Assessment of prognosis in immunoglobulin light chain amyloidosis patients with severe heart failure: a predictive value of right ventricular function.

Although the benefit of updated therapeutic regimens, including bortezomib, on the survival of immunoglobulin light chain (AL) amyloidosis patients with heart failure (HF) has been reported, predictors of mortality in the patients treated with the updated therapy remain unclear. We retrospectively enrolled AL amyloidosis patients who had severe HF at the time of diagnosis and received the updated therapy, including bortezomib (n = 19, 61 ± 6 years old, 68% male). Severe HF was defined as the presence of both NYHA functional class III or IV and BNP > 200 pg/ml or NT-pro-BNP > 900 pg/ml. One-year mortality rate during follow-up after commencement of the treatment was 37%. Left ventricular morphological parameters and indexes of left ventricular diastolic function on admission were similar in the non-survivors and survivors. However, non-survivors had higher incidences of atrial fibrillation and ventricular tachycardia, higher serum total bilirubin levels (1.34 ± 0.55 vs. 0.61 ± 0.29 mg/dl), higher right atrial volume index (RAVI 49.7 ± 29.9 vs. 27.3 ± 6.8 ml/m2), lower tricuspid annular peak velocities during systole (RVs' 8.0 ± 1.8 vs. 11.6 ± 3.7 cm/sec) and late diastole (RVa' 3.4 ± 0.9 vs. 11.4 ± 5.3 cm/sec), and larger inferior vena cava dimension (22.7 ± 6.4 vs. 16.3 ± 4.9 mm) than those in survivors. Kaplan-Meier curve analyses showed that larger RAVI and lower RVs' and RVa', but not left ventricular systolic/diastolic dysfunction, predicted higher mortality during 1-year follow-up. The present results suggest that the presence of right-sided heart abnormality on admission is associated with high 1-year mortality in AL amyloidosis patients with severe HF under the updated therapeutic regimens.

Intra- and Inter-rater Agreement on Magnetic Resonance Imaging Evaluation of Rotator Cuff Integrity After Repair.

PURPOSE: To investigate the intra- and inter-rater agreement of magnetic resonance imaging (MRI) evaluations of rotator cuff integrity at 6 and 24 months after arthroscopic rotator cuff repair (ARCR). METHODS: Three shoulder surgeons reviewed 68 MRI scans from 34 patients who had undergone ARCR and MRI examination at both 6 and 24 months after surgery. Postoperative rotator cuff integrity was investigated by using Owen, Sugaya, and Hayashida classifications to determine whether the rotator cuff was intact or whether there was a partial-thickness retear or full-thickness retear and Burks score to assess tendon appearance. Multirater kappa statistics were used to measure intra- and inter-rater agreement. Kappa values were interpreted according to guidelines adapted from the work of Landis and Koch. RESULTS: All classifications had similar intra- and inter-rater agreement (κ = 0.14 to 0.67, 0.23 to 0.60, respectively), but no intra- or inter-rater agreement scored "excellent." Inter-rater agreement after ARCR was higher at 24 months (κ = 0.31 to 0.60) than at 6 months (κ = 0.23 to 0.44) in all evaluations. Reviewers identified full-thickness retears with a moderate to good degree of inter-rater agreement in all evaluations, at both 6 months (κ = 0.42 to 0.73) and 24 months (κ = 0.61 to 0.80) after ARCR. However, poor inter-rater agreement (κ = 0.13 to 0.19) was found in the identification of partial-thickness retears in all evaluations at 6 months after ARCR. CONCLUSIONS: Shoulder surgeons showed better intra- and inter-rater agreement in predicting full-thickness tears compared with partial-thickness tears. The inter-rater agreement at 24 months after ARCR was superior to that at 6 months in predicting not only full-thickness retear but also partial-thickness retear. MRI evaluation of rotator cuff integrity at 6 months after ARCR may be less reliable, regardless of which classification system is used. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Intervendor Variabilities of Left and Right Ventricular Myocardial Velocities among Three Tissue Doppler Echocardiography Systems.

