Pulmonary tumor thrombotic microangiopathy with thrombus in pulmonary artery caused by diffuse sclerosing variant of thyroid papillary adenocarcinoma: A case report.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal disease associated with malignant tumors that progresses to pulmonary hypertension. Gastric cancer is the most common cause, followed by breast cancer and lung cancer, whereas PTTM due to thyroid cancer has not been reported. In addition to pulmonary obstruction by tumor embolism, tumor cells stimulate endothelial cells to release angiogenetic factors, which induce remodeling of pulmonary arteries and veins and lead to lymphatic obstruction. There is limited information on the relationship between thrombus and PTTM. We herein report an autopsy case with PTTM which was caused by diffuse sclerosing variant of thyroid papillary adenocarcinoma, in which differential diagnosis included the acute phase of chronic thromboembolic pulmonary hypertension.

Mortality, Recurrent Thromboembolism and Major Bleeding in Cancer-Associated and Non-Cancer Pulmonary Embolism Patients Treated With Direct Oral Anticoagulants.

BACKGROUND: Pulmonary embolism (PE) is a potentially fatal form of venous thromboembolism (VTE). This study compares the mortality, incidence of recurrent VTE, and incidence of major bleeding between non-cancer and cancer-associated PE patients treated with direct oral anticoagulants (DOACs).Methods and Results:This was a retrospective, observational, single-center study involving 130 consecutive patients (87 with active cancer; 43 without cancer) who received DOAC treatment for PE between January 2016 and December 2019. Kaplan-Meier analysis showed significantly higher mortality in cancer-associated PE patients than in non-cancer patients (35/87 [40%] vs. 1/43 [2%], P<0.001, log-rank test, HR 18.6 [95% CI: 2.5-136.0]). In contrast, the cumulative incidences of recurrent VTE and major bleeding were comparable between the 2 groups. Among the cancer-associated PE patients, the incidence for the composite outcome of recurrent VTE or major bleeding was significantly higher in patients undergoing chemotherapy than in those not undergoing chemotherapy (9/37 [24%] vs. 2/50 [4%], P=0.004, log-rank test, HR 6.9 [95% CI: 1.5-32.0]). CONCLUSIONS: Although cancer-associated PE patients treated with DOACs showed higher mortality compared with non-cancer patients, presumably because of the presence of cancer, the risk of recurrent VTE or major bleeding was comparable between the 2 groups. Thus, DOAC is an important treatment option for cancer-associated PE, although underlying cancer-related risks (e.g., chemotherapy) remain.

Left Upper Lobe Trisegmentectomy After Pulmonary Endarterectomy.

Major pulmonary resection has been successfully performed after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension in a few cases. A pulmonary nodule was detected in a 68-year-old man with a diagnosis of chronic thromboembolic pulmonary hypertension. After pulmonary hypertension was resolved with pulmonary endarterectomy, left upper lobe trisegmentectomy was performed for small lung cancer. Dissection of the pulmonary artery was carefully performed with a possibility of a fragile state on the arterial wall due to previous pulmonary endarterectomy. Pathologically, the arterial media with an uneven thickness was exposed to the vascular lumen in the resected pulmonary artery.

Effects of Tobacco Smoking on Cardiovascular Disease.

Tobacco smoking continues to be a major risk factor for cardiovascular disease (CVD) and the leading avoidable cause of death worldwide. Tobacco smoking has declined in high-income countries, but the average smoking rate in Japan remains high: 29.4% for men and 7.2% for women in 2017. Of note, the average smoking rate among middle-aged men remains approximately 40%, indicating that a high incidence of smoking-related CVD will continue for a couple of decades in Japan. The adverse effects of tobacco smoking on CVD are more extensive than previously thought. Physicians should be particularly alert to the development and progression of heart failure, atrial fibrillation, and venous thromboembolism, as well as ischemic CVD among tobacco smokers. Increasing use of heat-not-burn tobacco as cigarette alternatives is an emerging issue. Harmful effects do not disappear just by changing the delivery system of tobacco.

Usefulness of scoring right ventricular function for assessment of prognostic factors in patients with chronic thromboembolic pulmonary hypertension.

