Coronary microvascular resistance comparison of coronary arteries with and without considering vascular diameter: A retrospective, single-center study.

Background and Aims: Measurement of coronary microvascular resistance (MR) is essential for diagnosing nonocclusive coronary artery ischemia, but whether coronary branches of different diameters can be similarly assessed using hyperemic microvascular resistance index (hMVRI) calculated from average peak velocity (APV) remains unclear. We investigated the relationship between coronary arteries of different diameters and hMVRI. Methods: Thirty patients with suspected angina pectoris and nonobstructive coronary stenosis with fractional flow reserve >0.8 underwent evaluation of all coronary arteries using a Doppler velocity and pressure-equipped guidewire. Quantitative coronary angiography (QCA) was used to analyze vessel diameter (DQCA). Coronary blood flow (CBFQCA) was calculated as πDQCA 2/4 (0.5 × APV) and hMVRIQCA as distal coronary pressure divided by CBFQCA during maximal hyperemia. Results: The hMVRI was significantly higher for the right coronary artery than for the left anterior descending artery, but no significant differences between arteries were seen for CBFQCA and hMVRIQCA. Although the correlation between CBFQCA and APV was weak, CBFQCA divided into three groups according to DQCA showed very strong correlations with APV. Slopes of the straight line between APV and CBFQCA for small-, middle-, and large-diameter groups were 0.48, 0.30, and 0.21, respectively, with slope decreasing as diameter increased. Conclusions: Comparative evaluation of MR in coronary branches with varying vessel diameters requires vessel diameter to be accounted for.

Simple risk-score model for in-hospital major bleeding based on multiple blood variables in patients with acute myocardial infarction.

BACKGROUND: In-hospital bleeding is associated with poor prognosis in patients with acute myocardial infarction (AMI). We sought to investigate whether a combination of pre-procedural blood tests could predict the incidence of in-hospital major bleeding in patients with AMI. METHODS AND RESULTS: A total of 1684 consecutive AMI patients who underwent primary percutaneous coronary intervention (PCI) were recruited and randomly divided into derivation (n = 1010) and validation (n = 674) cohorts. A risk-score model was created based on a combination of parameters assessed on routine blood tests on admission. In the derivation cohort, multivariate analysis revealed that the following 5 variables were significantly associated with in-hospital major bleeding: hemoglobin level < 12 g/dL (odds ratio [OR], 3.32), white blood cell count >10,000/µL (OR, 2.58), platelet count <150,000/µL (OR, 2.51), albumin level < 3.8 mg/dL (OR, 2.51), and estimated glomerular filtration rate < 60 mL/min/1.73 m2 (OR, 2.31). Zero to five points were given according to the number of these factors each patient had. Incremental risk scores were significantly associated with a higher incidence of in-hospital major bleeding in both cohorts (P < 0.001). Receiver operating characteristic curve analysis of risk models showed adequate discrimination between patients with and without in-hospital major bleeding (derivation cohort: area under the curve [AUC], 0.807; 95% confidence interval [CI], 0.759-0.848; validation cohort: AUC, 0.793; 95% CI, 0.725-0.847). CONCLUSIONS: Our novel laboratory-based bleeding risk model could be useful for simple and objective prediction of in-hospital major bleeding events in patients with AMI.

Outcomes of Drug-Eluting Stent Thrombosis After Treatment for Acute Versus Chronic Coronary Syndrome.