BACKGROUND: Whether an intervendor discordance of myocardial velocities determined by tissue Doppler echocardiography (TDE) can be generalized remains unclear. We compared intervendor variabilities of left ventricular (LV) and right ventricular (RV) myocardial velocities among three TDE systems. METHODS: Examinations with TDE were performed in 41 healthy subjects and 11 patients with cardiovascular risk factors (CVR) using α-7 (V1, Hitachi Aloka Medical), Artida (V2, Toshiba Medical Systems), and Vivid E9 (V3, GE Healthcare) on the same day. Peak systolic (s'), early diastolic (e'), and late diastolic (a') myocardial velocities at medial and lateral sites of the mitral annulus and lateral site of the tricuspid annulus were measured using both pulsed-wave TDE and color TDE. Intra-observer and inter-observer variabilities were determined in 10 subjects and test-retest variability in 14 subjects. RESULTS: As for test-retest variability, reproducibilities of LV and RV myocardial velocities determined by pulsed-wave TDE and color TDE were relatively low but comparable between V1, V2, and V3. Myocardial velocities in healthy subjects determined by both pulsed-wave TDE and color TDE were significantly different among the three TDE systems. Myocardial velocities by pulsed-wave TDE in V3 were 2-12% lower (P < 0.05) than those by V2 and 5-14% lower (P < 0.05) than those by V1. Similar differences in myocardial velocities determined by both pulsed-wave TDE and color TDE were found in patients with CVR. CONCLUSIONS: LV and RV myocardial velocities determined by both pulsed-wave TDE and color TDE are vendor dependent, and reproducibility of the myocardial velocities determined by both TDE systems is relatively low.

Detection of QT prolongation through approximation of the T wave on Gaussian mixture modeling.

BACKGROUND: To establish a simple and accurate method for the automated identification of the end of a T wave, we approximated electrocardiograph (ECG) traces using a Gaussian mixture model in conjunction with a split-and-merge expectation-maximization algorithm. METHODS AND RESULTS: A total of 286 ECG traces of heart beats of 50 healthy men were used as control data and ECGs from 15 subjects recorded before and after 400mg oral moxifloxacin as positive controls. An experienced cardiologist determined the reference points by visual inspection of the original ECGs. The primary estimated point for the end of the T wave was selected as the point 2 ms before the point at which the gradient of the approximated wave was not steeper than the common threshold value. This point was then adjusted by applying modification rules proposed by an experienced cardiologist. The absolute value of the average interval between the resulting final estimated point and the manually selected reference point was 1.8±7.7 ms for the control data. After treatment with moxifloxacin, the average QT interval, corrected by Bazett's formula, showed a 17.2±27.1 ms prolongation with a lower bound of the 95% confidence interval of 4.9 ms. CONCLUSIONS: When the modification rules were applied, the accuracy of QT measurement was improved, and the present system was capable of detecting QT prolongation correctly.

Combinational risk factors of metabolic syndrome identified by fuzzy neural network analysis of health-check data.

BACKGROUND: Lifestyle-related diseases represented by metabolic syndrome develop as results of complex interaction. By using health check-up data from two large studies collected during a long-term follow-up, we searched for risk factors associated with the development of metabolic syndrome. METHODS: In our original study, we selected 77 case subjects who developed metabolic syndrome during the follow-up and 152 healthy control subjects who were free of lifestyle-related risk components from among 1803 Japanese male employees. In a replication study, we selected 2196 case subjects and 2196 healthy control subjects from among 31343 other Japanese male employees. By means of a bioinformatics approach using a fuzzy neural network (FNN), we searched any significant combinations that are associated with MetS. To ensure that the risk combination selected by FNN analysis was statistically reliable, we performed logistic regression analysis including adjustment. RESULTS: We selected a combination of an elevated level of γ-glutamyltranspeptidase (γ-GTP) and an elevated white blood cell (WBC) count as the most significant combination of risk factors for the development of metabolic syndrome. The FNN also identified the same tendency in a replication study. The clinical characteristics of γ-GTP level and WBC count were statistically significant even after adjustment, confirming that the results obtained from the fuzzy neural network are reasonable. Correlation ratio showed that an elevated level of γ-GTP is associated with habitual drinking of alcohol and a high WBC count is associated with habitual smoking. CONCLUSIONS: This result obtained by fuzzy neural network analysis of health check-up data from large long-term studies can be useful in providing a personalized novel diagnostic and therapeutic method involving the γ-GTP level and the WBC count.

