot analysis revealed the gene expressions of CYP17. By measuring plasma aldosterone and DHEA levels at the coronary sinuses and aortic roots during cardiac catheterization, we found that DHEA but not aldosterone was secreted from control subjects (P<0.0001 and P=0.74, respectively), whereas aldosterone but not DHEA was secreted from patients with heart failure (P=0.0017 and P=0.67, respectively). To examine the significance of DHEA, we measured myocyte cell sizes and the gene expression of B-type natriuretic peptide (BNP), using a neonatal rat cardiocyte culture system. We found that DHEA (10(-8) mol/L) significantly inhibited the increase in myocyte cell sizes and BNP mRNA levels upregulated by endothelin-1 (P=0.031 and P<0.0001, respectively). CONCLUSIONS: CYP17 gene expression and production of DHEA were demonstrated in human control heart. Also, we found that cardiac production of DHEA was suppressed in failing heart. We postulated that DHEA and/or its metabolites exert a cardioprotective action through antihypertrophic effects.

Plasma level of B-type natriuretic peptide as a prognostic marker after acute myocardial infarction: a long-term follow-up analysis.

BACKGROUND: Circulating levels of B-type natriuretic peptide (BNP), a cardiac hormone, reflect the severity of cardiac dysfunction. Because the plasma BNP level changes dramatically during the period after the onset of acute myocardial infarction (AMI), identification of a suitable sampling time is problematic. There have been several reports indicating that the plasma BNP level obtained in the acute phase of AMI can be used as a prognostic marker. We examined whether the plasma BNP level measured 3 to 4 weeks after the onset of AMI represents a reliable prognostic marker for patients with AMI. METHODS AND RESULTS: We analyzed 145 consecutive patients with AMI. Plasma BNP levels were measured during the 3 to 4 weeks after onset of AMI. Of those patients, 23 experienced fatal cardiac events during this study. The mean follow-up period was 58.6 months. Log BNP, left ventricular end-diastolic pressure, and pulmonary vascular resistance were all significantly higher in the cardiac death group, and there were more men and more patients with a history of heart failure in the cardiac death group. A Cox proportional hazards model analysis showed that log BNP was an independent predictor of cardiac death. The survival rate was significantly higher in patients with log BNP <2.26 (180 pg/mL) than in those with log BNP > or =2.26. CONCLUSIONS: The plasma BNP level obtained 3 to 4 weeks after the onset of AMI can be used as an independent predictor of cardiac death in patients with AMI.

Synergistic interaction of T-786-->C polymorphism in the endothelial nitric oxide synthase gene and smoking for an enhanced risk for coronary spasm.

OBJECTIVE: We previously reported that a T-786-->C polymorphism in the 5'-flanking region of the endothelial nitric oxide synthase gene and smoking were independently associated with coronary spasm; however, the interaction between this polymorphism and smoking remains to be elucidated. METHODS: We analyzed 209 men and 238 women who were admitted consecutively at our institution; all subjects received an intracoronary injection of acetylcholine (ACh) while undergoing coronary angiography for evaluation of chest pain: all subjects had no significant coronary stenosis. We divided these subjects into four groups: non-smokers with T/T genotype (Control Group A); non-smokers with C/T or C/C genotype (Group B); smokers with T/T genotype (Group C); and smokers with C/T or C/C genotype (Group D). We further examined quantitative coronary angiographies of the left anterior descending coronary artery in a subset of 54 consecutive men and 53 consecutive women. RESULTS: The frequencies of coronary spasm in Group B (male: 61%, female: 78%), Group C (62%, 59%) and Group D (91%, 92%) were significantly higher than in Group A (30%, 38%). In the males, ACh-induced vasoconstriction was greatest in Group D, and the change was weakest in Group A. In the females, ACh-induced vasoconstrictions were significantly greater in Groups B, C and D than in Group A. The T-786-->C polymorphism and smoking combine to increase the risk of coronary spasm.

Inhibitory effect of natriuretic peptides on aldosterone synthase gene expression in cultured neonatal rat cardiocytes.

