Prognostic value of brain natriuretic peptides in patients with pulmonary arterial hypertension: A systematic review and meta-analysis.

BACKGROUND: Multiple biomarkers have been investigated in the risk stratification of patients with pulmonary arterial hypertension (PAH). This systematic review and meta-analysis is the first to investigate the prognostic value of (NT-pro)BNP in patients with PAH. METHODS: A systematic literature search was performed using MEDLINE, Embase, Web of Science, the Cochrane Library and Google scholar to identify studies on the prognostic value of baseline (NT-pro)BNP levels in PAH. Studies reporting hazard ratios (HR) for the endpoints mortality or lung transplant were included. A random effects meta-analysis was performed to calculate the pooled HR of (NT-pro)BNP levels at the time of diagnosis. To account for different transformations applied to (NT-pro)BNP, the HR was calculated for a 2-fold difference of the weighted mean (NT-pro)BNP level of 247 pmol/L, for studies reporting a HR based on a continuous (NT-pro)BNP measurement. RESULTS: Sixteen studies were included, representing 6999 patients (mean age 45.2-65.0 years, 97.3% PAH). Overall, 1460 patients reached the endpoint during a mean follow-up period between 1 and 10 years. Nine studies reported HRs based on cut-off values. The risk of mortality or lung transplant was increased for both elevated NT-proBNP and BNP with a pooled HR based on unadjusted HRs of 2.75 (95%-CI: 1.86-4.07) and 3.87 (95% CI 2.69-5.57) respectively. Six studies reported HRs for (NT-pro)BNP on a continues scale. A 2-fold difference of the weighted mean NT-proBNP resulted in an increased risk of mortality or lung transplant with a pooled HR of 1.17 (95%-CI: 1.03-1.32). CONCLUSIONS: Increased levels of (NT-pro)BNP are associated with a significantly increased risk of mortality or lung transplant in PAH patients.

Left ventricular high frame rate echo-particle image velocimetry: clinical application and comparison with conventional imaging.

BACKGROUND: Echo-Particle Image Velocimetry (echoPIV) tracks speckle patterns from ultrasound contrast agent(UCA), being less angle-sensitive than colour Doppler. High frame rate (HFR) echoPIV enables tracking of high velocity flow in the left ventricle (LV). We aimed to demonstrate the potential clinical use of HFR echoPIV and investigate the feasibility and accuracy in patients. METHODS: Nineteen patients admitted for heart failure were included. HFR contrast images were acquired from an apical long axis view (ALAX), using a fully-programmable ultrasound system. A clinical UCA was continuously infused with a dedicated pump. Additionally, echocardiographic images were obtained using a clinical system, including LV contrast-enhanced images and pulsed-wave (PW) Doppler of the LV inflow and outflow in ALAX. 11 patients underwent CMR and 4 cardiac CT as clinically indicated. These CMR and CT images were used as reference. In 10 patients with good echoPIV tracking and reference imaging, the intracavitary flow was compared between echoPIV, conventional and UCA echocardiography. RESULTS: EchoPIV tracking quality was good in 12/19 (63%), moderate in 2/19 (10%) and poor in 5/19 (26%) subjects. EchoPIV could determine inflow velocity in 17/19 (89%), and outflow in 14/19 (74%) patients. The correlation of echoPIV and PW Doppler was good for the inflow (R2 = 0.77 to PW peak; R2 = 0.80 PW mean velocity) and moderate for the outflow (R2 = 0.54 to PW peak; R2 = 0.44 to PW mean velocity), with a tendency for echoPIV to underestimate PW velocities. In selected patients, echoPIV was able in a single acquisition to demonstrate flow patterns which required multiple interrogations with classical echocardiography. Those flow patterns could also be linked to anatomical abnormalities as seen in CMR or CT. CONCLUSION: HFR echoPIV tracks multidirectional and complex flow patterns which are unapparent with conventional echocardiography, while having comparable feasibility. EchoPIV tends to underestimate flow velocities as compared to PW Doppler. It has the potential to provide in one acquisition all the functional information obtained by conventional imaging, overcoming the angle dependency of Doppler and low frame rate of classical contrast imaging.

Right ventricular functional assessment by 2D multi-plane echocardiography prior to left ventricular assist device implantation.