Prognostic value of 6-min walk stress echocardiography in patients with interstitial lung disease.

BACKGROUND: The 6-min walk test (6MWT) provides prognostic information for patients with interstitial lung disease (ILD). Parameter determined by Doppler echocardiography after the 6MWT (6 MW stress echocardiography) is shown to be a predictor of future development of pulmonary hypertension in patients with connective tissue disease. However, the clinical utility of 6 MW stress echocardiography in predicting cardiopulmonary events in patients with ILD remains unknown. We examined whether parameters determined by 6 MW stress echocardiography independent predictors of adverse events in patients with ILD. METHODS: Echocardiographic examinations were performed in 68 consecutively enrolled patients with ILD (age, 65 ± 10 years, 65% men). A pressure gradient of tricuspid regurgitation (TRPG) and pulmonary vascular resistance (PVRecho) calculated using the following formula [PVRecho = (peak velocity of TR × 10/time-velocity integral of right ventricular outflow (RVOT-VTI)) + 0.16] were measured at baseline and at post 6MWT. Data for parameters of pulmonary functional tests and for 6MWT were collected. RESULTS: During a mean follow-up period of 22 ± 12 months, 22 patients experienced cardiopulmonary events. In univariate analysis, %VC, TRPG, PVRecho, TRPG post 6MWT, and PVRecho post 6MWT were significantly associated with cardiopulmonary events. Multivariate analysis using the Cox proportional hazards model indicated that %VC [hazard ratio (HR): 0.97, p = 0.009] and PVRecho post 6MWT (HR: 1.77, p = 0.004) were independent predictors of cardiopulmonary events in patients with ILD. CONCLUSIONS: In addition to parameters of pulmonary function tests, increased PVRecho post 6MWT is a significant predictor of cardiopulmonary events in patients with ILD. A 6 MW stress echocardiography is useful in assessing the risk of adverse events in patients with ILD.

Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects.

Homeobox transcription factor Nkx2-5, highly expressed in heart, is a critical factor during early embryonic cardiac development. In this study, using tamoxifen-inducible Nkx2-5 knockout mice, we demonstrate the role of Nkx2-5 in conduction and contraction in neonates within 4 days after perinatal tamoxifen injection. Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na+ channel pore-forming alpha-subunit (Na(v)1.5-alpha), the largest ion channel in the heart responsive for rapid depolarization of the action potential, which leads to increased intracellular Ca2+ for contraction (conduction-contraction coupling). In addition, expression of ryanodine receptor 2, through which Ca2+ is released from sarcoplasmic reticulum, was substantially reduced in Nkx2-5 knockout mice. These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction.

Effects of aldosterone on Cx43 gap junction expression in neonatal rat cultured cardiomyocytes.

BACKGROUND: The renin-angiotensin-aldosterone system affects cellular morphology and function in the heart under a variety of pathologic conditions. In the present study the effects of aldosterone on the expression of connexin (Cx) 43 gap junctions in cardiomyocytes were investigated. METHODS AND RESULTS: Cultured rat ventricular myocytes were exposed to aldosterone for 24 h. The protein and mRNA expression of Cx43 was estimated. Propagation of excitation was visualized by a multiple electrode array system. Treatment of the myocytes with 10(-8) mol/L aldosterone resulted in a significant upregulation of Cx43 (by approximately 1.5-fold in protein and by approximately 1.2-fold in mRNA). The immunoreactive signal of Cx43 was also increased. Conduction velocity (CV) was increased by approximately 24%. Treatment of the myocytes with aldosterone at higher concentrations (10(-6)-10(-4) mol/L) caused a significant downregulation of Cx43 protein (by approximately 0.3-fold) without affecting Cx43 mRNA levels, and decreased the CV by ~23%. The Cx43 upregulation and CV acceleration at 10(-8) mol/L aldosterone were prevented by pretreatment with eplerenone, but unaffected by mifepristone. Pretreatment of the myocytes with eplerenone or mifepristone did not prevent the Cx43 downregulation by aldosterone at 10(-6)-10(-4) mol/L. CONCLUSIONS: Aldosterone may be involved in arrhythmogenic gap junction remodeling through its dual effects on the expression of Cx43.

