Qureshi, Abdullah1; Gunn, Scott2; Bianchini, Veronica Garvia3; Smith, Benjamin1; Hoffman, Gabe4; Benvenuto, Stefanie4; Mcfarland, Mary Beth4; Jenkins, Katie5; Salopek, Tina5; Clark, Emily5; Smith, Taylor5; Gunn, Sherry5 Author Information

BACKGROUND: Differentiating pulmonary venoocclusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from idiopathic pulmonary arterial hypertension (IPAH) or heritable pulmonary arterial hypertension (HPAH) is important clinically. Mutations in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) cause heritable PVOD and PCH, whereas mutations in other genes cause HPAH. The aim of this study was to describe the frequency of pathogenic EIF2AK4 mutations in patients diagnosed clinically with IPAH or HPAH.METHODS: Sanger sequencing and deletion/duplication analysis were performed to detect mutations in the bone morphogenetic protein receptor type II (BMPR2) gene in 81 patients diagnosed at 30 North American medical centers with IPAH (n = 72) or HPAH (n = 9). BMPR2 mutation-negative patients (n = 67) were sequenced for mutations in four other genes (ACVRL1, ENG, CAV1, and KCNK3) known to cause HPAH. Patients negative for mutations in all known PAH genes (n = 66) were then sequenced for mutations in EIF2AK4. We assessed the pathogenicity of EIF2AK4 mutations and reviewed clinical characteristics of patients with pathogenic EIF2AK4 mutations.RESULTS: Pathogenic BMPR2 mutations were identified in 8 of 72 (11.1%) patients with IPAH and 6 of 9 (66.7%) patients with HPAH. A novel homozygous EIF2AK4 mutation (c.257+A>C) was identified in 1 of 9 (11.1%) patients diagnosed with HPAH. The novel EIF2AK4 mutation (c.257+A>C) was homozygous in two sisters with severe pulmonary hypertension. None of the 72 patients with IPAH had biallelic EIF2AK4 mutations.CONCLUSIONS: Pathogenic biallelic EIF2AK4 mutations are rarely identified in patients diagnosed with HPAH. Identification of pathogenic biallelic EIF2AK4 mutations can aid clinicians in differentiating HPAH from heritable PVOD or PCH.

Background-In this study, we looked at the prognostic value of echocardiographic and hemodynamic measures in a large cohort of patients with precapillary pulmonary hypertension before and after initiation of treatment.Methods and Results-Data were collected prospectively in a cohort of consecutive patients with precapillary pulmonary hypertension referred between 2002 and 2011. A range of clinical and echocardiographic variables were collected and stored on a database to assess predictors of survival. Invasive hemodynamic data including pulmonary artery pressure, pulmonary vascular resistance, capillary wedge pressure, and cardiac index were also obtained at baseline in all patients. Outcome was defined as mortality because of cardiovascular-related death. The study cohort comprised 777 patients (514 women) with precapillary pulmonary hypertension. A total of 195 (25%) died. In multivariable analysis, moderate or severe tricuspid regurgitation (hazard ratio [HR], 26.537; 95% confidence interval, 11.536-61.044; P< 0.001), right ventricular myocardial performance index (HR, 3.421; 95% confidence interval, 1.777-6.584; P< 0.001), and the presence of pericardial effusion (HR, 1.38; 95% confidence interval, 1.023-1.862; P= 0.035) were independent predictors of mortality. High pulmonary vascular resistance and right atrial pressure by invasive hemodynamic measurements were independent predictors of mortality (HR, 1.084; 95% confidence interval, 1.041-1.130, and 1.079, respectively; 95% confidence interval, 1.049-1.111; P< 0.001 for both), whereas patients with a higher cardiac index had better survival overall (HR, 0.384; 95% confidence interval, 0.307-0.481; P< 0.001).Conclusions-Right ventricular dysfunction, moderate-severe tricuspid regurgitation, low cardiac index, and raised right atrial pressure were associated with poor survival for both pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertensive disease patients. The severity of tricuspid regurgitation, myocardial performance index, presence of pericardial effusion, pulmonary vascular resistance, cardiac index, and right atrial pressure may be used to stratify risk of death.

