Comprehensive genetic screening for vascular Ehlers-Danlos syndrome through an amplification-based next-generation sequencing system.

Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification-based next-generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys-Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non-Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in-frame deletions, and one (2.9%) had a multi-exon deletion, including two deceased patients analyzed with formalin-fixed and paraffin-embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.

Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association.

AIMS: Although nitrates are widely used as a concomitant therapy with calcium channel blockers (CCBs) for vasospastic angina (VSA), their prognostic contribution remains unclear. The present study aimed to examine the prognostic impact of chronic nitrate therapy in patients with VSA. METHODS AND RESULTS: A total of 1429 VSA patients (median 66 years; male/female, 1090/339) were enrolled. The primary endpoint was defined as major adverse cardiac events (MACE). The propensity score matching and multivariable Cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. Among the study patients, 695 (49%) were treated with nitrates, including conventional nitrates [e.g. nitroglycerin (GTN), isosorbide mono- and dinitrate] in 551 and nicorandil in 306. Calcium channel blockers were used in >90% of patients. During the median follow-up period of 32 months, 85 patients (5.9%) reached the primary endpoint. Propensity score-matched analysis demonstrated that the cumulative incidence of MACE was comparable between the patients with and those without nitrates [11 vs. 8% at 5 years; hazard ratio (HR): 1.28; 95% confidence interval (CI): 0.72-2.28, P = 0.40]. Although nicorandil itself had a neutral prognostic effect on VSA (HR: 0.80; 95% CI: 0.28-2.27, P = 0.67), multivariable Cox model revealed the potential harm of concomitant use of conventional nitrates and nicorandil (HR: 2.14; 95% CI: 1.02-4.47; P = 0.044), particularly when GTN and nicorandil were simultaneously administered. CONCLUSIONS: Chronic nitrate therapy did not improve the long-term prognosis of VSA patients when combined with CCBs. Furthermore, the VSA patients with multiple nitrates would have increased risk for cardiac events.

Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association.

AIMS: Provocation tests of coronary artery spasm are useful for the diagnosis of vasospastic angina (VSA). However, these tests are thought to have a potential risk of arrhythmic complications, including ventricular tachycardia (VT), ventricular fibrillation (VF), and brady-arrhythmias. We aimed to elucidate the safety and the clinical implications of the spasm provocation tests in the nationwide multicentre registry study by the Japanese Coronary Spasm Association. METHODS AND RESULTS: A total of 1244 VSA patients (M/F, 938/306; median 66 years) who underwent the spasm provocation tests were enrolled from 47 institutes. The primary endpoint was defined as major adverse cardiac events (MACEs). The provocation tests were performed with either acetylcholine (ACh, 57%) or ergonovine (40%). During the provocation tests, VT/VF and brady-arrhythmias developed at a rate of 3.2 and 2.7%, respectively. Overall incidence of arrhythmic complications was 6.8%, a comparable incidence of those during spontaneous angina attack (7.0%). Multivariable logistic regression analysis demonstrated that diffuse right coronary artery spasm (P < 0.01) and the use of ACh (P < 0.05) had a significant correlation with provocation-related VT/VF. During the median follow-up of 32 months, 69 patients (5.5%) reached the primary endpoint. The multivariable Cox proportional hazard model revealed that mixed (focal plus diffuse) type multivessel spasm had an important association with MACEs (adjusted hazard ratio, 2.84; 95% confidence interval, 1.34-6.03; P < 0.01), whereas provocation-related arrhythmias did not. CONCLUSION: The spasm provocation tests have an acceptable level of safety and the evaluation of spasm type may provide useful information for the risk prediction of VSA patients.

Systemic Amyloid A Amyloidosis Secondary to Xanthogranulomatous Pyelonephritis.

The combination of systemic amyloid A (AA) amyloidosis and xanthogranulomatous pyelonephritis (XGP) resulting from a chronic urinary tract infection is extremely rare. We herein report a case of systemic AA amyloidosis secondary to XGP for which clinical remission developed after nephrectomy. To our knowledge, this is the first case report describing the clinical improvement of systemic AA amyloidosis secondary to XGP after nephrectomy in Japan. Clinicians should be aware of this uncommon combination and search for amyloid depositions in cases of XGP.

Gender differences in the clinical characteristics and outcomes of patients with vasospastic angina--a report from the Japanese Coronary Spasm Association.

