Long-Term Survival of Patients with Pulmonary Arterial Hypertension at a Single Center in Taiwan.

BACKGROUND: Clinical studies have suggested predictive parameters in mortality risk assessment for pulmonary arterial hypertension (PAH) patients. However, these studies predominantly include Caucasian population; information in Asian population is relatively deficient. In this study, we investigated the long-term survival of PAH patients and the predictors of mortality in our population. METHODS: We prospectively collected 70 patients with PAH at the Chang Gung Memorial Hospital between March 2002 and February 2015. Baseline data including functional class (FC), 6-minute walk distance (6MWD), hematological and biochemical data, echocardiography and cardiac catheterization were obtained before commencing PAH- targeted treatment. The follow-up period for analyses of survivors ended in October 2015. RESULTS: The mean age at diagnosis was 40.7 ± 15.2 years. Mean follow-up period was 4.6 ± 3.4 years, with 1-, 2-, 3-, and 5-year survival rates of 93%, 88%, 84%, and 77%, respectively. The baseline FC was worse in non-survivors than in survivors. More frequent presence of pericardial effusion, higher serum glucose levels, higher estimated systolic pulmonary artery pressure (SPAP) by echocardiography, and higher right atrial pressure (RAP) were found in non-survivors. Higher FC, lower 6MWD, and presence of pericardial effusion were associated with risk of mortality. Patients with worsening FC and increased serum uric acid had an increased risk of mortality during follow-up. CONCLUSIONS: The overall survival remained unsatisfactory in PAH patients. Baseline FC, 6MWD, pericardial effusion, RAP, and a worsening FC and an increased serum uric acid levels during follow-up were significant prognostic parameters.

Improvement of Right Ventricular Function in Pulmonary Arterial Hypertension with Disease-Specific Therapy - A Clinical Observational Study.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a serious and progressive disorder that can result in right ventricular (RV) dysfunction and mortality. Consequently, it is important to monitor RV function during management of PAH. The aim of this study was to investigate the change in RV function by echocardiography before and after disease-specific therapy. METHODS: We recruited 31 PAH patients with functional class (FC) III or IV. All the patients received a comprehensive assessment before disease-specific therapy was administered, including observation of clinical symptoms, 6-min walk distance (6MWD), serum brain natriuretic peptide (BNP) level, and transthoracic echocardiography. The assessment was repeated 12 weeks after therapy. RESULTS: Twenty-eight patients with a mean age of 40 years completed the study, of whom 82% were women. We found that the etiologies were mainly connective tissue disease-associated and idiopathic PAH. Of the patients in our study, 36% received endothelin receptor antagonist and 64% received phosphodiesterase-5 inhibitor. There was a significant improvement in FC after disease-specific therapy (p < 0.001). The 6MWD increased from 326 to 403 m (p < 0.001), and the serum BNP level decreased from 242 to 130 pg/mL (p = 0.008) after treatment. Echocardiography showed significant reduction in the right atrial and RV areas, pulmonary artery pressure, RV free wall thickness, and inferior vena cava diameter. The myocardial performance index and left ventricular eccentricity index were significantly reduced after therapy. CONCLUSIONS: For PAH patients in our study, disease-specific therapy for 12 weeks resulted in an improvement in FC, 6MWD, serum BNP levels, and RV function. KEY WORDS: Disease-specific therapy; Pulmonary arterial hypertension; Right ventricular function.

2014 Guidelines of Taiwan Society of Cardiology (TSOC) for the Management of Pulmonary Arterial Hypertension.

UNLABELLED: Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic condition, defined as a mean pulmonary arterial pressure exceeding 25 mmHg at rest. According to the recent classifications, it is grouped into pulmonary arterial hypertension (PAH), heart-related, lung-related, thromboembolic, and miscellaneous PH. In the past two decades, tremendous advances have occurred in the field of PH. These include (1) development of clinical diagnostic algorithm and a monitoring strategy dedicated to PAH, (2) defining strong rationales for screening at-risk populations, (3) advent of pulmonary specific drugs which makes PAH manageable, (4) recognition of needs of having proper strategy of combining existing pulmonary specific drugs, and/or potential novel drugs, (5) pursuit of clinical trials with optimal surrogate endpoints and study durations, (6) recognition of critical roles of PH/right ventricular function, as well as interdependence of ventricles in different conditions, especially those with various phenotypes of heart failure, and (7) for rare diseases, putting equal importance on carefully designed observation studies, various registries, etc., besides double blind randomized studies. In addition, ongoing basic and clinical research has led to further understanding of relevant physiology, pathophysiology, epidemiology and genetics of PH/PAH. This guidelines from the working group of Pulmonary Hypertension of the Taiwan Society of Cardiology is to provide updated guidelines based on the most recent international guidelines as well as Taiwan's domestic research on PH. The guidelines are mainly for the management of PAH (Group 1) ; however the majority of content can be helpful for managing other types of PH. KEY WORDS: Pulmonary arterial hypertension; Taiwan guidelines.