OBJECTIVES: The primary objective of the current analysis was to assess the association between the clinical presentation at index procedure and mortality in patients with second-generation drug-eluting stent thrombosis (G2-ST). BACKGROUND: Patients with acute coronary syndrome (ACS) have a higher risk for stent thrombosis (ST) as compared with those with chronic coronary syndrome (CCS). However, clinical outcomes of patients with G2-ST after treatment for ACS and CCS remain poorly understood. METHODS: From the REAL-ST (Retrospective Multicenter Registry of ST After First- and Second-Generation Drug-Eluting Stent Implantation) registry, this study evaluated 313 patients with G2-ST. According to baseline clinical presentation, patients were divided into the 2 groups: the ACS and CCS groups (n = 147 and n = 166, respectively). The primary endpoint was the cumulative 3-year incidence of all-cause death after the index ST events. Timing of ST, target lesion revascularization, and recurrent ST were also assessed. RESULTS: Early ST was more frequently observed in the ACS group (71.4% vs. 44.6%), while very late ST was less likely to occur in the ACS group than in the CCS group (11.6% vs. 30.7%). Cumulative 3-year incidence of all-cause death after the index ST events was comparable between the ACS and CCS groups (28.6% vs. 28.3%; hazard ratio: 1.14; 95% confidence interval: 0.75 to 1.73; p = 0.55). Compared with the CCS group, the ACS group showed higher incidences of target lesion revascularization and recurrent ST (23.8% vs. 17.2%; p = 0.06; and 9.9% vs. 1.4%; p = 0.001, respectively). CONCLUSIONS: Patients with G2-ST were associated with higher mortality irrespective of baseline clinical presentation.

Diagnostic Accuracy of Diastolic Fractional Flow Reserve for Functional Evaluation of Coronary Stenosis: DIASTOLE Study.

Background: In the resting conditions, narrowing the window of coronary pressure measurements from the whole cardiac cycle to diastole improves diagnostic performance of coronary pressure-derived physiological index. However, whether this also applies to the hyperemic conditions has not yet been thoroughly evaluated. Objectives: The purpose of this study was to assess whether diastolic fractional flow reserve (diastolic FFR) has better diagnostic performance in identifying ischemia-causing coronary lesions than conventional FFR in a prospective, multicenter, and independent core laboratory-based environment. Methods: In this prospective multicenter registry at 29 Japanese centers, we compared the diagnostic performance of FFR, diastolic FFR, resting distal to aortic coronary pressure (Pd/Pa), and diastolic pressure ratio (dPR) using myocardial perfusion scintigraphy (MPS) as the reference standard in 378 patients with single-vessel coronary disease. Results: Inducible myocardial ischemia was found on MPS in the relevant myocardial territory of the target vessel in 85 patients (22%). In the receiver-operating curve analyses, diastolic FFR had comparable area under the curve (AUC) compared with FFR (AUCdiastolic FFR: 0.66; 95% confidence interval [CI]: 0.58-0.73, vs AUCFFR: 0.66; 95% CI: 0.58-0.74, P = 0.624). FFR and diastolic FFR showed significantly larger AUCs than resting Pd/Pa (0.62; 95% CI: 0.54-0.70; P = 0.033 and P = 0.046) but did not show significantly larger AUCs than dPR (0.62; 95% CI: 0.55-0.70; P = 0.102 and P = 0.113). Conclusions: Diastolic FFR showed a similar diagnostic performance to FFR as compared with MPS. This result reaffirms the use of FFR as the most accurate invasive physiological lesion assessment. (Diagnostic accuracy of diastolic fractional flow reserve (d-FFR) for functional evaluation of coronary stenosis; UMIN000015906).

Aortic Stiffness Is Associated with Coronary Microvascular Dysfunction in Patients with Non-obstructive Coronary Artery Disease.

Objective Associations between aortic stiffness and cardiovascular disease events are mediated in part by pathways that include coronary microvascular dysfunction (CMD) and remodeling. However, the relationship between aortic stiffness and CMD remains unclear. The present study aimed to determine whether aortic stiffness causes CMD as evaluated by the hyperemic microvascular resistance index (hMVRI) in patients with non-obstructive coronary artery disease (CAD). Methods The intracoronary physiological variables in 209 coronary arteries were evaluated in 121 patients with non-obstructive CAD (fractional flow reserve >0.80) or reference vessels. The cardio-ankle vascular index (CAVI) as a measure of aortic stiffness and atherosclerotic risk factors were also measured. Results Univariate analyses showed that hMVRI correlated with age (ß=0.24, p=0.007), eicosapentaenoic acid (EPA; ß=-0.18, p=0.048), EPA/arachidonic acid (AA) (EPA/AA) ratio (ß=-0.22, p=0.014) and CAVI (ß=0.30, p=0.001). A multivariate regression analysis identified CAVI (ß=0.25, p=0.007) and EPA/AA ratio (ß=-0.26, SE=0.211, p=0.003) as independent determinants of hMVRI. Conclusion Aortic stiffness may cause CMD in patients with non-obstructive CAD via increased coronary microvascular resistance. Aortic stiffness is associated with CMD which is evaluated as hyperemic microvascular resistance in patients with non-obstructive CAD.