OBJECTIVES: Right ventricular (RV) failure post left ventricular assist device (LVAD) implantation is associated with increased morbidity and mortality. A novel RV multi-plane imaging method using two-dimensional echocardiography and electronic plane rotation (MPE) was used to quantify RV function prior to LVAD implantation and to identify potential added value in this patient population. METHODS: In twenty-five end-stage heart failure patients (age 58.9 ± 6.8 years, 76% male), systolic function of four different RV walls (lateral, anterior, inferior and inferior coronal) were evaluated from one focussed apical view using MPE. RESULTS: Feasibility of tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (RV-S') measurements were high (84-100%), with lower TAPSE values measured in the inferior (14.2 ± 4.6 mm) and inferior coronal (12.3 ± 5.0 mm) walls compared to the lateral (16.3 ± 4.5 mm) and anterior walls (16.0 ± 4.5 mm). RV wall longitudinal strain (RV-LS) measurement was most feasible in the lateral wall (80%; mean: -12.1 ± 4.2%). TAPSE and RV-LS values were significantly reduced in patients compared to matched healthy individuals (p = <0.001). Seven (28%) patients who developed moderate to severe RV failure (RVF) early post-implant (≤30 days) had lower pre-implant values across all multi-plane parameters compared to those without significant post-implant RVF, notably four-wall averaged TAPSE (11.1 ± 3.4 mm vs 15.9 ± 4.0 mm; p = 0.02). CONCLUSION: 2D MPE was highly feasible for RV wall quantification pre-LVAD surgery, detecting differences in regional wall function. This novel method comprehensively quantifies RV wall function and could complement current pre-LVAD screening protocols.

Prognostic significance of left atrial strain in sarcomere gene variant carriers without hypertrophic cardiomyopathy.

BACKGROUND: Genetic testing of relatives of hypertrophic cardiomyopathy (HCM) patients has led to a large group of genotype-positive, phenotype-negative (G+/Ph-) subjects. Prediction of progression to overt HCM in these subjects is challenging. While left atrial (LA) strain is reduced in HCM patients it is currently unknown whether this parameter can be used to predict HCM phenotype progression. METHODS: This study includes 91 G+/Ph- subjects and 115 controls. Standard echocardiographic parameters as well as left ventricular global longitudinal strain (LV GLS) and LA reservoir strain (LASr) were assessed for each patient. Logistic and Cox proportional hazard regression analyses were used to investigate predictors of G+/Ph- status and HCM during follow-up. RESULTS: Independent predictors of G+ status included pathological Q waves (OR 1.60 [1.15-2.23], p < .01), maximal wall thickness (MWT: OR 1.10 [1.07-1.14], p < .001), mitral inflow E wave (OR 1.06 [1.02-1.10, p = .001), A wave (OR 1.06 [1.03-1.10], p < .001), LV GLS (OR .96 [.94-.98], p < .001), and LASr (OR .99 [.97-.99], p = .03). In univariable Cox regression analysis, male sex (HR 2.78 [1.06-7.29], p = .04), MWT (HR 1.72 [1.14-2.57], p = .009) and posterior wall thickness (HR 1.65 [1.17-2.30], p = .004) predicted HCM during a median follow-up of 5.9 [3.2-8.6] years, whereas LASr did not (HR .95 [.89-1.02], p = .14). There were no significant predictors of HCM after multivariable adjustment. CONCLUSION: LASr is significantly impaired in G+/Ph- subjects and is an independent predictor of G+/Ph- status, but did not predict HCM development during follow-up.

Peripheral Blood T Cells of Patients with IPAH Have a Reduced Cytokine-Producing Capacity.