T-type Ca2+ channel blockers prevent cardiac cell hypertrophy through an inhibition of calcineurin-NFAT3 activation as well as L-type Ca2+ channel blockers.

T-type Ca2+ channels (TCCs) are involved in cardiac cell growth and proliferation in cultured cardiomyocytes. Underlying molecular mechanisms are not well understood. In this study, we investigated the role of TCCs in signal transduction in cardiac hypertrophy compared with L-type Ca2+ channels (LCCs). Cardiomyocytes dissociated from neonatal mouse ventricles were cultured until stabilization. Cell hypertrophy was induced by reapplication of 1% fatal bovine serum (FBS) following a period (24 h) of FBS depletion. Cell surface area increased from 862+/-73 microm2 to 2153+/-131 microm2 by FBS stimulation in control (250+/-1.8%). T-type Ca2+ current (I(CaT)) was inhibited dose-dependently by kurtoxin (KT) and efonidipine (ED) with IC50 0.07 microM and 3.2 microM, respectively in whole-cell voltage clamp. On the other hand, 1 microM KT which inhibits I(CaT) over 90% did not effect on L-type Ca2+ current (I(CaL)). 10 microM ED had the ability of I(CaL) blockade as well as that of I(CaT) blockade. 3 microM nisoldipine (ND) suppressed I(CaL) by over 80%. The increase in cell surface area following reapplication of FBS as observed in control (250+/-1.8%) was significantly reduced in the presence of 1 microM KT (216+/-1.2%) and virtually abolished in the presence of 10 microM ED (97+/-0.8%) and 3 microM ND (80+/-1.1%). Hypertrophy was associated with an increase in BNP mRNA of 316+/-3.6% in control and this increase was reduced as well in the presence of 1 microM KT (254+/-1.8%) and almost abolished in the presence of 10 microM ED (116+/-1.1%) and 3 muM ND (93+/-0.8%). Immunolabeling showed that translocation of nuclear factor of activated T cells (NFAT3) into the nucleus in response to FBS stimulation was markedly inhibited by either KT or ED as well as ND. Calcineurin phosphatase activity was upregulated 2.2-fold by FBS, but KT, ED and ND decreased this upregulation (1.7-fold, 0.8-fold, and 0.7-fold with KT, ED and ND respectively). These results suggest that blockade of Ca2+ entry into cardiomyocytes via TCCs may block pathophysiological signaling pathways leading to hypertrophy as well as via LCCs. The mechanism may be the inhibition of calcineurin-mediated NFAT3 activation resulting in prevention of its translocation into the nucleus.

Midkine plays a protective role against cardiac ischemia/reperfusion injury through a reduction of apoptotic reaction.

BACKGROUND: Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, eg, neural survival, carcinogenesis, and tissue repair. MK could have a protective action against ischemia/reperfusion (I/R) injury in the heart, because MK was shown to have cytoprotective activity in cultured neurons and tumor cells. We investigated this hypothesis in mice with and without genetic MK deletion. METHODS AND RESULTS: Myocardial injury after I/R was produced by transient occlusion of coronary arteries. In wild-type (Mdk+/+) mice, MK expression was increased after I/R in the periinfarct area. Infarct size/area at risk 24 hours after I/R in MK-deficient (Mdk-/-) mice was larger than in Mdk+/+ mice (55.4+/-9.1% versus 32.1+/-5.3%, P<0.05). Terminal dUTP nick end-labeling-positive myocyte population in the periinfarct area in Mdk-/- mice was higher than in Mdk+/+ mice (6.8+/-0.9% versus 3.2+/-0.6%, P<0.05). Left ventricular fractional shortening 24 hours after I/R in Mdk-/- mice was significantly less than that in Mdk+/+ mice (34.3+/-4.4% versus 50.8+/-2.1%, P<0.05). Supplemental application of MK protein to left ventricle of Mdk-/- mice at the time of I/R resulted in reduction of the infarct size. Application of exogenous MK to cultured cardiomyocytes resulted in increased Bcl-2 expression and decreased apoptosis after hypoxia/reoxygenation. CONCLUSIONS: These results suggest that MK plays a protective role against I/R injury, most likely through a prevention of apoptotic reaction. MK is a potentially important new molecular target for treatment of ischemic heart disease.

