Eicosapentaenoic Acid Level Predicts Long-Term Survival and Cardiovascular or Limb Event in Peripheral Arterial Disease.

Objectives: We examined the relationship between plasma eicosapentaenoic acid (EPA) level and long-term all-cause death (ACD) and cardiovascular or limb events in patients with peripheral arterial disease (PAD). Method: We performed a prospective cohort study on 637 PAD patients. The endpoints were ACD, major adverse cardiovascular events (MACEs), and lower extremity arterial events (LEAEs). Results: The incidences of ACD, MACEs, and LEAEs had correlation with EPA levels (p <0.05). Plasma EPA level had significant positive correlations with high-density lipoprotein cholesterol, triglyceride, and estimated glomerular filtration rate (eGFR), and negative correlation with C-reactive protein (CRP). In Cox stepwise multivariate analysis, lower EPA (hazard ratio [HR]: 0.996, 95% confidence interval [CI]: 0.993-1.000, p = 0.034), ankle brachial pressure index (ABI), body mass index, serum albumin, eGFR, age, CRP, D-dimer, critical limb ischemia, diabetes, cerebrovascular disease (CVD), and statin were related to ACD (p <0.05); lower EPA (HR: 0.997, 95% CI: 0.994-1.000, p = 0.038), ABI, serum albumin, eGFR, age, diabetes, coronary heart disease, CVD, and statin were related to MACEs (p <0.05); and lower EPA (HR: 0.988, 95% CI: 0.982-0.993, p <0.001), ABI, and low-density lipoprotein cholesterol were related to LEAEs (p <0.05). Conclusions: Low plasma EPA level was a significant risk factor for ACD, MACEs, and LEAEs in patients with PAD.

Review of Bleeding and Thrombotic Risks Associated With Antithrombotic Therapy After Transcatheter Structural Heart Interventions.

Transcatheter structural heart interventions have drastically evolved over the past 2 decades. However, most catheterization procedures require the deployment of devices in the body; therefore, the adhesion of thrombi to those devices is a major problem, resulting in the requirement of a period of postprocedural antithrombotic regimen. However, in recent years, bleeding associated with these antithrombotic therapies has also become a major concern, attracting the attention of investigators. This is complicated by the fact that patients at high thrombotic risk are also at high bleeding risk, making the issue of administrating antithrombotic therapy challenging. The objective of this review was to identify the important issues and summarize the current status of postoperative antithrombotic therapy and assessment of the bleeding risk following transcatheter structural heart interventions such as transcatheter aortic valve replacement, transcatheter edge-to-edge repair, and transcatheter left atrial appendage occlusion.

Fifteen-year clinical prognosis and cardiovascular or limb event associated with homocysteine levels in peripheral arterial disease.

BACKGROUND: There are limited reports on the relationship between plasma homocysteine (Hcy) levels and long-term all-cause death (ACD), cardiovascular events, or limb events in patients with peripheral arterial disease (PAD). We examined the relationship between plasma Hcy levels and 15-year these events in PAD patients. METHODS: We performed a prospective cohort study in 955 PAD patients. The patients were divided into four groups based on plasma Hcy levels with median (interquartile range). The endpoints were cumulative incidences of ACD, major adverse cardiovascular events (MACE), and MACE plus limb events (MACLE). RESULTS: The incidences of ACD, MACE, and MACLE were correlated with plasma Hcy levels (P < 0.05). In multiple regression analysis, plasma Hcy had positive correlations with C-reactive protein (CRP), men, and critical limb ischemia (CLI) and negative correlations with estimated glomerular filtration rate (eGFR) and high-density lipoprotein cholesterol (p < 0.05). In Cox multivariate analysis, higher Hcy (HR 1.614, 95 % CI 1.229-2.119, p = 0.001), age, CRP, brain natriuretic peptide (BNP), D-dimer, lower body mass index, ankle brachial pressure index (ABI), serum albumin, eGFR, CLI, coronary heart disease (CHD), cerebrovascular disease, and diabetes were related to ACD; higher Hcy (HR 1.242, 95 % CI 1.004-1.535, p = 0.045), age, BNP, lower ABI, serum albumin, diabetes, and CHD were related to MACE; and higher Hcy (HR 1.290, 95 % CI 1.057-1.574, p = 0.012), BNP, lower ABI, serum albumin, CHD, and diabetes were related to MACLE (P < 0.05). Statins improved ACD, MACE, and MACLE (p < 0.01). CONCLUSIONS: Plasma Hcy was a risk factor for 15-year ACD, MACE, and MACLE in patients with PAD.