Vascular changes at the puncture segments of arteriovenous fistula for hemodialysis access.

OBJECTIVE: Repeated puncture is a mechanical injury to the hemodialysis accesses. We systemically observed the vascular changes at the puncture segments of arteriovenous fistulas. METHODS: The native arteriovenous fistulas in 104 patients on maintenance hemodialysis using the buttonhole technique for puncture were studied. We used the duplex scan to observe the intimal lesions, the maximal diameters at the arterial and venous puncture segments, and the references. RESULTS: Intimal lesions were found in 42% and 40% of the arterial and venous puncture segments, none of which resulted in significant luminal stenosis. The differences between diameters at the arterial or venous puncture segments and the corresponding references were significant (arterial, 11.07 +/- 4.45 vs 6.85 +/- 2.35 mm, P < .001; venous, 8.82 +/- 4.13 vs 5.54 +/- 2.22 mm, P < .001). All segments, except only three arterial and four venous puncture segments, were larger than the corresponding references. The degree of vascular dilatation, defined as the diameter difference between the puncture segments and the references calibrated by the reference diameter, were 64.1 +/- 49.6% at arterial puncture segments and 59.9 +/- 42.2% at venous segments. Multivariate analysis revealed that the patient age and the puncture duration were strongly correlated with the degree of vascular dilatation at both the arterial (P = .018 and .007, respectively) and venous puncture segments (P = .020 and .011, respectively). CONCLUSION: Puncture of arteriovenous fistula using a buttonhole technique resulted in a consistent vascular dilatation and moderately high incidence of intimal thickness, but no significant luminal stenosis was found.

Association between endothelial dysfunction and hyperuricaemia.

OBJECTIVE: We used high-resolution peripheral vascular ultrasound imaging to assess endothelial function in hyperuricaemic patients. METHODS: Hyperuricaemia was defined as a serum uric acid concentration of > 7.7 mg/dl in men or > 6.6 mg/dl in women. Measurements of endothelium-dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerin-mediated vasodilation were performed in 46 hyperuricaemic patients and an equal number of healthy age- and gender-matched normal controls by high-resolution two-dimensional ultrasonographic imaging of the brachial artery. The serum levels of glucose, creatinine, alanine aminotransferase (ALT), lipid profiles and high-sensitivity CRP were measured for both the study groups. RESULTS: The serum uric acid levels averaged 9.24 (1.16) and 6.18 (0.99) mg/dl in the hyperuricaemic and control groups, respectively. Body weight and BMI were significantly higher in the hyperuricaemic group than in the control group. The serum levels of creatinine, ALT, triglyceride and high-sensitivity CRP were significantly different between the two groups. The FMD values were significantly lower in the hyperuricaemic patients than in the controls [4.45% (3.13%) vs 7.10% (2.48%); P < 0.001]. The FMD values were negatively associated with serum uric acid levels (r = -0.273; P = 0.009). Multivariate regression analysis showed that the presence of hyperuricaemia (ß = -0.384; P < 0.001) and body weight (ß = 0.215; P = 0.017) were independent determinants of low FMD values. CONCLUSION: Hyperuricaemia is associated with endothelial dysfunction. Decreased nitric oxide bioavailability may be the main reason.

Prognostic value of arterial/alveolar oxygen tension ratio (a/APO2) in acute pulmonary embolism.

BACKGROUND: Because the arterial/alveolar oxygen tension ratio (a/APO2) is relatively constant throughout the entire range of fractional inspired oxygen concentration (FiO2), its use in determining the prognosis of acute pulmonary embolism (APE) was investigated. METHODS AND RESULTS: This study retrospectively assessed 202 consecutive patients with APE confirmed by computed tomography or high probability lung scintigraphy. All patients underwent initial arterial blood gas analysis during the first 24 h of admission. Receiver-operating characteristic analyses were performed to determine the a/APO2 cut-off value for predicting 30-day death or 30-day composite events. Cut-off values for a/APO2 were used to determine stability in all patients and 2 subgroups (0.49 for all patients; 0.49 for FiO2 =0.21; 0.46 for FiO2 >0.21). Using the cut-off value of a/APO2 <0.49 for predicting 30-day death, the negative predictive value (NPV) was 90%, and the positive predictive value (PPV) was 30.3%. For the 30-day composite end point, the NPV was 81.3%, and the PPV was 40.9%. Excluding massive APE, the a/APO2 also had high NPV and moderate PPV in predicting short-term prognosis. This study additionally demonstrated a linear relationship between platelet count and a/APO2. CONCLUSIONS: The cut-off value of a/APO2 <0.49 exhibits stability at variable FiO2 values and is a useful prognostic predictor in APE.