Prognostic significance of circadian variability of RR and QT intervals and QT dynamicity in patients with chronic heart failure.

BACKGROUND: In patients with chronic heart failure (CHF), circadian variability of RR and QT intervals may be altered because of neurohumoral activation and functional and structural remodeling of the heart. OBJECTIVE: The aim of this study was to evaluate the prognostic significance of circadian variability of the RR and QT intervals and QT dynamicity (QT/RR slope) in CHF patients. METHODS: We prospectively enrolled 121 patients with stable CHF in sinus rhythm (age 67 +/- 14 years, mean +/- SD; range 34 to 87 years). The RR, QT, and rate-corrected QT (QTc) intervals and the QT/RR slope measured from 24-hour Holter electrocardiogram were fitted by cosine curves. RESULTS: During the follow-up period of 34 +/- 17 months, 40 (33%) patients died of cardiac causes, 10 of which were sudden. All patients showed significant circadian rhythms in the RR, QT, and QTc intervals and the QT/RR slope by cosine-curve fitting. In addition to the expected higher heart rate, longer QT interval, and steeper QT/RR slope, we found that patient who died of cardiac causes had reduced circadian variability of QT interval (10 +/- 10 ms vs 21 +/- 13 ms) and a later maximum RR interval (4.1 +/- 0.9 AM vs 2.3 +/- 2.1 AM) compared with survivors, among many other statistically significant circadian parameter differences. These 2 parameters were independent predictors of cardiac death in multivariate Cox proportional hazards regression analysis. CONCLUSION: Circadian variability analyses of Holter-derived RR and QT intervals may provide prognostic information beyond that provided by 24-hour averages of these parameters.

Heavy ion radiation up-regulates Cx43 and ameliorates arrhythmogenic substrates in hearts after myocardial infarction.

OBJECTIVE: Radiation has been shown to enhance intercellular communication in the skin and lungs through an increase of connexin43 (Cx43) expression. If analogous Cx43 up-regulation is induced in the diseased heart, it would provide a new perspective in radiation therapy for arrhythmias. The aim of the present study is to test this hypothesis. METHODS: Non-transmural myocardial infarction (MI) was created in 24 rabbits by microsphere injection into the coronary arteries. Twenty-four rabbits without MI were used as controls. Targeted external heavy ion beam irradiation (THIR; 15 Gy) was applied 2 weeks after MI with an accelerator (HIMAC, Chiba, Japan). RESULTS: The THIR was associated with an increase of Cx43 mRNA and protein levels in the left ventricle in control as well as in MI rabbits. THIR also increased lateralization of Cx43, which was no longer colocalized with cadherins. In MI hearts, immunoreactive Cx43 signals were reduced in the peri-infarct zone, and the reduction was reversed by THIR. In-vivo epicardial potential mapping on the free wall (64 unipolar electrodes to cover 7 x 7 mm) in MI hearts revealed reduced conduction velocity, whereas dispersion of the activation-recovery interval (ARI) was increased compared with controls, and these changes were reversed by THIR. The vulnerability for ventricular tachyarrhythmias (VT/VF), which was estimated by programmed stimulation, was increased in MI hearts, and this increased vulnerability to arrhythmias was reversed by THIR. CONCLUSIONS: THIR increases Cx43 expression, improves the conductivity, decreases the spatial heterogeneity of repolarization, and reduces the vulnerability of rabbit hearts to ventricular arrhythmias after MI. THIR could have an antiarrhythmic potential through an improvement of electrical coupling.

Soleal vein dilatation assessed by ultrasonography is an independent predictor for deep vein thrombosis after major orthopedic surgery.