BACKGROUND: Although previously thought to be synthesized solely in adrenal cortex, we have recently showed that aldosterone is also produced in and the expression of CYP11B2 mRNA was induced in the failing or hypertensive human ventricle. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones with wide biological effects, including inhibition of renin and aldosterone production. We hypothesized that natriuretic peptides reduce the expression of CYP11B2 mRNA in the heart. METHODS AND RESULTS: To test this hypothesis, we examined whether endogenous or exogenous natriuretic peptides reduce the expression of CYP11B2 mRNA using real-time reverse transcription-polymerase chain reaction. By using HS 142-1, a functional guanylyl cyclase-A type receptor antagonist, we showed that angiotensin II (AngII) pretreated with HS 142-1 increased CYP11B2 mRNA expression (1.62+/-0.12-fold, HS 142-1+AngII 10(-7) mol/L versus AngII 10(-7) mol/L alone, P<0.0001). The treatment with exogenous (10(-6) mol/L) ANP and BNP reduced CYP11B2 mRNA expression (ANP, P=0.0042; BNP, P=0.0012). CONCLUSIONS: We showed that endogenous and exogenous natriuretic peptides reduced CYP11B2 mRNA expression in cultured neonatal rat cardiocytes. This may inhibit the cardiac renin-angiotensin-aldosterone system by suppressing the gene expression of CYP11B2 and restraining cardiac hypertrophy and fibrosis.

Expression of aldosterone synthase gene in failing human heart: quantitative analysis using modified real-time polymerase chain reaction.

We have shown that aldosterone, previously thought to be synthesized solely in the adrenal cortex, is also produced in the failing human heart. One way to induce aldosterone synthesis in the heart would be to increase the expression of CYP11B2, the enzyme catalyzing the terminal step in aldosterone synthesis. However, CYP11B2 expression has never been examined in cardiac tissue from patients with heart failure. We assayed CYP11B2 expression in left ventricular tissue obtained at autopsy from seven patients. Total RNA was extracted from frozen samples. CYP11B2 gene expression was then quantitatively analyzed using a modified real-time PCR method that enabled assay of samples containing very small amounts of template DNA. The template DNA was initially amplified 1024-fold by subjecting it to 10 PCR cycles in the absence of the TaqMan probe. Thereafter, conventional real-time PCR was simultaneously performed on both target and standard samples. We measured the small quantities of CYP11B2 gene transcript and found the levels to be significantly higher in samples from heart failure patients than in those from cardiovascular disease-free patients. Our modified real-time PCR method enables quantitative analysis of gene expression using very small amounts of template DNA. CYP11B2 expression is up-regulated in the failing human heart.

Aldosterone is produced from ventricles in patients with essential hypertension.

This study was designed to examine whether aldosterone is produced from the hearts of patients with essential hypertension without left ventricular systolic dysfunction (LVSD). The study population consisted of 20 patients with essential hypertension without LVSD and 22 control subjects. Plasma levels of aldosterone, serum ACE activity, and B-type natriuretic peptide levels were measured in the anterior interventricular vein (AIV), coronary sinus, and aortic root during cardiac catheterization. The plasma aldosterone levels were significantly higher in AIV and coronary sinus than in aortic root (99+/-11 versus 88+/-10 pg/mL, P<0.01, and 100+/-12 versus 88+/-10 pg/mL, P<0.01, respectively) in the hypertension group. On the other hand, there were no significant differences in aldosterone levels for these sites in the control group. There were no significant differences in ACE activity levels between aortic root, AIV, and coronary sinus in either the hypertension or control group. The levels of B-type natriuretic peptide were significantly higher in AIV than in aortic root in both groups. The difference in aldosterone levels between AIV and aortic root (Delta Aldo[AIV-Ao]) had a significant positive correlation with the difference in ACE activity between AIV and aortic root (DeltaACE[AIV-Ao]) (r=0.501, P<0.05) in the hypertension group. Both Delta Aldo[AIV-Ao] and DeltaACE[AIV-Ao] had a significant positive correlation with diastolic blood pressure (r=0.498, P<0.05; r=0.577, P<0.01, respectively) in the hypertension group. We conclude that production of aldosterone is activated in the left ventricles in patients with essential hypertension without LVSD in proportion to the severity of hypertension.