Molecular characterization of a prolyl endopeptidase from a feather-degrading thermophile Meiothermus ruber H328.

Prolyl endopeptidase from an aerobic and Gram-negative thermophile Meiothermus ruber H328 (MrPEP) was purified in native and recombinant forms, but both preparations had comparable characteristics. Production of the native MrPEP was increased 10-fold by adding intact chicken feathers. The gene for MrPEP (mrH_2860) was cloned from the genome of strain H328 and found to have no signal sequence at the N-terminus. MrPEP is composed of two major domains: the ß-propeller domain and the peptidase domain with a typical active site motif and catalytic triad. Based on extensive investigations with different types of peptide substrates and FRETS-25Xaa libraries, MrPEP showed strict preferences for Pro residue at the P1 position but broader preferences at the P2 and P3 positions in substrate specificity with stronger affinity for residues at the P3 position of substrate peptides that are longer than four residues in length. In conclusion, the molecular characterization of MrPEP resembles its animal counterparts more closely than bacterial counterparts in function and structure.

A Patient with Bilateral Primary Aldosteronism Refractory to Oral Eplerenone Who Responded to Esaxerenone with Increased Renin Activity.

BACKGROUND When mineralocorticoid receptor antagonist therapy is initiated for primary aldosteronism, the response of plasma renin activity indicates the level of cardiovascular risk. The purpose of this article was to compare the effect of mineralocorticoid receptor blockers on plasma renin activity levels in a patient with primary aldosteronism. CASE REPORT The patient was a 45-year-old male with severe hypertension. Because his aldosterone/renin ratio was high and a saline infusion test was positive, primary aldosteronism was diagnosed. Computed tomography revealed a low-density mass measuring 10 mm in the left adrenal gland. Segmental adrenal vein sampling demonstrated bilateral primary aldosteronism, so pharmacotherapy was started. Before treatment, his plasma renin activity was 0.5 ng/mL/hour. Eplerenone was commenced and the dose was increased to 100 mg/day. However, his plasma renin activity was still 0.8 ng/mL/hour and the maximum dose of eplerenone did not elevate plasma renin activity above 1 ng/mL/hour. Since plasma renin activity remained below 1 ng/mL/hour with mineralocorticoid receptor antagonist therapy, this patient was considered to have a higher cardiovascular risk than patients with essential hypertension. Accordingly, eplerenone was switched to esaxerenone, a new generation mineralocorticoid receptor blocker that became available in May 2019. After switching to esaxerenone (5 mg/day), the patient's plasma renin activity increased to 1.8 ng/mL/hour and subsequently remained at 1 ng/mL/hour or higher. CONCLUSIONS This is the first case report to present interesting changes of plasma renin activity in a primary aldosteronism patient after switching from eplerenone to esaxerenone. Elevation of plasma renin activity by esaxerenone in our primary aldosteronism patient reflected a mineralocorticoid receptor antagonistic effect that may have alleviated excessive mineralocorticoid receptor activation and volume expansion.

Lower Circulating Omega-3 Polyunsaturated Fatty Acids Are Associated with Coronary Microvascular Dysfunction Evaluated by Hyperemic Microvascular Resistance in Patients with Stable Coronary Artery Disease.