BACKGROUND: Deep vein thrombosis (DVT) develops after major orthopedic surgery despite the current use of prophylaxis. DVT frequently develops in the soleal vein (SV) and might develop easily at the site of SV dilatation because of blood flow stasis. However, whether preoperative SV dilatation detected by ultrasonography predicts DVT after major orthopedic surgery remains unknown. OBJECTIVE: We examined whether SV dilatation detected by preoperative ultrasonography predicts DVT after major orthopedic surgery. METHODS: Ultrasonography was performed preoperatively and postoperatively in 243 patients with orthopedic diseases (mean age of 67±13 years, 77% women) who underwent total hip arthroplasty (THA, n=180) or total knee arthroplasty (TKA, n=63). Presence of DVT was diagnosed by ultrasonography and SV diameter ≥10mm was defined as SV dilatation. Patients with preoperative DVT were excluded. RESULTS: Sixty-nine patients (28%) developed postoperative DVT. SV dilatation was found in 24 patients (10%), and 16 (67%) of those patients had postoperative DVT. Multivariate logistic regression analysis showed that female gender [odds ratio (OR): 4.09, p=0.004], TKA (OR: 2.52, p=0.011), and SV dilatation (OR: 6.67, p<0.001), but not presence of comorbidities, medications, or plasma d-dimer value, independently predict postoperative DVT. Subgroup analyses according to the operation site showed that female gender (OR: 3.27, p=0.043) and SV dilatation (OR: 3.72, p=0.022) were independent predictors of postoperative DVT in the THA group. SV dilatation (OR: 12.0, p=0.027) was an independent predictor of postoperative DVT also in the TKA group. CONCLUSIONS: In addition to gender and TKA, SV dilatation detected by ultrasonography is an independent predictor of DVT after major orthopedic surgery. Determination of SV diameter by ultrasonography before major orthopedic surgery is useful for assessing the risk of postoperative DVT.

Development of a polarization-modulation spectroscopy system for the temporally resolved measurement of linear polarization in plasma emission.

A system to measure linear polarization in the HeI 21P-31D emission line (667.8 nm) was developed for application to plasma polarization spectroscopy. To verify the system performance, the normalized Stokes parameters were evaluated. A measurement error of less than 1% with a time resolution of 1 ms was achieved for monochromatic light in the state of complete linear polarization.

Clinical results of surgical treatment for femoral neck fractures with the Targon® FN.

84 cases (male 15 cases, female 69 cases) of intracapsular femoral neck fractures treated with the Targon® FN (TFN) were available for review. Mean patient age was 74.0 years (range 36-100 years). 55 fractures were undisplaced whereas 29 were displaced. Mean follow-up term was 16.4 months. We surveyed patient mobility before injury and after operation as well as postoperative complications. On a four-stage mobility scale we found 3/55 patients with undisplaced fractures loosing mobility by more than one grade (5.5%), whereas 5/29 (17.2%) displayed this kind of functional decline after displaced fractures. Overall postoperative complication rate was 10.7% (9 cases). These complications included nonunion (1 case), avascular necrosis (7 cases) and peri-implant fracture (1case). Internal fixation with the TFN seems to have an acceptable complication rate in both undisplaced and displaced fractures compared to other recent studies.

Pulmonary vascular resistance estimated by Doppler echocardiography predicts mortality in patients with interstitial lung disease.