Lipoprotein(a) is a Promising Residual Risk Factor for Long-Term Clinical Prognosis in Peripheral Arterial Disease.

Objectives: We investigated the relationship between plasma lipoprotein(a) [Lp(a)] level and long-term prognosis, cardiovascular events, or pure leg events (LE) in patients with peripheral arterial disease (PAD). Materials and Methods: We prospectively enrolled 1104 PAD patients. The endpoints were LE, cerebrovascular- or cardiovascular-related death (CVRD), all-cause death (ACD), and major adverse cardiovascular events (MACE). Results: The incidences of LE, CVRD, ACD, and MACE were correlated with Lp(a) level (P<0.05). Lp(a) was positively correlated with low-density lipoprotein cholesterol and C-reactive protein (CRP) and negatively correlated with estimated glomerular filtration rate (eGFR). In the Cox multivariate regression analysis, high Lp(a), CRP, age, low ankle-brachial pressure index (ABI), eGFR, albumin, critical limb ischemia (CLI), cerebrovascular disease (CVD), and diabetes were associated with LE; high Lp(a), age, CRP, low ABI, body mass index, eGFR, albumin, CLI, coronary heart disease (CHD), CVD, and diabetes were associated with CVRD; high Lp(a), CRP, age, low ABI, eGFR, albumin, CLI, and CVD were associated with ACD; and high Lp(a), CRP, age, low eGFR, albumin, CLI, CHD, and diabetes were associated with MACE (P<0.05). Statins improved all endpoints (P<0.01). Conclusion: Lp(a) was a significant residual risk factor for LE, CVRD, ACD, and MACE in PAD patients.

Influence of Microalbuminuria on Long-Term Survival and Cardiovascular or Limb Events in Peripheral Arterial Disease.

Objective: This study aimed to examine the relationship between microalbuminuria and long-term life expectancy or limb events in patients with peripheral arterial disease (PAD). Materials and Methods: A prospective cohort study was performed in 714 patients with PAD. The primary outcomes were cardiovascular or cerebrovascular death (CCVD) and all-cause death (AD), and secondary outcomes were major adverse cardiovascular events (MACE) and cardiovascular and/or limb events (CVLE). Results: The 5, 10, and 15 year survival rates were 82.4%, 53.1%, and 33.0%, respectively. The prevalence of patients with increased microalbuminuria was 39.2%. Higher microalbuminuria, age, C-reactive protein (CRP), lower serum albumin, estimated glomerular filtration rate (eGFR), ankle-brachial pressure index (ABI), diabetes, cerebral infarction, and coronary heart disease (CHD) were associated with CCVD; higher microalbuminuria, age, CRP, D-dimer, lower serum albumin, eGFR, and critical limb ischemia were related to AD; higher microalbuminuria, age, CRP, lower serum albumin, ABI, diabetes, and CHD were related to MACE; higher microalbuminuria, age, lower ABI, cerebral infarction, and CHD were related to CVLE in Cox multivariate analyses (p<0.05). Statins reduced CCVD, AD, MACE, and CVLE (p<0.001). Conclusion: Higher microalbuminuria was a significant predictor for CCVD, AD, MACE, and CVLE in PAD patients.

Impact of brain natriuretic peptide for predicting long-term life expectancy and cardiovascular or limb events in peripheral arterial disease.