Right ventricular (RV) function is associated with prognosis in chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to establish an RV dysfunction score using RV echocardiographic parameters to clarify the clinical characteristics in patients with CTEPH and to compare RV dysfunction score with parameters such as World Health Organization (WHO) functional class, hemodynamics, exercise capacity, and plasma BNP level. We enrolled 35 inpatients with CTEPH (mean age, 62 ± 15 years, 15 males). We constructed 'an RV dysfunction score' calculated as the summation of each point awarded for the presence of four parameters: tricuspid annular plane systolic excursion (TAPSE) < 16 mm, 1 point; tissue Doppler-derived tricuspid lateral annular systolic velocity (S') < 10 cm/s, 1 point; right ventricular fractional area change (RVFAC) < 35%, 1 point; and right ventricular myocardial performance index (RV-MPI) > 0.4, 1 point. TAPSE, S', RVFAC, and RV-MPI was 18.7 ± 4.8 mm, 11.9 ± 3.1 cm/s, 33.5 ± 13.9%, and 0.39 ± 0.2, respectively. The RV dysfunction score was associated with symptom [WHO functional class (p = 0.026)], hemodynamics [mean PAP (p = 0.01), cardiac index (p = 0.009), pulmonary vascular resistance (p = 0.001), and SvO2 (p = 0.039)], exercise capacity [6-min walk distance (p = 0.046), peakVO2 (p = 0.016), and VE/VCO2 slope (p = 0.031)], and plasma BNP level (p = 0.005). This RV dysfunction score using the four RV echocardiographic parameters could be a simple and useful scoring system to evaluate prognostic factors in patients with CTEPH.

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

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

Impact of preoperative regular physical activity on postoperative course after open abdominal aortic aneurysm surgery.

Early ambulation after open abdominal aortic aneurysm (AAA) surgery is assumed to play a key role in preventing postoperative complications and reducing hospital length of stay. However, the factors predicting early ambulation after open AAA surgery have not yet been sufficiently investigated. Here, we investigated which preoperative and intraoperative variables are associated with start time for ambulation in patients after open AAA surgery. A total of 67 consecutive patients undergoing open AAA surgery were included in the study [male, 62 (92 %); mean age, 68 years (range, 47-82 years), mean AAA diameter, 53 mm (range, 28-80 mm)]. Preoperative physical activity was examined by means of 6-min walk distance (6MWD) and a medical interview. Patients were divided into two groups, according to when independence in walking was attained: early group <3 days (n = 36) and late group ≥3 days (n = 31), and the pre-, intra-, and postoperative recovery data were compared. There were no significant differences in patient baseline characteristics or intraoperative data between the two groups. The number of patients engaging in preoperative regular physical activity and 6MWD were significantly greater (p = 0.042 and p = 0.034, respectively) in the early group than in the late group. In addition, time to hospital discharge was significantly shorter in the early group than in the late group (p = 0.031). Binary logistic regression analysis showed that preoperative regular physical activity was the only independent factor for identifying patients in the early group (odds ratio 2.769, 95 % confidence interval 1.024-7.487, p = 0.045). These results suggest that engaging in regular physical activity is an effective predictor of early ambulation after open AAA surgery.

Imatinib is partially effective for the treatment of pulmonary capillary hemangiomatosis.

A 43-year-old man presented with dyspnea on exertion. Right heart catheterization demonstrated pulmonary arterial hypertension (PAH). He was treated with bosentan, sildenafil and intravenous epoprostenol. Despite the administration of such intensive therapy, the patient's condition deteriorated to a World Health Organization functional class (WHO-FC) of IV. He participated in a clinical trial of imatinib for PAH. After three months of treatment with imatinib, the chest X-ray and echocardiography findings improved, and the WHO-FC class was III. One year after, however, the PAH worsened again, and the patient died 2.6 years after the first diagnosis. At autopsy, patchy capillary proliferation was observed in the lungs. The definitive diagnosis was pulmonary capillary hemangiomatosis.

Associations of proteinuria and the estimated glomerular filtration rate with incident hypertension in young to middle-aged Japanese males.

OBJECTIVE: To investigate the independent associations of proteinuria and the estimated glomerular filtration rate (eGFR) with incident hypertension. METHODS: We investigated 29,181 Japanese males 18-59years old without hypertension in 2000 and examined whether proteinuria and the eGFR predicted incident hypertension independently over 10years. Incident hypertension was defined as a newly detected blood pressure of ≥140/90mmHg and/or the initiation of antihypertensive drugs. Proteinuria and the eGFR were categorized as dipstick negative (reference), trace or ≥1+ and ≥60 (reference), 50-59.9 or <50ml/min/1.73m(2), respectively. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of incident hypertension. RESULTS: At baseline, 236 (0.8%) and 477 (1.6%) participants had trace and ≥1+ dipstick proteinuria, while 1416 (4.9%) and 129 (0.4%) participants had an eGFR of 50-59.9 and <50ml/min/1.73m(2), respectively. The adjusted HRs were significant for proteinuria ≥1+ (HRs 1.20, 95% CI: 1.06-1.35) and an eGFR of <50ml/min/1.73m(2) (1.29, 1.03-1.61). When two non-referent categories were combined (dipstick≥trace vs. negative and eGFR<60 vs. ≥60ml/min/1.73m(2)), the association was more significant for proteinuria (1.15, 1.04-1.27) than for eGFR (0.99, 0.92-1.07). CONCLUSIONS: Proteinuria and a reduced eGFR are independently associated with future hypertension in young to middle-aged Japanese males.