Pulmonary arterial hypertension (PAH) is rare disease that is categorized as idiopathic (IPAH) when no underlying cause can be identified. Lungs of most patients with IPAH contain increased numbers of T cells and dendritic cells (DCs), suggesting involvement of the immune system in its pathophysiology. However, our knowledge on circulating immune cells in IPAH is rather limited. We used flow cytometry to characterize peripheral blood DCs and T cells in treatment-naive IPAH patients, compared with connective-tissue disease-PAH (CTD-PAH) patients and healthy controls (HCs). At diagnosis, T-helper (Th) cells of IPAH patients were less capable of producing TNFα, IFNγ, IL-4 and IL-17 compared to HCs. IPAH patients showed a decreased frequency of Th2 cells and significantly enhanced expression of the CTLA4 checkpoint molecule in naive CD4+ T cells and both naive and memory CD8+ T cells. Frequencies and surface marker expression of circulating DCs and monocytes were essentially comparable between IPAH patients and HCs. Principal component analysis (PCA) separated IPAH patients-but not CTD-PAH patients-from HCs, based on T-cell cytokine profiles. At 1-year follow-up, the frequencies of IL-17+ production by memory CD4+ T cells were increased in IPAH patients and accompanied by increased proportions of Th17 and Tc17 cells, as well as decreased CTLA4 expression. Treatment-naive IPAH patients displayed a unique T-cell phenotype that was different from CTD-PAH patients and was characterized by reduced cytokine-producing capacity. These findings point to involvement of adaptive immune responses in IPAH, which may have an implication for the development of therapeutic interventions.

Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension.

INTRODUCTION: Autoreactivity against pulmonary vascular structures is thought to be involved in idiopathic pulmonary arterial hypertension (IPAH), but the underlying mechanisms remain poorly understood. We hypothesised that aberrant B-cell activation contributes to IPAH aetiology. METHODS: Mice with enhanced B-cell activation due to B-cell-specific overexpression of the B-cell receptor (BCR) signalling molecule Bruton's tyrosine kinase (BTK) were subjected to lung injury and examined for several pulmonary hypertension (PH) indices. Peripheral blood lymphocytes from patients with IPAH (n=13), connective tissue disease-associated PAH (CTD-PAH, n=9), congenital heart disease PAH (n=7), interstitial lung disease associated PH (n=17) and healthy controls (n=19) were characterised by 14-colour flow cytometry. RESULTS: Following pulmonary injury, BTK-overexpressing mice showed prolonged activation of B cells and CXCR5+ follicular T-helper (Tfh) cells, as well as features of PH development. Patients with CTD-PAH and CHD-PAH displayed reduced proportions of circulating non-switched-memory B cells (p=0.03, p=0.02, respectively). Interestingly, we observed increased BTK protein expression in naive (p=0.007) and memory B-cell subsets of patients with IPAH and CTD-PAH. BTK was particularly high in patients with IPAH with circulating autoantibodies (p=0.045). IPAH patients had low frequencies of circulating CXCR5+ Tfh cells (p=0.005). Hereby, the increased BTK protein expression in B cells was associated with high proportions of Tfh17 (p=0.018) and Tfh17.1 (p=0.007) cells within the circulating Tfh population. CONCLUSIONS: Our study shows that pulmonary injury in combination with enhanced B-cell activation is sufficient to induce PH symptoms in mice. In parallel, immune homeostasis in patients with IPAH is compromised, as evidenced by increased BCR signalling and cTfh17 polarisation, indicating that adaptive immune activation contributes to IPAH disease induction or progression.

Bicuspid aortic valve annulus: assessment of geometry and size changes during the cardiac cycle as measured with a standardized method to define the annular plane.

PURPOSE: Bicuspid aortic valve (BAV) is a complex malformation affecting not merely the aortic valve. However, little is known regarding the dynamic physiology of the aortic annulus in these patients and whether it is similar to tricuspid aortic valves (TAV). Determining the BAV annular plane is more challenging than for TAV. Our aim was to present a standardized methodology to determine BAV annulus and investigate its changes in shape and dimensions during the cardiac cycle. METHODS: BAV patients were prospectively included and underwent an ECG-gated cardiac CTA. The annulus plane was manually identified on reconstructions at 5% intervals of the cardiac cycle with a new standardized method for different BAV types. Based on semi-automatically defined contours, maximum and minimum diameter, area, area-derived diameter, perimeter, asymmetry ratio (AR), and relative area were calculated. Differences of dynamic annular parameters were assessed also per BAV type. RESULTS: Of the 55 patients included (38.4 ± 13.3 years; 58% males), 38 had BAV Sievers type 1, 10 type 0, and 7 type 2. The minimum diameter, perimeter, area, and area-derived diameter were significantly higher in systole than in diastole with a relative change of 13.7%, 4.8%, 13.7%, and 7.2% respectively (all p < 0.001). The AR was ≥ 1.1 in all phases, indicating an elliptic shape, with more pronounced flattening in diastole (p < 0.001). Different BAV types showed comparable dynamic changes. CONCLUSIONS: BAV annulus undergo significant changes in shape during the cardiac cycle with a wider area in systole and a more elliptic conformation in diastole regardless of valve type. KEY POINTS: • A refined method for the identification of the annulus plane on CT scans of patients with bicuspid aortic valves, tailored for the specific anatomy of each valve type, is proposed. • The annulus of patients with bicuspid aortic valves undergoes significant changes during the cardiac cycle with a wider area and more circular shape in systole regardless of valve type. • As compared to previously published data, the bicuspid aortic valve annulus has physiological dynamics similar to that encountered in tricuspid valves but with overall larger dimensions.