AIMS:The aim of this study was to assess the papillary muscle strain as a contributor to recurrent mitral regurgitation (MR) after mitral valve repair for fibroelastic deficiency.METHODS AND RESULTS:Sixty-four patients with isolated posterior mitral valve prolapse and severe MR referred for surgery were prospectively recruited between 2008 and 2012. Two- and three-dimensional echocardiography and speckle tracking were performed in all patients. The longitudinal strain of the anterolateral (AL) and posteromedial (PM) papillary muscles was individually calculated as well as the global longitudinal strain of both papillary muscles was measured before and after mitral repair and normalized to left ventricle end-diastolic volume. Eight patients (12.5%) had at least moderate MR 6 months after mitral repair. The longitudinal strain of the AL (preop -4.94 ± 2.2 vs. postop -3.28 ± 1.3, P < 0.001) and the PM papillary muscles (preop -12.64 ± 5.3 vs. postop -4.12 ± 6.77, P < 0.001) as well as the global strain of both papillary muscles (preop -7.59 ± 3.48 vs. postop -1.07 ± 6, P < 0.001) were all reduced after surgical repair. The longitudinal strain of the PM papillary muscle was the strongest predictor of recurrent MR (when less than or equal to -14.78). The global preoperative papillary muscle strain was also a determinant of recurrent MR when the global strain was greater than -9.05% (area under the curve: 0.895, sensitivity: 100%, and specificity: 76.8%).CONCLUSIONS:Patients with isolated posterior mitral leaflet prolapse are less likely having any residual MR post repair when the global papillary muscle strain of both papillary muscles is close or equal to zero. Strain of the papillary muscles may be an important determinant in predicting residual MR in patients who undergo mitral valve repair.

BACKGROUND:Quantitative assessment of right ventricular (RV) systolic function largely depends on right ventricular ejection fraction (RVEF). Three-dimensional speckle tracking (3D-ST) has been used extensively to quantify left ventricular function, but its value for RV assessment has not been established. OBJECTIVES:This study sought to prospectively assess whether 3D-ST would be a reliable method for assessing RV systolic function and whether strain values were associated with survival. METHODS:Comprehensive 2-dimensional echocardiographic assessment, 3D-ST of the RV free wall, and measurement of RVEF was performed in 97 consecutive patients with established pulmonary hypertension (PHT) (RVEF 31.4 ± 9.6%, right ventricular systolic pressure [RVSP] 76.5 ± 26.2 mm Hg) and 60 healthy volunteers (RVEF 43.8 ± 9.4%, RVSP 25.9 ± 4.3 mm Hg). RESULTS:Area strain (AS) (-24.3 ± 7.3 vs. -30.8 ± 7.2; p < 0.001), radial strain (23.2 ± 14.4 vs. 34.9 ± 18.2; p < 0.001), longitudinal strain (LS) (-15.5 ± 3.8 vs. -17.9 ± 4.4; p = 0.001), and circumferential strain (CS) (-12.2 ± 4.5 vs. -15.7 ± 6.1; p < 0.001) were all reduced in patients with PHT, compared with normal individuals. AS and CS strongly correlated to RVEF (r = 0.851, r = -0.711; p < 0.001). Systolic dyssynchrony index was greater in PHT (0.14 ± 0.06 vs. 0.11 ± 0.07; p = 0.003) and correlated to RVEF (r = -0.563, p < 0.001). AS (hazard ratio [HR]: 3.49; 95% confidence interval [CI]: 1.21 to 7.07; p = 0.017), CS (HR: 4.17; 95% CI: 1.93 to 12.97; p < 0.001), LS (HR: 7.63; 95% CI: 1.76 to 10.27; p = 0.001), and RVEF (HR: 2.43; 95 CI: 1.00 to 5.92; p = 0.050) were significant determinants of all-cause mortality. Only AS (p = 0.029) and age (p = 0.087) were predictive of death after logistic regression analysis. CONCLUSIONS:PHT patients have reduced RV strain patterns and more dyssynchronous ventricles compared with controls, which was relatable to clinical outcomes. AS best correlated with RVEF and provides prognostic information independent of other variables.