Enhancement of endothelium-dependent flow-mediated vasodilation in hyperthyroidism.

OBJECTIVE: Vascular responsiveness changes in hyperthyroid patients remains controversial. This study attempts to determine whether the vasomotor activity can be influenced by hyperthyroid conditions, and, if so, whether changes induced by hyperthyroidism may be restored to normal during the euthyroid state after treatment. DESIGN: A case-control clinical study. PATIENTS AND MEASUREMENTS: Forty-five pretreated hyperthyroid patients (mean age 36.62 +/- 10.12 years, 36 female) were compared with 45 gender- and age-matched control subjects (mean age 38.98 +/- 11.17 years, 40 female). Brachial artery endothelium-dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerin-mediated vasodilation (NMD) responses were assessed noninvasively by high-resolution ultrasound imaging. Among the 45 hyperthyroid patients, 27 patients underwent the same procedures prospectively in the post-treatment euthyroid state. RESULTS: The FMD values were significantly increased in hyperthyroid patients vs. those of controls (8.94 +/- 5.65%vs. 3.77 +/- 3.42%, P < 0.001), whereas NMD levels were not significantly different (18.17 +/- 7.76%vs. 17.28 +/- 6.63%, P = 0.560). Multiple regression analysis revealed that the presence of hyperthyroidism was the only significant factor associated with FMD. In the follow-up study of 27 hyperthyroid patients, the FMD values were significantly decreased in the post-treatment euthyroid state compared with those in the pretreated hyperthyroid state (6.40 +/- 4.27%vs. 8.83 +/- 4.61%, P = 0.021), although these values were still higher than those of controls. CONCLUSIONS: This study demonstrated that endothelium-dependent FMD was increased in the hyperthyroid patients, and could be partially restored by treatment with antithyroid agents.

Abnormal flow-mediated vasodilation in normal-tension glaucoma using a noninvasive determination for peripheral endothelial dysfunction.

PURPOSE: To assess peripheral vascular endothelial function in patients with normal-tension glaucoma (NTG) by using a noninvasive method: endothelium-dependent flow-mediated vasodilation (FMD). METHODS: Forty patients with NTG and 40 healthy age- and sex-matched normal control subjects underwent measurement of FMD and endothelium-independent nitroglycerin-mediated vasodilation (NMD) via high-resolution, two-dimensional (2D) ultrasonographic imaging of the brachial artery. The patients also underwent blood sampling for biochemistry, lipid profile, and high-sensitivity C-reactive protein (hsCRP) analysis. RESULTS: The NTG group exhibited significant impairment of FMD compared with the control group (NTG: 2.64% +/- 2.22%, control: 5.96% +/- 2.50%, P < 0.001). Multivariate analysis demonstrated that the presence of NTG was the strongest independent predictor of FMD. The lipid profile and hsCRP did not differ significantly between the two groups. CONCLUSIONS: This study demonstrated impaired FMD in patients with NTG and the results provide evidence of a generalized peripheral vascular endothelial dysfunction in patients with NTG.

Genetic variations of apolipoprotein A5 gene is associated with the risk of coronary artery disease among Chinese in Taiwan.

Recently, a T/C polymorphism of the promoter region of the APOA5 gene at position -1131 and a G/T polymorphism at position 553 were found to be associated with increased levels of plasma triglyceride. Triglyceride plays a role in coronary artery disease (CAD), so this case-control study tested for a possible link between these two APOA5 polymorphisms, their common haplotypes and the risk of CAD. The subjects included 211 CAD patients and 677 unrelated controls. A significantly higher level of triglycerides and a lower level of high-density lipoprotein cholesterol (HDL-C) were noted for carriers with -1131C than for non-carriers (P<0.001 and 0.013, respectively) among controls. Plasma triglyceride levels were significantly higher (P=0.014) in controls with genotypes that contained the c.553T allele than in homozygotes for the G allele. Subjects homozygous for the wild-type haplotype had significantly lower triglyceride levels and higher HDL-C levels than subjects with all other haplotype pairs. The -1131C homozygous carriers and c.553T heterozygous carriers were found more frequently in 211 patients with CAD than in the 317 age/sex-matched controls (P=0.008 and 0.023, respectively) in univariate analysis. The significant association between c.553T allele carriers with CAD remained in multivariate regression analysis (OR, 1.79; CI, 1.07-3.00; P=0.028), after adjustments were made for other risk factors. Notably, haplotype analysis further verified that the APOA5 -1131C and c.553T bi-loci haplotype was significantly overpresented in CAD, as compared to the controls. These results indicate that the variants of APOA5 gene modulate plasma triglyceride and may use them to predict CAD susceptibility in Taiwanese Chinese.