BACKGROUND: Brain natriuretic peptide (BNP) is introduced as a predictor of the degree of ventricular dysfunction and is associated with mortality. There are limited reports on the relationship of BNP with long-term all-cause death (AD) and cardiovascular or limb events in peripheral artery disease (PAD). We examined the relationship between BNP level and these events in PAD patients. METHODS: We performed a prospective cohort study in 938 PAD patients. The patients were divided into four groups based on BNP levels with median (interquartile range): Q1: ≤20.4; Q2: 20.5-42.8; Q3: 42.9-103.4; and Q4: ≥103.5 pg/mL. The endpoints were AD, freedom from major adverse cardiovascular events (MACE), and MACE plus limb events (MALE). RESULTS: The median follow-up time was 65 months. There were 383 deaths (40.8%) during follow-up period. AD depended on BNP levels (P<0.01), with 5-year freedom from AD rates of Q1: 94%, Q2: 84%, Q3: 69%, and Q4: 55%. The Kaplan-Meier estimates of freedom from AD, MACE, and MALE had significant differences among Q1- Q4 groups (P<0.001). In multiple regression analysis, BNP had significant negative correlations with eGFR, serum albumin, and BMI and positive correlations with diabetes (P<0.05). In Cox multivariate analysis, higher BNP, age, CRP, D-dimer, lower BMI, ABI, serum albumin, and eGFR were related to AD; and higher BNP, age, lower ABI, serum albumin, CAD, and DM were related to MACE and MALE (P<0.05). Statins improved AD, MACE, and MALE (P<0.01). CONCLUSIONS: BNP was a promising biomarker for AD, MACE, and MALE in patients with PAD.

The Geriatric Nutritional Risk Index Predicts Long-Term Survival and Cardiovascular or Limb Events in Peripheral Arterial Disease.

AIM: The Geriatric Nutritional Risk Index (GNRI) was developed to assess the nutritional risk and is associated with mortality. However, there are limited reports on the relationship between the GNRI and overall survival (OS) in peripheral artery disease (PAD). Therefore, the purpose of this study was to examine the relationship between GNRI and OS and cardiovascular or limb events in patients with PAD. METHODS: A prospective cohort study was performed on 1,219 patients with PAD. The baseline GNRI was calculated from the serum albumin level and body mass index obtained at the first visit. The patients were divided into four groups according to the GNRI: G0 (＞98), G1 (92-98), G2 (82-91), and G3 (＜82). The endpoints were OS and freedom from major adverse cardiovascular events (MACE) and MACE plus limb events (MACLE). RESULTS: The median follow-up period was 73 months. There were 626 deaths (51.4%) during the follow-up. The rate of cardiovascular death was 51.3%. OS clearly depended on the GNRI (p＜0.01), with five-year OS rates of 80.8% for G0, 62.0% for G1, 40.0% for G2, and 23.3% for G3. In multivariate analyses, the GNRI, age, ankle-brachial pressure index (ABPI), critical limb ischemia, estimated glomerular filtration rate (eGFR), and C-reactive protein (CRP) were independent factors associated with OS, and GNRI, age, ABPI, coronary artery disease, diabetes mellitus, eGFR, and CRP were associated with MACE and MACLE (all p＜0.05). Statins were found to improve OS, MACE, and MACLE (p＜0.01). CONCLUSIONS: GNRI is an independent predictor for OS, MACE, and MACLE in patients with PAD.

Asymptomatic cerebral infarction is a predictor of long-term survival and vascular or limb events in peripheral arterial disease.