Usefulness of serum cardiac troponins T and I to predict cardiac molecular changes and cardiac damage in patients with hypertrophic cardiomyopathy.

Cardiac troponins provide diagnostic and prognostic information on ischemic heart disease, but their roles in hypertrophic cardiomyopathy (HCM) are unclear. We sought to investigate the associations between elevated serum cardiac troponins T (cTnT) and I (cTnI) levels and cardiac injury in patients with HCM. We measured serum cTnT and cTnI in a peripheral vein of 73 consecutive HCM patients in stable condition. In addition, to examine the transcardiac release of cTnT and that of cTnI, we measured them in the aortic root and coronary sinus. Mitochondrial- and Ca(2+)-handling-related gene expression assays were analyzed by endomyocardial biopsy specimens. Based on the median value of serum cTnT, we divided the patients into two groups [group A: cTnT < 0.008 ng/mL, (n = 35), group B: cTnT group ≥ 0.008 ng/mL, (n = 38)]. Left ventricular (LV) mass index was significantly higher, while LV ejection fraction was significantly lower, in group B than in group A. Meanwhile, there was a significantly positive correlation between the transcardiac gradient of serum cTnT or cTnI, and the mRNA level of troponin I3 (r = 0.473, r = 0.516, respectively). The mRNA level of troponin T2 significantly correlated with mRNA levels of sarco-endoplasmic reticulum Ca(2+)-ATPase 2, cytochrome c oxidase subunit 5B, and troponin I3 (r = 0.486, r = 0.957, r = 0.633, respectively). These findings indicate that both elevated serum cTnT and cTnI might be associated with cardiac dysfunction in patients with HCM, resulting from the impairment of mitochondrial function and Ca(2+)-handling protein.

Relationship of myocardial fibrosis to left ventricular and mitochondrial function in nonischemic dilated cardiomyopathy--a comparison of focal and interstitial fibrosis.

BACKGROUND: Mitochondrial damage is associated with histologic myocardial fibrosis. Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) can be used to identify focal fibrosis. We examined whether myocardial fibrosis on CMR and collagen volume fraction (CVF) from biopsies correlated with left ventricular (LV) and mitochondrial function in patients with nonischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: Fifty-nine DCM patients underwent CMR, cardiac catheterization, and endomyocardial biopsy. Minimum first derivative of LV pressure (LVdP/dt(min)) was measured as an index of LV relaxation. Mitochondrial RNA expression was also analyzed. For quantitative analysis of myocardial fibrosis, percentage LGE (%LGE) and CVF were calculated. Patients were divided into 2 groups on the basis of the presence (LGE group; n = 27) or absence (non-LGE group; n = 32) of LGE. Mean CVF and absolute value of LVdP/dt(min) were significantly higher and lower, respectively, in the LGE group than in the non-LGE group. Multivariate analysis revealed that %LGE was an independent determinant of LVdP/dt(min). The abundance of mitochondrial enzyme mRNA was significantly lower in the LGE group. CONCLUSIONS: Noninvasive CMR imaging is more useful in predicting diastolic dysfunction than invasive histologic assessments. In addition, it might indicate mitochondrial dysfunction in DCM.

Cerebral embolism due to atrial myopathy in a cardiac amyloidosis patient diagnosed by cardiac magnetic resonance imaging.

A 55-year-old woman was admitted with heart failure. On the third hospital day, she suddenly developed cerebral infarction. The resting 12-lead electrocardiography showed normal sinus rhythm, and atrial fibrillation or flutter were never detected on electrocardiographic monitoring throughout the whole hospital days. She had no other conventional risk factor for cerebral infarction. Transthoracic echocardiography showed left ventricular hypertrophy. Transesophageal echocardiogram revealed strong spontaneous echo contrast in the left atrium (LA), and the blood flow in the left atrial appendage was extremely decreased (22.3 cm/s). Late gadolinium enhancement in cardiac magnetic resonance (CMR) imaging showed global subendocardial hyperenhancement of the left ventricle and both atria. Endomyocardial biopsy specimen was positive for amyloid by Congo red staining. Marked amyloid infiltration to both atria might cause atrial dysfunction leading to thrombus formation in the LA. CMR is thought to be a useful noninvasive tool to detect atrial myopathy in cardiac amyloidosis patients. .