Functional polymorphisms of FGA, encoding alpha fibrinogen, are associated with susceptibility to venous thromboembolism in a Taiwanese population.

To determine the genetic risk factors for venous thromboembolism (VTE), this study examined 14 genetic variants from 10 hemostatic genes in 186 Taiwanese VTE patients and the same number of matched controls, which demonstrated FGA (encoding alpha fibrinogen) Thr312Ala polymorphism was the only variant significantly associated with VTE. Nine genetic polymorphisms on the fibrinogen cluster region of chromosome 4q28 were further studied, in which four FGA polymorphisms were found in strong linkage disequilibrium and were significantly associated with VTE by genotype and allele frequency analyses. Haplotype analysis showed significantly different FGA haplotype frequencies between VTE patients and controls with the haplotype F1, containing -1051G, -3A, 312Ala and TaqI duplication alleles, significantly associated with susceptibility to VTE (P = 0.001). Haplotype-pair analysis results also indicated a strong association of the haplotype-pair F1F1 with VTE in various VTE patient subgroups. In vitro functional analysis indicated that FGA -1051G, -3A and TaqI duplication alleles enhanced significantly the transcription level of FGA; however, control subjects with FGA genotypes containing these alleles had no elevated plasma fibrinogen levels. In conclusion, our experimental data indicated that functional genetic variants in FGA are risk factors for VTE in Taiwanese populations. Determination of FGA genotypes will likely contribute to primary prevention of this condition.

Cardiac catheterization complicated by iliacus abscess: a rare complication of transfemoral approach--a case report.

Iliacus abscess is an extremely rare complication of percutaneous transfemoral artery catheterization. This is a report of a case of iliacus abscess and Acinetobacter baumanii sepsis following percutaneous transfemoral artery catheterization. After a 43-day course of intravenous antibiotics treatment and repeated drainage, clinical recovery was achieved, though without complete radiologic resolution.

Thrombosed arteriovenous fistula for hemodialysis access is characterized by a marked inflammatory activity.

BACKGROUND: Thrombosis is the dominant cause of failure of arteriovenous fistulas for hemodialysis access. Vascular inflammation, an important pathologic change in various human vascular diseases, may be involved in the thrombotic process of arteriovenous fistulas. METHODS: The inflammatory activities of 23 thrombosed and 13 non-thrombosed stenotic arteriovenous fistulas were compared by investigating the contents of macrophages and lymphocytes, and the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) using immunohistochemistry method. The expression of matrix metalloproteinase (MMP)-2 and MMP-9, which play important roles in thrombosis of human coronary artery, was also investigated. The immunoreaction results were characterized using a semiquantitative scoring system. RESULTS: The macrophage and lymphocyte contents of the thrombosed group were abundant, and markedly greater than those of the non-thrombosed group (P < 0.001 and P = 0.001, respectively). The infiltration of macrophages and neovasculature were spatially closely correlated. The expressions of VCAM-1, IL-6, and TNF-alpha, but not ICAM-1, were significantly higher in the thrombosed group (P = 0.031, P = 0.010, P < 0.001, and P= 1.000, respectively). The expression of MMP-2 was not different in either groups (P = 0. 344). Differential expression of MMP-9 by macrophages near the vascular lumen, but not those distant from the lumen, was observed in most thrombosed specimens. CONCLUSION: This study demonstrated that the thrombosed arteriovenous fistula was characterized by marked inflammation. We hypothesize that the preferential expression of MMP-9 at luminal edge may cause disruption of the anticoagulant endothelial barrier and contribute to luminal thrombosis of arteriovenous fistulas.

Electrophysiological characteristics of accessory pathways with prolonged retrograde conduction.