The consumption of omega-3 polyunsaturated fatty acids (PUFAs) reduces the incidence of cardiovascular events and sudden cardiac death. Coronary microvascular dysfunction (CMD) is a predictor of cardiac mortality, but little information is known on the relationship between CMD and omega-3 PUFAs. This study aimed to identify the relationship between the serum levels of omega-3 PUFAs and the CMD evaluated by the hyperemic microvascular resistance index (hMVRI) to assess coronary microvascular function in patients with stable coronary artery disease (CAD).Intracoronary physiological variables (fractional flow reserve (FFR), hMVRI, mean distal coronary pressure (Pd), and average peak velocity (APV)) were measured in 108 patients. These parameters were evaluated in 150 coronary arteries with stenosis of intermediate severity and without significant ischemia (FFR > 0.80). The PUFA levels and atherosclerotic risk factors were also measured. Univariate analysis shows that hMVRI was negatively correlated with eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (ß = -0.31, P = 0.001) and EPA (ß = -0.25, P = 0.009) and was positively correlated with dihomo-γ-linolenic acid (ß = 0.26, P = 0.006). Multivariate regression analysis shows that the EPA/AA ratio was the only independent determinant of hMVRI (ß = -0.234, SE = 0.231, P = 0.024). Furthermore, hMVRI decreased significantly from the lowest to highest tertiles of the EPA/AA ratio (P = 0.007). The EPA/AA ratio was positively correlated with APV at hyperemia (ß = 0.26, P = 0.008) but not with Pd at hyperemia.A lower serum EPA/AA ratio may cause CMD in patients with stable CAD.

Rapid and lasting enhancement of dopaminergic modulation at the hippocampal mossy fiber synapse by electroconvulsive treatment.

Electroconvulsive therapy (ECT) is an established effective treatment for medication-resistant depression with the rapid onset of action. However, its cellular mechanism of action has not been revealed. We have previously shown that chronic antidepressant drug treatments enhance dopamine D1-like receptor-dependent synaptic potentiation at the hippocampal mossy fiber (MF)-CA3 excitatory synapse. In this study we show that ECT-like treatments in mice also have marked effects on the dopaminergic synaptic modulation. Repeated electroconvulsive stimulation (ECS), an animal model of ECT, strongly enhanced the dopamine-induced synaptic potentiation at the MF synapse in hippocampal slices. Significant enhancement was detectable after the second ECS, and further repetition of ECS up to 11 times monotonously increased the magnitude of enhancement. After repeated ECS, the dopamine-induced synaptic potentiation remained enhanced for more than 4 wk. These synaptic effects of ECS were accompanied by increased expression of the dopamine D1 receptor gene. Our results demonstrate that robust neuronal activation by ECS induces rapid and long-lasting enhancement of dopamine-induced synaptic potentiation at the MF synapse, likely via increased expression of the D1 receptor, at least in part. This rapid enhancement of dopamine-induced potentiation at the excitatory synapse may be relevant to the fast-acting antidepressant effect of ECT. NEW & NOTEWORTHY: We show that electroconvulsive therapy (ECT)-like stimulation greatly enhances synaptic potentiation induced by dopamine at the excitatory synapse formed by the hippocampal mossy fiber in mice. The effect of ECT-like stimulation on the dopaminergic modulation was rapidly induced, maintained for more than 4 wk after repeated treatments, and most likely mediated by increased expression of the dopamine D1 receptor. These effects may be relevant to fast-acting strong antidepressant action of ECT.

Drug discovery in renal disease--towards a more efficient framework.

The time and cost involved in bringing new drugs to the market hamper their approval. This problem is especially apparent in the case of renal diseases. Efficient drug research requires an a priori understanding of disease pathophysiology, target validation, rational and efficient drug discovery strategies and early testing of the physiological and pharmacological effects of the new agent in humans. Drug development initiated by academia benefits from international research networks and relies on internationally acceptable high-quality nonclinical data packages and bulk investigational drugs. Academics should, therefore, better understand pharmaceutical practice regulations and novel, efficient drug-development strategies. Many researchers remain unfamiliar with these areas and should collaborate with regulatory authorities to discover and validate surrogate markers for use in drug development, and to efficiently and effectively maximize the benefits and minimize the adverse effects of new drugs. The Japanese government and regulatory authorities have implemented a framework to encourage such collaborations; extension of this framework beyond its current reach is envisaged.

Very late bare metal stent thrombosis presenting with acute myocardial infarction: 14 years after coronary stenting.

Fourteen years previously, a 67-year-old man underwent percutaneous coronary intervention (PCI) for proximal left anterior descending artery lesion with a bare metal stent (BMS) for acute myocardial infarction (AMI) and attained an excellent result. Ticlopidine (200 mg) was administered for one month and 100 mg of aspirin was daily has been continued. One year after PCI, coronary angiography showed no restenosis. However, 14 years after PCI, he suffered from AMI due to stent thrombosis. Intracoronary aspiration thrombectomy and implantation of a drug-eluting stent were successful. This report demonstrates evidence of a very late case of stent thrombosis with the use of BMS.