Cardiovascular events increased at normal and high-normal blood pressure in young and middle-aged Japanese male smokers but not in nonsmokers.

OBJECTIVE: To clarify whether the impact of normal and high-normal BP (BP) per se on cardiovascular disease (CVD) and all-cause death differs depending on smoking status. METHODS AND RESULTS: A prospective observational cohort study (median follow-up period: 7.5 years) was performed among 25,077 healthy nondiabetic Japanese men aged 20-61 years (mean age 37.3 years), whose BP was less than 150/95 mmHg and who were not on medication. Hazard ratios (HRs), adjusted by known risk factors and a change in annual BP during the follow-up, were calculated by the Cox proportional model with less than 119/75 mmHg as a reference. Among smokers, CVD events increased significantly from a SBP of 120 mmHg, with HRs of 2.68 (120-129 mmHg), 4.28 (130-139 mmHg), and 11.7 (140-149 mmHg). The CVD events also increased from a DBP of 75 mmHg (P for trend less than 0.0001), with 75-79 mmHg and 90-94 mmHg considered statistically significant. Among noncurrent smokers, 110-149 mmHg (SBP) and 75-89 mmHg (DBP) were not associated with elevated HRs for CVD. The relation between BP and all-cause mortality was similar among both current and noncurrent smokers: 140-149 mmHg (SBP) and 90-94 mmHg (DBP) were significantly associated with elevated risk, and 130-139 mmHg (SBP) among noncurrent smokers associated with elevated risk. CONCLUSION: Young and middle-aged healthy Japanese individuals with normal and high-normal BP (120-139/75-89 mmHg) were at risk for CVD among smokers, even after adjusting for an annual change in BP.

The significance of measuring body fat percentage determined by bioelectrical impedance analysis for detecting subjects with cardiovascular disease risk factors.

BACKGROUND: Body fat percentage (BF%) determined by bioelectrical impedance analysis is widely used at home and in medical check-ups. However, the clinical significance of measuring BF% has not been studied in detail. METHODS AND RESULTS: A cross-sectional study was carried out on a cohort of 10,774 middle-aged Japanese men who had undergone an annual check-up in 2008. Cut-off points were evaluated for body mass index (BMI), waist circumference (WC), and BF% for detecting participants with cardiovascular disease (CVD) risk factors (diabetes mellitus, hypertension, dyslipidemia), and effectiveness compared for each marker's cut-off point. Additionally, the effects of smoking on cut-off points were evaluated. The cut-off points of BMI, WC, and BF% for detecting participants with 1 or more CVD risk factors were 22.7kg/m(2), 81.4cm, and 20.3%, respectively. The cut-off points of BF% for 1 or more CVD risk factors classified 3.43% more subjects into correct categories than those of BMI (P<0.001). The cut-off points of BMI, WC, and BF% for detecting individuals with 3 CVD risk factors in current smokers were 24.9kg/m(2), 87.8cm, and 23.7%, while those in non-smokers were 23.3kg/m(2), 83.9cm, and 22.3%, respectively. CONCLUSIONS: BF% could be more effective in detecting individuals with early stage CVD risk accumulation than BMI. The cut-off points for current smokers were lower than those for non-smokers in all markers.

Impact of low levels of vascular endothelial growth factor after myocardial infarction on 6-month clinical outcome. Results from the Nagoya Acute Myocardial Infarction Study.

BACKGROUND: Vascular endothelial growth factor (VEGF) is induced by myocardial ischemia and is thought to facilitate cardiovascular repair after acute myocardial infarction (AMI). However, the association between the plasma VEGF levels and clinical outcome in AMI patients is unclear. METHODS AND RESULTS: We evaluated 879 AMI patients undergoing successful primary revascularization within 24h of symptom onset. The patients were classified into 3 groups according to tertiles of plasma VEGF levels at 7 days after the onset of AMI. Major adverse cardiovascular and cerebrovascular events (MACCE), defined as cardiac death, recurrent acute coronary syndrome, hospital readmission for heart failure, or stroke, were assessed during the 6-month follow-up period. The incidence of MACCE was the least frequent in the middle tertile. Compared to the middle tertile, patients in the low tertile were at a significantly higher risk for MACCE even after adjusting for baseline characteristics (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.18-6.06, P=0.019). An absence of statin treatment before onset and a younger age (HR 0.54, 0.87; 95%CI 0.33-0.90, 0.76-0.99; P=0.017, 0.037; respectively) were significantly associated with low VEGF. CONCLUSIONS: Low plasma VEGF levels at 7 days after the onset of AMI were associated with a significantly increased risk for MACCE during 6 months of follow-up.