Electrophysiological characteristics of an accessory pathway (AP) with a long ventriculoatrial (VA) interval (arbitrarily defined as > or = 50 ms and absence of continuous electrical activity) and no retrograde decremental property are described in this study. Fifteen patients (group 1) were compared with 171 patients with normal VA conduction (group 2). Mean VA conduction time was 77 +/- 24 versus 34 +/- 12 ms in group 1 versus group 2, respectively. Group 1 patients were older (55 +/- 14 vs 40 +/- 14 years), the male to female ratio was higher (2.8 vs 1.6), and APs were more prevalent on the right (60%) but manifest APs were lower (20% vs 54%) compared to group 2 patients (P < 0.05 in all cases). QRS morphology during induced atrioventricular reciprocating tachycardia was identical in both groups but the tachycardia cycle length was longer in group 1 (373 +/- 29 vs 344 +/- 50 ms, P < 0.05). Retrograde AP block cycle length and effective refractory period were greater in group 1 (362 +/- 59 vs 293 +/- 57 ms; 330 +/- 58 vs 273 +/- 55 ms, both P < 0.05). Adenosine (up to 18 mg) and verapamil (5-10 mg) failed to block the VA conduction via AP during ventricular pacing. In group 1 the number of radiofrequency lesions for a successful ablation were significantly less (3 +/- 2 vs 6 +/- 5, P < 0.05). In conclusion, APs with a long VA interval and no decremental retrograde conduction have electrophysiological characteristics that are different from those with a short VA interval. Role of aging deserves further exploration.

Highly increased cell proliferation activity in the restenotic hemodialysis vascular access after percutaneous transluminal angioplasty: implication in prevention of restenosis.

BACKGROUND: The effect of percutaneous transluminal angioplasty (PTA) in the treatment of hemodialysis vascular access stenosis is attenuated by a high restenosis rate, which results mainly from neointimal hyperplasia. Cellular proliferation is one of the most important biological mechanisms involved in neointimal hyperplasia and may be a potential target of intervention to prevent restenosis. METHODS: We investigated the activity of cellular proliferation of restenotic lesions by means of immunohistochemistry, using an antibody to the proliferating cell nuclear antigen. Specimens from 10 primary stenotic and 20 restenotic lesions of 30 Brescia-Cimino fistulae were obtained during revision. RESULTS: The proliferation index of the restenotic group was strikingly significantly greater than that of the primary stenotic group (intima, P < 0.001; media, P = 0.001). Proliferation indices of patients with diabetes in the restenotic group were significantly higher than those of patients without diabetes (intima, P = 0.028; media, P = 0.002). In the restenotic group, proliferation indices correlated negatively with the interval from PTA to restenosis (intima, r = -0.741; P < 0.001; media, r = -0.589; P = 0.006) and positively with the number of PTAs per lesion (intima, r = 0.754; P < 0.001; media, r = 0.506; P = 0.004). CONCLUSION: We show markedly high cellular proliferation activity in early restenotic lesions of arteriovenous fistulae. These findings indicate that adjunctive antiproliferative therapy is mandatory in preventing restenosis after PTA, especially in patients with diabetes.

Atrioventricular nodal reentry tachycardia with multiple AH jumps: electrophysiological characteristics and radiofrequency ablation.

This article describes the additional use of incremental atrial burst pacing (A1A1) and double atrial extrastimulation with a predefined fast pathway conducted A2 (A1A2A3), rather than single atrial extrastimulation (A1A2) only, to characterize typical atrioventricular nodal reentrant tachycardia (AVNRT). The authors noted an additional 32% of patients had multiple anterograde AV nodal physiology demonstrated when A1A1 or A1A2A3 protocols were deployed compared to more conventional A1A2 protocols. The A2H2max (449 +/- 147 vs 339 +/- 94 ms) and A3H3max (481 +/- 120 vs 389 +/- 85 ms) were higher in 31 patients where multiple jumps in the AV nodal conduction curve were obtained (group 1) compared to 192 patients where only single jump was obtained (group 2) (both P < 0.01). Postablation, the degree of reduction of A2H2max (49%) and A3H3max (50%) in group 1 was greater than in group 2 (38% and 42%, respectively, P < 0.05). In seven of group 1 patients in whom A1A2A3 stimulation was required to reveal multiple jumps, the A2H2max remained unchanged after ablation (237 +/- 89 vs 214 +/- 59, P > 0.05). A3H3max was the only parameter that shortened significantly after ablation. Generally, successful ablation resulted in loss of multiple discontinuities in A1A1/A1H1 or A2A3/A3H3 curves. In conclusion, a combination of A1A2, A1A1, and A1A2A3 are required to fully elucidate AVNRT. Significant shortening of AHmax or loss of multiple jumps after ablation indicates successful elimination of AVNRT in these patients.