BACKGROUND: Accumulating evidence has demonstrated the gender differences in the clinical characteristics and outcomes of patients with ischemic heart disease. However, it remains to be elucidated whether it is also the case for vasospastic angina (VSA). METHODS AND RESULTS: We enrolled a total of 1,429 VSA patients (male/female, 1090/339; median age 66 years) in our nationwide multicenter registry by the Japanese Coronary Spasm Association. As compared with male patients, female patients were characterized by older age (median 69 vs. 66 years), lower incidence of smoking (20% vs. 72%) and less significant organic stenosis (9% vs. 16%) (all P=0.001). Multivariate analysis demonstrated that the predictors of major adverse cardiac events (MACE) were considerably different by genders; women were more associated with age and electrical abnormalities, whereas men with structural abnormalities. Overall 5-year MACE-free survival was comparable between both genders. However, when the patients were divided into 3 groups by age [young (<50 years), middle-aged (50-64 years) and elderly (≥65 years)], the survival was significantly lower in the young female group (young 82%, middle-aged 92%, elderly 96%, P<0.01), where a significant interaction was noted between age and smoking. In contrast, the survival was comparable among the 3 age groups of male patients. CONCLUSIONS: These results indicate that there are gender differences in the characteristics and outcomes of VSA patients, suggesting the importance of gender-specific management of the disorder.

Subendocardial Infarction in Severe Bicuspid Aortic Stenosis without Coronary Stenosis Confirmed by Contrast-enhanced Computed Tomography and Autopsy.

A 59-year-old man with aortic stenosis (AS) showed cardiopulmonary arrest requiring extracorporeal circulation. Although coronary angiography did not show coronary artery stenosis, he had an elevated creatine kinase-myocardial band value of 1,298 U/L. Echocardiography revealed severe AS and global hypokinesia of the thickened myocardium. Contrast-enhanced computed tomography (CT) detected a circumferential subendocardial perfusion defect of the left ventricular myocardium. Eventually, the patient died from brain anoxia. Autopsy revealed circumferential subendocardial infarction of the left ventricular myocardium. This is the first case of circumferential subendocardial defect on CT corresponding to circumferential subendocardial infarction on autopsy in severe AS without coronary stenosis.

Analysis of J waves during myocardial ischaemia.

AIMS: The aim of this study was to investigate the relationship between J-wave dynamics and arrhythmias during myocardial ischaemia in patients with vasospastic angina (VSA). METHODS AND RESULTS: Sixty-seven consecutive patients diagnosed with VSA by a provocation test for coronary spasm were grouped according to whether they had a J wave in the baseline electrocardiograms or not (VSA-JW group, n = 14; VSA-non-JW group: n = 53). We retrospectively studied the associations between J-wave and ST-segment dynamics and induced ventricular fibrillations (VFs) during coronary spasm.  In the VSA-JW group, 7 of the 14 patients showed changes in J-wave morphology and/or gains in J-wave voltage, followed by VF in 4 patients. Compared with patients without VF, the four patients with VF showed similar maximal voltage in the baseline J waves but a higher voltage during induced coronary spasms (0.57 ± 0.49 vs. 0.30 ± 0.11 mV; P = 0.011). In three patients with VF, J waves progressively increased and were accompanied by the characteristic coved-type or lambda-shaped ST-segment elevations. In the VSA-non-JW group, only four patients showed new appearances of J waves during coronary spasms and another patient without a distinct J wave developed VF. Ventricular fibrillations were induced more frequently in the VSA-JW group than in the VSA-non-JW group [4/14 (29%) vs. 1/53 (2%); P = 0.012]. CONCLUSION: J-wave augmentations were caused by myocardial ischaemia during coronary spasms. The presence and augmentation of J waves, especially prominent J waves with the characteristic ST-elevation patterns, were associated with VF.

Ventricular septal perforation naturally reduced in takotsubo cardiomyopathy.

An 80-year-old female was transferred to our hospital with dyspnea. Chest X-ray showed severe pulmonary congestion and electrocardiogram showed ST-segment elevation, abnormal Q, and negative T waves in leads V1-4. Transthoracic echocardiography demonstrated left ventricular apical akinesia with apical ventricular septal perforation. Emergent coronary angiography showed no coronary artery stenosis, and right-heart catheterization revealed a pulmonary to systemic flow ratio (Qp/Qs) of 2.2 on oximetry run. She was diagnosed with takotsubo cardiomyopathy with an associated complication of ventricular septal perforation. Her cardiac function gradually improved with nonsurgical treatment. An oximetry run performed 67 days later revealed that Qp/Qs decreased to 1.2. The size of ventricular septal perforation associated with takotsubo cardiomyopathy reduces naturally by conservative treatment, unlike that in acute myocardial infarction. .