Smoking and smoking cessation in relation to all-cause mortality and cardiovascular events in 25,464 healthy male Japanese workers.

BACKGROUND: Smoking is still a major health problem among males in Japan. The effects of smoking and quitting on mortality and cardiovascular disease (CVD) need updating. METHODS AND RESULTS: This was a prospective cohort study with a median follow-up of 7.5 years of a total of 25,464 healthy male Japanese workers aged 20-61 years who were not on any medication. The adjusted hazard ratios (HR; 95% confidence interval) for all-cause death were 1.51 (0.73, 2.94), 1.68 (1.07, 2.70), 1.30 (0.70, 2.34), and those for total CVD events 1.91 (0.72, 4.67), 2.94 (1.65, 5.63), and 3.25 (1.69, 6.54) for light smokers (1-10 cigarettes/day), moderate smokers (11-20/day), and heavy smokers (≥ 21/day) compared to never-smokers, respectively. Total CVD events increased dose-dependently as the number of cigarettes/day increased. Acute myocardial infarction was increased at any level of smoking. Stroke was increased at a moderate level of smoking. Quitting for ≥ 4 years, compared with continuing smokers, reduced the HR for all-cause death to 0.64 (0.38, 1.01), and total CVD events to 0.34 (0.17, 0.62). CONCLUSIONS: In healthy young- and middle-aged Japanese males, a significant increase in HR for total CVD events was confirmed for a smoking level of 11-20 cigarettes/day. Quitting reduced the HR for total CVD events, with quitting for ≥ 4 years being statistically significant. A similar trend was observed for all-cause mortality.

Pitavastatin, an HMG-CoA reductase inhibitor, ameliorates endothelial function in chronic smokers.

BACKGROUND: Smoking is a major cardiovascular risk factor, leading to endothelial dysfunction. The present study investigated the hypothesis that pitavastatin, an HMG-CoA reductase inhibitor, may improve endothelial function in chronic smokers via its antioxidant properties. METHODS AND RESULTS: The 30 male chronic smokers who exhibited mild hypercholesterolemia at the time of physical check-up were enrolled and randomized to the pitavastatin group (2 mg/day, n=15) or the untreated control group (n=15). Before and after the 4-week treatment period, endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent dilation by glyceryl trinitrate (GTD) were examined, and the FMD/GTD ratio was calculated. The pitavastatin group showed a significant restoration of endothelial function (percent change in FMD: +49.6% vs +1.4%; percent change in FMD/GTD ratio: +26.6% vs 4.5%, P<0.05 respectively), and a significant reduction in oxidative stress levels (malondialdehyde-low-density lipoprotein-cholesterol: 16.6% vs +7.5%; free radical activity: 1.8% vs +9.7%, P<0.05 respectively) compared with the control group. Pitavastatin had no effect on the number of circulating CD34(+)CD133(+) progenitor cells, endothelial progenitor cells, or the MMP-2, MMP-9 and VEGF levels. In vitro oxidative stress monitoring assay revealed that pitavastatin protected endothelial cells against oxidative stress. CONCLUSIONS: Pitavastatin restores endothelial function, even in chronic smokers, possibly through its antioxidative properties. (Circ J 2010; 74: 195 - 202).

Differentiation capacity of endothelial progenitor cells correlates with endothelial function in healthy young men.

BACKGROUND: Endothelial progenitor cells (EPCs) have been assumed to maintain vascular endothelial integrity, so the present study investigated whether the functional capacity of EPCs correlates with endothelial function in healthy young subjects, as has been confirmed in aged subjects with atherosclerotic disease. METHODS AND RESULTS: EPCs in 41 healthy, young male nonsmokers (age 33.1 +/-3.9 years, mean +/- SD) were characterized. The correlation between flow-mediated vasodilation (FMD) and the number of EPCs or the plasma concentrations of growth factors, such as vascular endothelial growth factor, did not reach statistical significance. However, FMD was significantly correlated with the EPC differentiation index, defined as the ratio of the number of EPCs to the total number of adherent cells (r=0.391, P=0.011) and the abundance of endothelial nitric oxide synthase mRNA (r=0.340, P=0.030). CONCLUSIONS: In healthy young men, despite a lack of correlation of the number or colony counts of EPCs, the ability of circulating progenitor cells to differentiate into an endothelial lineage is closely correlated with endothelial function. This cell function assay may serve as a novel biomarker for vascular function in healthy subjects in the pre-atherosclerotic stage.