Aims: The purpose of this study was to examine long-term life expectancy including cerebrovascular events (CVE) and fate of the leg in patients with peripheral arterial disease (PAD) with or without cerebral infarction (CI) detected by computed tomography (CT). Methods and results: A prospective cohort study was performed in 932 patients with PAD. The endpoints were overall survival (OS), CVE, stroke-free survival (SFS), freedom from major adverse cardiovascular events (MACE), and freedom from major adverse cardiovascular and limb events (MACLE). The prevalence of CI on CT was 56.8%. There were 413 deaths (44.3%) during follow-up. The rate of cardiovascular deaths among those who died was 53.5%. The 3-, 5-, and 10-year OS rates were 82.0%, 76.9%, and 46.2%, respectively. In Cox multivariate analyses, age, ankle brachial pressure index (ABI), critical limb ischaemia (CLI), estimated glomerular filtration rate (eGFR), albumin level, and CI were independent factors associated with OS (P < 0.05); age, ABI, CLI, atrial fibrillation (AF), and CI were related to CVE (P < 0.05); age, ABI, CLI, diabetes, coronary heart disease (CHD), AF, eGFR, lower albumin, and CI were related to SFS (P < 0.05); age, ABI, CLI, diabetes, CHD, eGFR, lower albumin, and CI were associated with MACE (P < 0.05); and age, ABI, diabetes, CHD, eGFR, lower albumin and CI were related to MACLE (P < 0.05). Statins improved MACE and MACLE (P < 0.05), and AF increased MACLE (P < 0.05). Conclusions: CI on CT was an independent predictor for mortality, CVE, SFS, MACE, and MACLE. Statins improved MACE and MACLE, but AF increased CVE and MACLE in patients with PAD.

Left Atrial Appendage Closure Under Intracardiac Echocardiographic Guidance: Feasibility and Comparison With Transesophageal Echocardiography.

BACKGROUND: Transcatheter left atrial appendage closure is an alternative therapy for stroke prevention in atrial fibrillation patients. These procedures are currently guided with transesophageal echocardiography and fluoroscopy in most centers. As intracardiac echocardiography (ICE) is commonly used in other catheter-based procedures, we sought to determine the safety and effectiveness of intracardiac echocardiography-guided left atrial appendage closure with the Watchman device. METHODS AND RESULTS: A total of 27 patients (11 males, 77.0±8.5 years) with atrial fibrillation receiving Watchman left atrial appendage closure under intracardiac echocardiography guidance at a single center were investigated. All patients were implanted successfully. There were no major procedural complications. The overall procedure-related complication rate was 14.8%, mainly due to access site hematoma. Transesophageal echocardiography demonstrated successful closure of the left atrial appendage in all patients at 45 days after device implant. CONCLUSIONS: Transcatheter left atrial appendage closure with intracardiac echocardiography guidance is safe and feasible.

Comparative effects of long-acting and short-acting loop diuretics on cardiac sympathetic nerve activity in patients with chronic heart failure.

OBJECTIVE: Short-acting loop diuretics are known to enhance cardiac sympathetic nerve activity (CSNA) in patients with chronic heart failure (CHF). The effects of two loop diuretics-long-acting azosemide and short-acting furosemide-on CSNA were evaluated using (123)I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with CHF. METHODS: The present study was a subanalysis of our previously published study, which had reported that serial (123)I-MIBG studies were the most useful prognostic indicator in patients with CHF. Patients with CHF (n=208, left ventricular ejection fraction <45%) but no history of cardiac events for at least 5 months prior to the study were identified according to their histories of acute decompensated heart failure requiring hospitalisation. Patients underwent (123)I-MIBG scintigraphy immediately before hospital discharge and at a 6-month follow-up. The delayed % denervation, delayed heart/mediastinum count (H/M) ratio and washout rate (WR) were determined using (123)I-MIBG scintigraphy. A total of 108 patients were selected, and propensity score matching was used to compare patients treated with either oral azosemide (n=54) or furosemide (n=54). RESULTS: After treatment, (123)I-MIBG scintigraphic parameters improved in both groups. However, the degree of change in % denervation was -13.8±10.5 in the azosemide group and -5.7±12.7 in the furosemide group (p<0.01), the change in H/M ratio was 0.20±0.16 in the azosemide group and 0.06±0.19 in the furosemide group (p<0.01), and the change in WR was -11.3±9.2% in the azosemide group and -3.0±12.7% in the furosemide group (p<0.01). Moreover, multivariate analysis showed an independent and significant positive relationship between furosemide and δ-WR from hospital discharge to 6 months after treatment in patients with CHF (p=0.001). CONCLUSIONS: These findings indicate that azosemide suppresses CSNA compared with furosemide in patients with CHF. TRIAL REGISTRATION NUMBER: UMIN000000626 (UMIN-CTR Clinical Trial).