BACKGROUND: Pulmonary hypertension (PH) is a strong predictor of mortality in patients with interstitial lung disease (ILD). However, patients with ILD often have poor outcomes even in the absence of PH. Pulmonary vascular resistance (PVR) assessed by right heart catheterization is a predictor of mortality in patients with ILD. However, the clinical utility of PVR assessed by Doppler echocardiography (PVRecho) as a predictor of the outcome in patients with ILD remains unclear. The aim of this study was to examine whether PVRecho independently predicts mortality in patients with ILD. METHODS: Echocardiographic examinations were performed in 133 consecutively enrolled patients with ILD (age, 67±9 years; 53% men). Tricuspid annular plane systolic excursion (TAPSE) was measured, and PVRecho was calculated by the following formula: PVRecho=[TRV×10/time-velocity integral of right ventricular outflow (RVOT-VTI)]+0.16. Data for parameters of pulmonary functional tests and for serum biomarkers, which were measured within 3 months before or after the echocardiographic examinations, were collected. RESULTS: During a mean follow-up period of 18±7 months, 13 patients died due to respiratory failure (n=10), heart failure (n=1), or unknown causes (n=2). In univariate analysis, body mass index, idiopathic pulmonary fibrosis, use of an antifibrotic drug (AD), RVOT-VTI, PVRecho, percentage of predicted vital capacity (%VC), percentage of predicted forced expiratory volume in 1second, and percentage of predicted diffusion capacity of the lungs for carbon monoxide (%DLco), but not TAPSE or serum biomarkers, were significantly associated with mortality. Cox proportional hazard multivariate analysis indicated that %VC [hazard ratio (HR): 0.92, p=0.001], use of AD (HR: 4.05, p=0.043), and PVRecho (HR: 3.79, p=0.029) independently predict mortality in patients with ILD. Replacement of %VC with %DLco in the multivariate analysis did not change the results: %DLco (HR: 0.90, p=0.001), use of AD (HR: 7.53, p=0.029), and PVRecho (HR: 3.65, p=0.020). CONCLUSIONS: In addition to parameters of pulmonary function tests and use of AD, increased PVRecho is an independent predictor of mortality in patients with ILD who were evaluated for screening of PH by echocardiography.

Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block.

BACKGROUND: The ionic basis of acquired QT prolongation and torsade de pointes (TdP) unrelated to drugs is not fully understood. METHODS AND RESULTS: We created a rabbit model with chronic complete atrioventricular block (AVB) (n=34), which showed prominent QT prolongation (by 120%), high incidence of spontaneous TdP (71%), and cardiac hypertrophy. Patch-clamp experiments were performed in left ventricular myocytes from 9 rabbits (8 with TdP, 1 without TdP) at approximately 21 days of AVB and from 8 sham-operated controls with sinus rhythm. Action potential duration was prolonged in AVB myocytes compared with control (+61% at 0.5 Hz, +21% at 3 Hz). Both rapidly and slowly activating components of the delayed rectifier K(+) current (I(Kr) and I(Ks)) in AVB myocytes were significantly smaller than in control by 50% and 55%, respectively. There was no significant difference in Ca(2+)-independent transient outward current (I(to1)). L-type Ca(2+) current (I(Ca,L)) in control and AVB myocytes was similar in peak amplitude, but the half voltage for activation was shifted to the negative direction (5.9 mV) in AVB myocytes. Voltage dependence of I(Ca,L) inactivation was not different in control and AVB myocytes. The inward rectifier K(+) current (I(K1)) significantly increased in AVB myocytes compared with control. CONCLUSIONS: In the rabbit, chronic AVB leads to prominent QT prolongation and high incidence of spontaneous TdP. Downregulation of both I(Kr) and I(Ks) in association with altered I(Ca,L) activation kinetics may underlie the arrhythmogenic ventricular remodeling.

Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression.

BACKGROUND: Homozygous mutant mice with a defect of klotho gene expression (kl/kl) show multiple age-related disorders and premature death from unknown causes. METHODS AND RESULTS: The kl/kl mice subjected to 20-hour restraint stress showed a high rate (20/30) of sudden death, which was associated with sinoatrial node dysfunction (conduction block or arrest). Heart rate and plasma norepinephrine of kl/kl mice, unlike those of wild-type (WT) mice, failed to increase during the stress. Intrinsic heart rate after pharmacological blockade of autonomic nerves in kl/kl mice was significantly lower than that in WT mice (380+/-33 versus 470+/-44 bpm; n=7). The sinus node recovery time after an overdrive pacing (600 bpm, 30 seconds) in kl/kl mice was significantly longer than in WT mice (392+/-37 versus 233+/-24 ms; n=6). In isolated sinoatrial node preparations, the positive chronotropic effect of isoproterenol was significantly less, whereas the negative chronotropic effect of acetylcholine was significantly greater in kl/kl than in WT mice. There was no degenerative structural change in the sinoatrial node of kl/kl mice. The precise localization of klotho was analyzed in newly prepared klotho-null mice with a reporter gene system (kl(-geo)). Homozygous kl(-geo) mice showed characteristic age-associated phenotypes that were almost identical to those of kl/kl mice. In the kl(-geo) mice, klotho expression was recognized exclusively in the sinoatrial node region in the heart in addition to parathyroid, kidney, and choroid plexus. CONCLUSIONS: In the heart, klotho is expressed solely at the sinoatrial node. klotho gene expression is essential for the sinoatrial node to function as a dependable pacemaker under conditions of stress.