BACKGROUND Quantitative assessment of right ventricular (RV) systolic function largely depends on right ventricular ejection fraction (RVEF). Three-dimensional speckle tracking (3D-ST) has been used extensively to quantify left ventricular function, but its value for RV assessment has not been established.OBJECTIVES This study sought to prospectively assess whether 3D-ST would be a reliable method for assessing RV systolic function and whether strain values were associated with survival.METHODS Comprehensive 2-dimensional echocardiographic assessment, 3D-ST of the RV free wall, and measurement of RVEF was performed in 97 consecutive patients with established pulmonary hypertension (PHT) (RVEF 31.4 +/- 9.6%, right ventricular systolic pressure [RVSP] 76.5 +/- 26.2 mm Hg) and 60 healthy volunteers (RVEF 43.8 +/- 9.4%, RVSP 25.9 +/- 4.3 mm Hg). RESULTS Area strain (AS) ( 24.3 7.3 vs. +/- 30.8 +/- 7.2; p < 0.001), radial strain (23.2 +/- 14.4 vs. 34.9 18.2; p < 0.001), longitudinal strain (LS) (+/- 15.5 +/- 3.8 vs. +/- 17.9 +/- 4.4; p 0.001), and circumferential strain (CS) ( 12.2 +/- 4.5 vs. +/- 15.7 +/- 6.1; p < 0.001) were all reduced in patients with PHT, compared with normal individuals. AS and CS strongly correlated to RVEF (r 0.851, r +/- 0.711; p < 0.001). Systolic dyssynchrony index was greater in PHT (0.14 +/- 0.06 vs. 0.11 +/- 0.07; p 0.003) and correlated to RVEF (r +/- 0.563, p < 0.001). AS (hazard ratio [HR]: 3.49; 95% confidence interval [CI]: 1.21 to 7.07; p 0.017), CS (HR: 4.17; 95% CI: 1.93 to 12.97; p < 0.001), LS (HR: 7.63; 95% CI: 1.76 to 10.27; p 0.001), and RVEF (HR: 2.43; 95 CI: 1.00 to 5.92; p 0.050) were significant determinants of all-cause mortality. Only AS (p 0.029) and age (p 0.087) were predictive of death after logistic regression analysis.CONCLUSIONS PHT patients have reduced RV strain patterns and more dyssynchronous ventricles compared with controls, which was relatable to clinical outcomes. AS best correlated with RVEF and provides prognostic information independent of other variables. (C) 2014by theAmerican College ofCardiology Foundation.

Introduction: In this study, we examined the longitudinal strain of primary papillary muscles (anterolateral and posteromedial) of the mitral valve and the left ventricle (LV) before and after repa...

Pulmonary arterial hypertension (PAH) is an uncommon disease in the general population, but a disease with significant morbidity and mortality. The prevalence of heritable PAH (HPAH) remains unknown. The reason for incomplete penetrance of HPAH is not well understood. A patient's clinical response to disease-specific therapy is complex, involving the severity of the patient's disease, other comorbidities, appropriateness of the prescribed therapy, and patient compliance. Warfarin is often used as an adjuvant therapy in patients with PAH.

The purpose of this study was to evaluate the effect of a 12-week intradialytic progressive resistance training (PRT) regimen on circulating pro- and anti-inflammatory cytokines. Forty-nine patients (62.6 ± 14.2 years) were recruited from the outpatient hemodialysis unit of the St. George Public Hospital, Sydney, Australia. Patients were randomized to: PRT + usual care (n = 24) or usual care control (n = 25). The PRT group performed two sets of 10 exercises at high intensity using free-weights, 3 times per week for 12 weeks during dialysis, while the control group did not exercise. Tumor necrosis factor-alpha, interleukin-1b, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10, and interleukin-12 were measured in serum before and after the intervention period. Muscle cross-sectional area (CSA), intramuscular lipid, intermuscular adipose tissue, and subcutaneous and total thigh fat, evaluated via computed tomography of the non-dominant mid-thigh, were also collected at both time points. All cytokines were significantly elevated in the total cohort at baseline compared with normative data. There were no cytokine changes over time or between groups (p > 0.05). In secondary analyses pooling the groups, changes in logIL-6 and IL-8 were inversely related to changes subcutaneous thigh fat (p < 0.05) while changes in logIL-6 were also inversely related to changes in thigh muscle CSA, and total thigh fat (p < 0.03). These data suggest that 12 weeks of intradialytic progressive resistance training does not improve circulating pro- and anti-inflammatory markers. Further research is required to elucidate the implications and mechanisms of the relationships between IL-6 and IL-8 and body composition in ESRD.