Fibronectin type III domain containing 5 expression in skeletal muscle in chronic heart failure-relevance of inflammatory cytokines.

BACKGROUND: Chronic heart failure (CHF) is commonly associated with muscle atrophy and increased inflammation. Irisin, a myokine proteolytically processed by the fibronectin type III domain containing 5 (FNDC5) gene and suggested to be Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α activated, modulates the browning of adipocytes and is related to muscle mass. Therefore, we investigated whether skeletal muscle FNDC5 expression in CHF was reduced and if this was mediated by inflammatory cytokines and/or angiotensin II (Ang-II). METHODS: Skeletal muscle FNDC5 mRNA/protein and PGC-1α mRNA expression (arbitrary units) were analysed in: (i) rats with ischemic cardiomyopathy; (ii) mice injected with tumour necrosis factor-α (TNF-α) (24 h); (iii) mice infused with Ang-II (4 weeks); and (iv) C2C12 myotubes exposed to recombinant cytokines or Ang-II. Circulating TNF-α, Ang-II, and irisin was measured by ELISA. RESULTS: Ischemic cardiomyopathy reduced significantly FNDC5 protein (1.3 ± 0.2 vs. 0.5 ± 0.1) and PGC-1α mRNA expression (8.2 ± 1.5 vs. 4.7 ± 0.7). In vivo TNF-α and Ang-II reduced FNDC5 protein expression by 28% and 45%, respectively. Incubation of myotubes with TNF-α, interleukin-1ß, or TNF-α/interleukin-1ß reduced FNDC5 protein expression by 47%, 37%, or 57%, respectively, whereas Ang-II had no effect. PGC-1α was linearly correlated to FNDC5 in all conditions. In CHF, animals circulating TNF-α and Ang-II were significantly increased, whereas irisin was significantly reduced. A negative correlation between circulating TNF-α and irisin was evident. CONCLUSION: A reduced expression of skeletal muscle FNDC5 in ischemic cardiomyopathy is likely modulated by inflammatory cytokines and/or Ang-II via the down-regulation of PGC-1α. This may act as a protective mechanism either by slowing the browning of adipocytes and preserving energy homeostasis or by regulating muscle atrophy.

Interventional closure of the left atrial appendage for stroke prevention.

BACKGROUND: Transcatheter left atrial appendage (LAA) closure is an alternative therapy for stroke prevention in atrial fibrillation (AF) patients. However; real-world efficacy, safety and complications have yet to be investigated. We sought to determine the procedural outcomes and potential complications of LAA closure in routine clinical practice at a high-volume center. METHODS AND RESULTS: The study group comprised 179 patients (105 males; 72.7±9.0 years) with AF undergoing LAA closure at a single center in Germany. The rate of successful implantation was 98.9% (2 patients did not undergo implantation) and the overall procedure-related complication rate was 11.2% (major: 3.3%: tamponade 2; possibility of transient ischemic attack (TIA) 1; device dislocation 3; minor: 7.8%: pericardial effusion 2; air embolization with transient ST segment elevation 3; thrombus on device/sheath 3; puncture complications 5). At 45 days; 99.4% showed successful sealing of the LAA and 94.5% discontinued oral anticoagulation (OAC). TIA occurred in 2 patients during 6-month follow-up; but no cases of stroke were reported. There were no hemorrhagic stroke or device-related deaths. Only 1 patient was hospitalized with traumatic subdural hematoma. Minor bleeding was reported in 5 patients. CONCLUSIONS: Transcatheter LAA closure in a high-volume center is safe and feasible. Life-threatening complications are rare. Discontinuation of OAC 45 days after implantation was also safe.

Impaired HDL function in obese adolescents: impact of lifestyle intervention and bariatric surgery.