Balloon rupture during coronary angioplasty causing dissection and intramural hematoma of the coronary artery; a case report.

A 73-year-old male with diabetes mellitus was referred for coronary angiography (CAG). He presented with stable effort angina pectoris. CAG showed a significant stenotic lesion in the proximal-segment of the left anterior descending (LAD) coronary artery with heavy calcification. He then underwent angioplasty for the LAD stenosis. On the second balloon dilatation, the balloon was inflated to 22 atm, at which point the balloon waist had not yet yielded and balloon rupture occurred. Immediately after the procedure, CAG showed no-reflow phenomena and chest pain occurred. Intravascular ultrasound (IVUS) imaging revealed a dissection into the media with extension into the medial space without reentry, and demonstrated significant stenosis and obstruction of the distal LAD with a semilunar echo-dense intramural hematoma. To bail out, two bare metal stents were deployed. After the procedure, proper stents expansion and no residual dissection flap were detected either by IVUS or CAG. The final CAG showed a good result with TIMI-3 coronary flow. This case highlights balloon rupture during coronary angioplasty with heavy calcification caused no-reflow phenomena by dissection and intramural hematoma of the coronary artery. We could bail out hematoma by coronary stent implantation with complete cover of the coronary dissection.

Alternative promoter identified between a hypermethylated upstream region of repetitive elements and a CpG island in human ABO histo-blood group genes.

We have studied the expression of human histo-blood group ABO genes during erythroid differentiation, using an ex vivo culture of AC133(-)CD34(+) cells obtained from peripheral blood. 5'-Rapid amplification of cDNA ends analysis of RNA from those cells revealed a novel transcription start site, which appeared to mark an alternative starting exon (1a) comprising 27 bp at the 5'-end of a CpG island in ABO genes. Results from reverse transcription-PCR specific to exon 1a indicated that the cells of both erythroid and epithelial lineages utilize this exon as the transcription starting exon. Transient transfection experiments showed that the region just upstream from the transcription start site possesses promoter activity in a cell type-specific manner when placed 5' adjacent to the reporter luciferase gene. Results from bisulfite genomic sequencing and reverse transcription-PCR analysis indicated that hypermethylation of the distal promoter region correlated with the absence of transcripts containing exon 1a, whereas hypermethylation in the interspersed repeats 5' adjacent to the distal promoter was commonly observed in all of the cell lines examined. These results suggest that a functional alternative promoter is located between the hypermethylated region of repetitive elements and the CpG island in the ABO genes.

Expression of ABO or related antigenic carbohydrates on viral envelopes leads to neutralization in the presence of serum containing specific natural antibodies and complement.

No definitive biologic function has been associated with the human ABO histo-blood group polymorphism, or any other terminal carbohydrate differences within or between closely related species. We have experimentally addressed the question of whether viral particles can become glycosylated as determined by the glycosylation (eg, ABO) status of the producer cell and as a result be affected by human serum containing specific natural antibodies (NAbs). Measles virus was produced in cells transfected with cDNA encoding, either human A-transferase, B-transferase, an inactive "O-transferase," or a pig alpha1-3galactosyltransferase (alpha1-3GT) synthesizing the Galalpha1-3Gal structure. The viruses were shown to carry the same ABO structures as the cells; that is, A but not B if produced in A-type cells, and B but not A if produced in B-type cells. Only O was detected on the virus produced from O-type cells, whereas reduced amounts of O appeared on the A- and B-type viral particles. In addition, the Galalpha1-3Gal structure was transferred onto measles only when grown in human cells expressing this structure. When subjected to human preimmune sera, the A-type, the B-type, and the Galalpha1-3Gal viral particles were partially neutralized in a complement-dependent manner. However, the O-type or the Galalpha1-3Gal-negative viral particles were not neutralized. The neutralization appeared to be mediated by specific NAb, as judged by specific inhibition using synthetic A and Galalpha1-3Gal oligosaccharides. Such viral glycosylation may thus partly explain why the ABO antigens and other similar intraspecies as well as interspecies polymorphic carbohydrates have evolved and been maintained over long evolutionary periods.