Impact of statins in patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association.

BACKGROUND: Statins are generally used for patients with coronary artery disease. However, the impact of statins in patients with vasospastic angina (VSA) is not fully understood. METHODS: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without statins were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure, and appropriate implantable cardioverter defibrillator shock. Propensity score matching and a multivariable Cox proportional hazard model were used to adjust for selection bias in treatment and potential confounding factors. RESULTS: In the whole population, 469 patients received statins, while 960 patients did not receive statins. Patients with statins had a greater prevalence of comorbidities, including hypertension, diabetes, dyslipidemia, and smoking, in comparison to those without statins. The prevalence rates of previous myocardial infarction, significant organic stenosis, and medication use (including calcium channel blockers, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, and beta blockers) were greater in patients with statins than in those without statins. After propensity matching (n = 211 for both groups), a Kaplan-Meier curve analysis revealed that the incidence of MACE was comparable between patients with and without statins (p = 0.686). MACEs occurred in 6.0% of patients with statins and in 5.9% of those without statins (p = 0.98). CONCLUSION: In this multicenter registry study, statin therapy did not reduce clinical events in VSA patients.

Efficacy and safety of bosentan treatment for portopulmonary hypertension associated with syncope.

Pulmonary arterial hypertension (PAH) in patients with portal hypertension is also referred to as portopulmonary hypertension (PPHTN). Here, we report a case of PPHTN caused by alcoholic liver cirrhosis in a 43-year-old male who experienced repetitive syncope on exertion. The continuous monitoring of pulmonary artery pressure and radial artery pressure revealed that his PAH was aggravated with a drop in systemic arterial pressure during an exercise test. Bosentan, an endothelin A/B receptor antagonist, improved the patient's hemodynamic parameters and abolished his syncope without adverse effects. This is the first report that bosentan may be effective and safe for PPHTN associated with syncope.

The impact of antiplatelet therapy on patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association.

BACKGROUND: Antiplatelet therapy (APT) is generally used in patients with coronary artery disease. However, for patients with vasospastic angina (VSA), the impact of APT is not fully understood. METHODS: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without APT were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure and appropriate ICD (Implantable cardioverter defibrillator) shock. Propensity score matching and a multivariable cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. RESULTS: In the whole population, 669 patients received APT, while 760 patients did not receive APT. Patients with APT had a greater prevalence of comorbidities, such as hypertension, diabetes, dyslipidemia and smoking, than those without APT. The prevalences of previous myocardial infarction, spontaneous ST changes, significant organic stenosis and medications including calcium channel blocker, nitrate, statin and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker were greater in patients with APT than those without APT. After propensity matching (n = 335 for both groups), during the median follow-up period of 32 months, the incidence rate of MACE was comparable between the patients with and without APT (P = 0.24). MACEs occurred in 5.7% of patients with APT and in 3.6% of those without APT (P = 0.20). All-cause death occurred in 0.6% of patients with APT and 1.8% of those without APT (p = 0.16). CONCLUSION: In this multicenter registry study, anti-platelet therapy exerted no beneficial effects for VSA patients.

Usefulness of Repeat Angiography to Establish Spontaneous Coronary Artery Dissection in Small Vessels.

Background: Spontaneous coronary artery dissection (SCAD) is a rare disease that is often misdiagnosed, except in typical cases. Although intracoronary imaging and multislice coronary computed tomography angiography (CCTA) are useful in establishing dissection, they may not be feasible in all instances, especially in small vessels. Methods and Results: We describe a series of 7 patients with acute coronary syndrome secondary to small vessel SCAD that was detected only upon repeat coronary angiography (CAG). This cohort had a mean (±SD) age of 50±6 years, was predominantly female (n=6; 86%), and had few coronary risk factors. Three patients (43%) had dissection of the distal segment of the right coronary artery, 3 (43%) had distal left circumflex artery dissection, and 1 patient (14%) had a diagonal branch dissection. None of the patients required percutaneous coronary intervention, and received conservative therapy only, because the infarct area was sufficiently small. No definitive diagnosis of SCAD could be established in any of the patients at first admission because CAG alone or CCTA did not reveal the presence of a flap or intraluminal hemorrhage. However, in such patients without a definitive diagnosis, repeat CAG in the chronic stage showed enlargement of vessels, suggesting the healing of an SCAD. Conclusions: Repeat CAG may be useful for suggesting the occurrence of SCAD.