Effects of perindopril on aldosterone production in the failing human heart.

The present study was designed to examine whether the production of aldosterone from the heart is suppressed by angiotensin-converting enzyme (ACE) inhibition in patients with heart failure. Forty-one patients with left ventricular systolic dysfunction were randomly divided into either the perindopril group (n = 21, perindopril 4 mg/day) or the placebo group (n = 20). Plasma levels of aldosterone and ACE activity were measured in the anterior interventricular vein, coronary sinus, and aortic root during cardiac catheterization. The levels of aldosterone as well as ACE activity were significantly higher at the anterior interventricular vein and the coronary sinus than at the aortic root in the placebo group (aldosterone: 92.1 +/- 9.0 vs 70.6 +/- 8.3 pg/ml [p <0.001]; 90.3 +/- 9.2 vs 70.6 +/- 8.3 pg/ml [p <0.001], respectively; ACE activity: 13.6 +/- 0.8 vs 12.2 +/- 0.7 IU/L [p <0.001], 13.4 +/- 0.8 vs 12.2 +/- 0.7 IU/L [p <0.001], respectively). On the other hand, there were no differences in the levels of aldosterone or ACE activity between the anterior interventricular vein and aortic root or between the coronary sinus and aortic root (aldosterone: 68.1 +/- 8.4 vs 69.9 +/- 9.4 pg/ml [p = NS]; 67.3 +/- 8.9 vs 69.9 +/- 9.4 pg/ml [p = NS], respectively; ACE activity: 9.7 +/- 0.8 vs 9.9 +/- 0.8 IU/L [p = NS]; 9.8 +/- 0.8 vs 9.9 +/- 0.8 IU/L, respectively) in the perindopril group. The levels of aldosterone as well as ACE activity were significantly lower at the anterior interventricular vein and coronary sinus in the perindopril group than in the placebo group. The difference in the level of aldosterone between the anterior interventricular vein and aortic root (Delta aldosterone [anterior interventricular vein - aortic root]) had a significant positive correlation with that of ACE activity (Delta ACE [anterior interventricular vein - aortic root]) (r = 0.536, p <0.001), whereas ACE activity in the aortic root had no significant correlation with either the aldosterone levels in the aortic root or Delta aldosterone (anterior interventricular vein - aortic root). Perindopril suppressed cardiac aldosterone production by mainly suppressing cardiac ACE activity in patients with heart failure. Thus, aldosterone production is activated in the failing ventricle and is suppressed by perindopril mainly via the suppression of cardiac ACE activity in patients with heart failure.

Paraoxonase gene Gln192Arg (Q192R) polymorphism is associated with coronary artery spasm.

We recently reported that oxidative stress is involved in the pathogenesis of coronary spasm. We hypothesized that oxidative-stress-related genetic factors and certain polymorphisms in the paraoxonase gene (PON1) and platelet-activating factor acetylhydrolase (PAF-AH) might influence the pathogenesis of coronary spasm. We therefore examined the possible association between the PON1 Q192R or PAF-AH V279F polymorphisms and coronary spasm in 214 patients with coronary spasm and 212 control subjects. Genotypes were determined by polymerase chain reaction/restriction fragment length polymorphism analysis. The incidence of the PON1-192R allele was significantly higher in the coronary spasm group than in the control group (65% vs 53%; P=0.0005). The PAF-AH-279F allele was not associated with coronary spasm (15% vs. 16%; P=0.8781). Multiple logistic regression analysis with forward stepwise selection involving the PON1-192R allele and the environmental risk factors revealed that the most predictive independent risk factor for coronary spasm was the PON1-192R allele (significance=0.0016, OR=2.52), followed by cigarette smoking (significance=0.0007, OR=2.01). We also measured plasma levels of TBARS (thiobarbituric acid-reactive substances) as a marker of oxidative stress. TBARS levels were higher in R/R types than in Q/Q types (2.115+/-0.086 nmol/ml [ n=25] vs 1.676+/-0.102 nmol/ml [ n=11], P<0.01). Thus, there is a significant association between the PON1-192R allele and coronary spasm; the PON1-192R allele may play an important role in the genesis of coronary spasm, probably by attenuating the suppression of oxidative stress.