Two-dimensional (2D) speckle echocardiography enables objective assessment of left ventricular function through the analysis of myocardial strain, which can be measured by different speckle-tracking software. The aim of this study was to compare two different commercially available cardiac ultrasound systems and their manufacturer-specific speckle-tacking software for the quantification of global myocardial strain in a healthy population.Twenty-eight healthy subjects (age: 38 +/- 12, 64% males) underwent two 2D echocardiograms within the same day using different cardiac ultrasound systems: Vivid 7 (GE Ultrasound, Horten, Norway) and Artida 4D (Toshiba Medical Systems). Standard apical and short-axis views of the left ventricle were obtained in each subject with a frame-rate range of 60 +/- 20 frames/s. Global longitudinal, radial, and circumferential strain values were analysed using their respective speckle-tracking software for Vivid (2D-strain EchoPac PC v.7.0.1, GE Healthcare, Horten, Norway) and Toshiba systems (2D Wall Motion Tracking, Toshiba Medical Systems). Global strain values were estimated from the average of regional left ventricular strain values. Agreement between the two systems and software was assessed by Bland-Altman method. Mean left ventricular ejection fraction was 59 +/- 7%. Global longitudinal, radial, and circumferential strain values were, respectively, -21.95 +/- 1.8, 46.97 +/- 5.5, and -23.18 +/- 3.3% when using 2D-strain EchoPac and -22.28 +/- 2.1, 40.74 +/- 4.3, and -27.17 +/- 4.7% when 2D Wall Motion Tracking was used (P = NS). Limits of agreement between both speckle-tracking software were narrower for global longitudinal strain (-2.25 to 3.65) than for radial and circumferential strain (-2.23 to 12.44 and -1.36 to 10.54, respectively).Two commercially available speckle-tracking software appear to be comparable when quantifying left ventricular function in a healthy population. Global longitudinal strain is a more robust parameter than radial and circumferential strain for the assessment of myocardial function when different cardiac ultrasound systems are used for analysis.

Aim: A more precise understanding of the aetiology and sequelae of muscle wasting in end-stage renal disease (ESRD) is required for the development of effective interventions to target this pathology.Methods: We investigated 49 patients with ESRD (62.6 +/- 14.2 years, 0.3-16.7 years on haemodialysis). Thigh muscle cross-sectional area (CSA), intramuscular lipid and intermuscular adipose tissue (IMAT) were measured via computed tomography as indices of muscle quantity (i.e. CSA) and quality (i.e. intramuscular lipid and IMAT). Additional health and clinical measures were investigated to determine associations with these variables.Results: Age, energy intake, disease burden, pro-inflammatory cytokines, nutritional status, strength and functioning were related to muscle quantity and quality. Potential aetiological factors entered into forward stepwise regression models indicated that hypoalbuminaemia and lower body mass index accounted significantly and independently for 32% of the variance in muscle CSA (r = 0.56, P < 0.001), while older age and interleukin-8 accounted for 41% of the variance in intramuscular lipid (r = 0.64, P < 0.001) and body mass index accounted for 45% of the variance in IMAT (r = 0.67, P < 0.001). Stepwise regression models revealed that intramuscular lipid was independently predictive of habitual gait velocity and 6 min walk distance, while CSA was independently predictive of maximal isometric strength (P < 0.05).Conclusion: Ageing, poor nutritional status and elevated interleukin-8 are factors potentially contributing to the loss of muscle quality and quantity in ESRD. These deficits can predict functional impairments, with intramuscular lipid accumulation most closely related to decline of submaximal musculoskeletal performance (walking), and low muscle CSA most closely related to decline of maximal performance (peak isometric strength).

Skeletal muscle wasting is common and insidious in patients who receive maintenance hemodialysis treatment for the management of ESRD. The objective of this study was to determine whether 12 wk of high-intensity, progressive resistance training (PRT) administered during routine hemodialysis treatment could improve skeletal muscle quantity and quality versus usual care. Forty-nine patients (62.6 +/- 14.2 yr; 0.3 to 16.7 yr on dialysis) were recruited from the outpatient hemodialysis unit of the St. George Public Hospital (Sydney, Australia). Patients were randomized to PRT + usual care (n = 24) or usual care control only (n = 25). The PRT group performed two sets of 10 exercises at a high intensity (15 to 17/20 on the Borg Scale) using free weights, three times per week for 12 wk during routine hemodialysis treatment. Primary outcomes included thigh muscle quantity (cross-sectional area [CSA]) and quality (intramuscular lipid content via attenuation) evaluated by computed tomography scan. Secondary outcomes included muscle strength, exercise capacity, body circumference measures, proinflammatory cytokine C-reactive protein, and quality of life. There was no statistically significant difference in muscle CSA change between groups. However, there were statistically significant improvements in muscle attenuation, muscle strength, mid-thigh and mid-arm circumference, body weight, and C-reactive protein in the PRT group relative to the nonexercising control group. These findings suggest that patients with ESRD can improve skeletal muscle quality and derive other health-related adaptations solely by engaging in a 12-wk high-intensity PRT regimen during routine hemodialysis treatment sessions. Longer training durations or more sensitive analysis techniques may be required to document alterations in muscle CSA.