OBJECTIVE: HDL regulates endothelial function via stimulation of nitric oxide production. It is documented that endothelial function is impaired in obese adolescents, and improved by lifestyle interventions (LI). DESIGN AND METHODS: HDL function in obese adolescents and the impact of LI or Roux-en-Y gastric bypass surgery (RYGB) was assessed. HDL was isolated from 14 adolescents with normal body mass index (HDLcontrol ), 10 obese (HDLobese ) before and after 6 month LI, and five severe obese adolescents before and one year after RYGB. HDL-mediated phosphorylation of endothelial nitric oxide synthase (eNOS)-Ser(1177) , eNOS-Thr(495) , and PKC-ßII was evaluated. In addition the HDL proteome was analyzed. RESULTS: HDLobese -mediated eNOS-Ser(1177) phosphorylation was reduced, whereas eNOS-Thr(495) phosphorylation increased significantly when compared to HDLcontrol . No impact of obesity was observed on PKC-ßII phosphorylation. LI and RYGB had no impact on HDL-mediated phosphorylation of eNOS and PKC-ßII. A principle component plot analysis of the HDL particle separated controls and severe obese, whereas the interventions did not trigger sufficient differences to the HDL proteome to permit distinction. CONCLUSION: These results demonstrated that HDL-function is impaired in obese adolescents, and that LI or RYGB did not correct this dysfunction. This might be an argument for developing earlier prevention strategies in obese adolescents to avoid HDL dysfunction.

Correlation between endothelial function measured by finger plethysmography in children and HDL-mediated eNOS activation -- a preliminary study.

BACKGROUND: The noninvasive measurement of endothelial function is a very powerful tool to assess cardiovascular disease. Especially in children this is not an easy task, and therefore an easy method like the Endo-Pat device is helpful. Due to the still existing uncertainties of the validity of endothelial measurement by the Endo-PAT device in children, we thought to analyze the correlation between endothelial functional measurement by Endo-PAT, and the capability of HDL to modify nitric oxide (NO) production by phosphorylation of endothelial nitric oxide synthase at the stimulatory site (Ser(1177)) and the inhibitory site (Thr(495)). METHODS: The reactive hyperemic index (RHI) was measured in 11 school children by the Endo-PAT device. HDL was isolated by ultracentrifugation, and the capability to stimulate eNOS phosphorylation was assessed in cell culture. RESULTS: A close correlation between the RHI and the eNOS-Ser(1177) phosphorylation (r=0.66, p=0.02) and the eNOS-Thr(495) phosphorylation (r=-0.60, p=0.04) was detected. CONCLUSION: The results obtained in our limited study performed in healthy children supports the validity of endothelial function measurement in children using the Endo-PAT device. Nevertheless, studies measuring FMD and the RHI index need to confirm the strength of the Endo-Pat device also in children.

Cachexia in chronic heart failure: endocrine determinants and treatment perspectives.

It is well documented in the current literature that chronic heart failure is often associated with cachexia, defined as involuntary weight loss of 5 % in 12 month or less. Clinical studies unraveled that the presence of cachexia decreases significantly mean survival of the patient. At the molecular level mainly myofibrillar proteins are degraded, although a reduced protein synthesis may also contribute to the loss of muscle mass. Endocrine factors clearly regulate muscle mass and function by influencing the normally precisely controlled balance between protein breakdown and protein synthesis The aim of the present article is to review the knowledge in the field with respect to the role of endocrine factors for the regulation of cachexia in patients with CHF and deduce treatment perspectives.

Long-survival case of thymic carcinoma with superior vena cava tumor thrombus.

Sarcomatoid carcinoma of the thymus is rare and responds poorly to treatment. Invasion of great vessels and metastasis are significant predictors for poor prognosis. Thymic tumors commonly cause superior vena cava (SVC) obstruction by extrinsic compression or invasion, but intraluminal permeation is the most uncommon cause. We report a rare, long-surviving case of sarcomatoid carcinoma with SVC syndrome developed by tumor thrombus. She underwent SVC replacement and extended thymectomy. The resection indicated intracaval extension without direct invasion of thymic tumor, histologically diagnosed as sarcomatoid carcinoma. After adjuvant chemotherapy, she continues to show no apparent recurrence for five years.