Rapid electrical stimulation of contraction modulates gap junction protein in neonatal rat cultured cardiomyocytes: involvement of mitogen-activated protein kinases and effects of angiotensin II-receptor antagonist.

OBJECTIVES: The aim of this study was to investigate the effects of rapid electrical stimulation (RES) of contraction on the expression of connexin (Cx)43 gap junction in neonatal rat cultured ventricular myocytes and the consequent changes of conduction properties. BACKGROUND: The expression and distribution of gap junctions in cardiac muscle can be changed readily under a variety of pathological conditions because of dynamic turnover of Cxs. The effects of RES of contraction on gap junction remodeling are not well understood. METHODS: Neonatal rat ventricular myocytes cultured for five days were subjected to RES (field stimulation) at 3.0 Hz for up to 120 min. RESULTS: Rapid electrical stimulation resulted in a significant upregulation of Cx43 (by approximately 1.5-fold in protein and by approximately 1.9-fold in messenger ribonucleic acid at 60 min). Immunoreactive signal of Cx43 was also increased. Angiotensin II (AngII) content was increased significantly by RES >15 min. Phosphorylated forms of extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinases, and p38 mitogen-activated protein kinases (MAPKs) were all increased dramatically by RES with peaks at 5 - 60 min. Propagation of excitation was visualized by extracellular potential mapping by using a multiple electrode array system. Conduction velocity was increased significantly by RES for 60 to 90 min (25% - 27% increase). Treatment of myocytes with losartan (100 nmol/l) prevented most of these effects of RES; RES-induced upregulation of Cx43 was also prevented by specific inhibitors for ERK and p38 MAPKs. CONCLUSIONS: A short-term RES causes upregulation of Cx43 in cardiomyocytes and a concomitant increase of conduction velocity, mainly through an autocrine action of AngII to activate ERK and p38 MAPKs.

Prevention of ventricular extrasystole by mexiletine in patients with normal QT intervals is associated with a reduction of transmural dispersion of repolarization.

BACKGROUND: Antiarrhythmic potential of mexiletine in patients with congenital and acquired long-QT syndrome (LQTS) has been attributed to a reduction of transmural dispersion of repolarization (TDR). A similar mechanism could be involved in the antiarrhythmic activity of the drug in patients with normal QT intervals, but the issue remains to be investigated. METHODS AND RESULTS: We analyzed 24-h Holter ECG recordings from 17 patients in sinus rhythm showing premature ventricular complexes (PVCs) with normal QT intervals (age, 62+/-10 years, mean+/-S.D.). Treatment of the patients with oral mexiletine (300 mg/day for 21-40 days) resulted in a significant reduction of PVCs (from 13899+/-18887 to 6949+/-12822 beats/24 h, p<0.01). Rate-dependent behavior of ventricular repolarization was analyzed by plotting QT intervals (QT(peak), QT(end)), and the interval from T-wave peak to T-wave end (TPE) against preceding respective RR intervals of sinus beats. Both the QT(peak) and QT(end) tended to be shortened by mexiletine at RR intervals from 600 ms to 1000 ms, although the changes did not reach statistical significances. TPE, which reflects TDR, was shortened significantly at relatively long RR intervals (by 14+/-9% at RR of 900 ms, p<0.05). There was a linear relationship between the percentage shortening of TPE and the percentage reduction of PVCs (r=0.86, p<0.04). TPE> or =70 ms was significantly associated with PVC suppression >75% with an odds ratio of 0.60 (95% confidence interval 0.36-0.98, per 1 ms increment). CONCLUSION: Inhibitory effect of mexiletine against PVCs in patients with normal QT intervals is mediated at least in part by a reduction of TDR. Mexiletine may be effective in patients exhibiting longer baseline TPE.