Clinical characteristics and long-term prognosis of contemporary patients with vasospastic angina: Ethnic differences detected in an international comparative study.

BACKGROUND: Possible ethnic differences in clinical characteristics and long-term prognosis of contemporary patients with vasospastic angina (VSA) remain to be elucidated. METHODS AND RESULTS: The Japanese Coronary Spasm Association (JCSA) conducted an international, prospective, and multicenter registry study for VSA patients. A total of 1457 VSA patients (Japanese/Caucasians, 1339/118) were enrolled based on the same diagnostic criteria. Compared with Caucasian patients, Japanese patients were characterized by higher proportions of males (68 vs. 51%) and smoking history (60 vs. 49%). Japanese patients more often had angina especially during the night and early morning hours, compared with Caucasians. Ninety-five percent of Japanese and 84% of Caucasian patients underwent pharmacological provocation test. Importantly, no significant differences in the patterns of coronary spasm were apparent, with diffuse spasm most frequently noted in both ethnicities. The prescription rate of calcium-channel blockers was higher in Japanese (96 vs. 86%), whereas the uses of nitrates (46 vs. 59%), statins (43 vs. 65%), renin-angiotensin-system inhibitors (27 vs. 51%), and ß-blockers (10 vs. 24%) were more common in Caucasian patients. Survival rate free from major adverse cardiac events (MACE) was slightly but significantly higher in Japanese than in Caucasians (86.7 vs. 76.6% at 5 years, P < 0.001). Notably, multivariable analysis revealed that the JCSA risk score correlated with MACE rates not only in Japanese but also in Caucasian patients. CONCLUSION: These results indicate that there are ethnic differences in clinical profiles and long-term prognosis of contemporary VSA patients.

Limited role of coronary angioplasty and stenting in coronary spastic angina with organic stenosis.

OBJECTIVES: We investigated the efficacy of percutaneous coronary intervention (PCI) in patients with coronary spastic angina (CSA) and severe organic stenosis. BACKGROUND: Coronary spasm occurs at the site of organic stenosis in most patients with CSA and severe stenosis, whereas multivessel spasm occurs frequently in those with normal coronary arteries. The incidence of multivessel spasm and the efficacy of PCI in patients with CSA and severe stenosis have not been fully elucidated. METHODS: Forty-five patients with CSA and severe stenosis underwent spasm provocative testing with intracoronary acetylcholine before and 7 +/- 3 months after PCI (20 patients had angioplasty and 25 patients had stenting), when all patients were free of restenosis. RESULTS: Spasm was induced at the site of severe stenosis in 30 patients (66.7%) with (n = 12) or without (n = 18) spasm induced in another vessel. In the remaining 15 patients, spasm was induced at a different site in the stenotic vessel and/or in another vessel. Repeat provocative tests were performed in 43 of 45 patients. Although spasm was never induced at exactly the same site of the initial stenosis that had been dilated, spasm was induced at a different site in the dilated vessel and/or in another vessel, in 33 (76.7%) of 43 patients. Multivessel spasm occurred in 28 (62.2%) of 45 patients on one or both provocations. CONCLUSIONS: Spasm was frequently induced at a site different from the initial stenosis, even in the absence of restenosis after PCI. Calcium antagonists should be continued in most patients with CSA who show no restenosis after PCI.

Hemodynamic basis of the reduced oxygen uptake relative to work rate during incremental exercise in patients with chronic heart failure.

BACKGROUND: The ratio of the increase in oxygen uptake to the increase in work rate (DeltaVO2/DeltaWR) during incremental exercise is reduced in patients with severe chronic heart failure (CHF). However, the pathophysiological basis of the reduced O2 uptake relative to work rate has not been elucidated. METHODS: To elucidate the hemodynamic basis of the reduced ratio of DeltaVO2/DeltaWR during exercise in severe CHF, 48 patients with CHF (15 patients in class I, 21 in class II and 12 in class III) performed maximal ergometer exercise with respiratory gas analysis. Cardiac output and systemic O2 extraction were measured at 1-min intervals during exercise. RESULTS: Both peak VO2 and peak cardiac output decreased as the severity of CHF advanced. Patients in class III showed significantly reduced DeltaVO2/DeltaWR than those in class I (8.2+/-0.9 vs. 9.8+/-1.5 ml/min/W, P<0.01). Cardiac output at rest was significantly lower, and O2 extraction at rest was significantly higher in class III than class I. The ratio of the increase in cardiac output to the increase in work rate (DeltaCO/DeltaWR) was significantly lower in class III than class I (42.5+/-14.5 vs. 60.6+/-10.3 ml/min/W), and the ratio of the increase in O2 extraction to the increase in work rate (DeltaO2 extraction/DeltaWR) was significantly higher in class III than class I (0.45+/-0.13 vs. 0.34+/-0.08%/W). The DeltaVO2/DeltaWR was significantly correlated with the DeltaCO/DeltaWR (r=0.67, P<0.01), and the DeltaCO/DeltaWR was inversely correlated with DeltaO2 extraction/DeltaWR (r=-0.65, P<0.01). CONCLUSIONS: Decreased O2 supply due to reduced cardiac output was not fully compensated by the increased O2 extraction. Reduced ratio of DeltaVO2/DeltaWR in advanced CHF reflected the severely attenuated cardiac output response to exercise.

Prognostic stratification of patients with vasospastic angina: a comprehensive clinical risk score developed by the Japanese Coronary Spasm Association.

OBJECTIVES: The present study aimed to develop a comprehensive clinical risk score for vasospastic angina (VSA) patients. BACKGROUND: Previous studies demonstrated various prognostic factors of future adverse events in VSA patients. However, to apply these prognostic factors in clinical practice, the assessment of their accumulation in individual patients is important. METHODS: The patient database of the multicenter registry study by the Japanese Coronary Spasm Association (JCSA) (n = 1,429; median 66 years; median follow-up 32 months) was utilized for score derivation. RESULTS: Multivariable Cox proportional hazard model selected 7 predictors of major adverse cardiac events (MACE). The integer score was assigned to each predictors proportional to their respective adjusted hazard ratio; history of out-of-hospital cardiac arrest (4 points), smoking, angina at rest alone, organic coronary stenosis, multivessel spasm (2 points each), ST-segment elevation during angina, and beta-blocker use (1 point each). According to the total score in individual patients, 3 risk strata were defined; low (score 0 to 2, n = 598), intermediate (score 3 to 5, n = 639) and high (score 6 or more, n = 192). The incidences of MACE in the low-, intermediate-, and high-risk patients were 2.5%, 7.0%, and 13.0%, respectively (p < 0.001). The Cox model for MACE between the 3 risk strata also showed prognostic utility of the scoring system in various clinical subgroups. The average prediction rate of the scoring system in the internal training and validation sets were 86.6% and 86.5%, respectively. CONCLUSIONS: We developed a novel scoring system, the JCSA risk score, which may provide the comprehensive risk assessment and prognostic stratification for VSA patients.

Clinical characteristics and long-term prognosis of vasospastic angina patients who survived out-of-hospital cardiac arrest: multicenter registry study of the Japanese Coronary Spasm Association.

BACKGROUND: Coronary artery spasm plays an important role in the pathogenesis of ischemic heart disease; however, its role in sudden cardiac death remains to be fully elucidated. We examined the clinical characteristics and outcomes of patients with vasospastic angina (VSA) in our nationwide multicenter registry by the Japanese Coronary Spasm Association. METHODS AND RESULTS: Between September 2007 and December 2008, 1429 patients with VSA (male/female, 1090/339; median, 66 years) were identified. They were characterized by a high prevalence of smoking and included 35 patients who survived out-of-hospital cardiac arrest (OHCA). The OHCA survivors, as compared with the remaining 1394 non-OHCA patients, were characterized by younger age (median, 58 versus 66 years; P<0.001) and higher incidence of left anterior descending coronary artery spasm (72% versus 53%, P<0.05). In the OHCA survivors, 14 patients underwent implantable cardioverter-defibrillator (ICD) implantation while intensively treated with calcium channel blockers. Survival rate free from major adverse cardiac events was significantly lower in the OHCA survivors compared with the non-OHCA patients (72% versus 92% at 5 years, P<0.001), including appropriate ICD shocks for ventricular fibrillation in 2 patients. Multivariable analysis revealed that OHCA events were significantly correlated with major adverse cardiac events (hazard ratio, 3.25; 95% confidence interval, 1.39 to 7.61; P<0.01). CONCLUSIONS: These results from the largest vasospastic angina cohort indicate that vasospasm patients who survived OHCA are high-risk population. Further studies are needed to determine whether implantable cardioverter-defibrillator therapy improves patient prognosis.