A value-based healthcare approach: Health-related quality of life and psychosocial functioning in women with Turner syndrome.

OBJECTIVE: As part of the value-based healthcare programme in our hospital, a set of patient-reported outcome measures was developed together with patients and implemented in the dedicated Turner Syndrome (TS) outpatient clinic. This study aims to investigate different aspects of health-related quality of life (HR-QoL) and psychosocial functioning in women with TS in order to establish new possible targets for therapy. DESIGN/PARTICIPANTS: A comprehensive set of questionnaires (EQ-5D, PSS-10, CIS-20, Ferti-QoL, FSFI) was developed and used to capture different aspects of HR-QoL and psychosocial functioning in a large cohort of adult women with Turner syndrome. All consecutive women, ≥18 years, who visited the outpatient clinic of our tertiary centre were eligible for inclusion. RESULTS: Of the eligible 201 women who were invited to participate, 177 women (age 34 ± 12 years, mean ± SD) completed at least one of the validated questionnaires (88%). Women with TS reported a lower health-related quality of life (EQ-5D: 0.857 vs 0.892, P = .003), perceived more stress (PSS-10:14.7 vs 13.3; P = .012) and experienced increased fatigue (CIS-20: P < .001) compared to the general Dutch population. A relationship between noncardiac comorbidities (eg diabetes, orthopaedic complaints) and HR-QoL was found (R = .508). CONCLUSIONS: We showed that TS women suffer from impaired HR-QoL, more perceived stress and increased fatigue compared to healthy controls. A relationship between noncardiac comorbidities and HR-QoL was found. Especially perceived stress and increased fatigue can be considered targets for improvement of HR-QoL in TS women.

The prognostic value of various biomarkers in adults with pulmonary hypertension; a multi-biomarker approach.

BACKGROUND: This study aimed to investigate the prognostic value of six different biomarkers in patients with pulmonary hypertension (PH) and to explore whether a multi-biomarker approach can contribute to a better risk stratification. METHODS: In this prospective study, patients with PH were included at the day of the diagnostic right heart catheterization between May 2012 and October 2016. Venous blood sampling included; NT-proBNP, high sensitive troponin-T, high sensitive CRP, galectin-3, red blood cell distribution width and eGFR. Associations between biomarker levels and the primary endpoint (death or lung transplantation) and secondary endpoint (death, lung transplantation or heart failure) were assessed with Cox regression, adjusted for age and sex. Additionally, adjustment for the REVEAL risk score was performed. RESULTS: In total, 106 patients were included (median age 58.7 [IQR 47.0-69.2] years, 64% women, 51% pulmonary arterial hypertension). After a median follow-up duration of 23.9 [IQR 15.1-40.0] months, respectively 29 and 37 patients reached the primary and secondary endpoint. All six biomarkers, except eGFR, were significantly associated with the endpoints. A multi-biomarker approach including the number of elevated biomarkers per patient, demonstrated that patients were at higher risk of adverse events as more biomarker levels were elevated (HR for each extra elevated biomarker; 1.33, 95% CI 1.07-1.64, P = .01). However, a single as well as a combination of multiple biomarkers, did not yield prognostic value independent of the REVEAL risk score. CONCLUSIONS: Various biomarkers are associated with the event-free survival in adults with PH. However, risk stratification exclusively based on single or a combination of biomarkers seems not superior to existing risk scores.

Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide, Troponin-T, and Growth-Differentiation Factor 15 in Adult Congenital Heart Disease.

BACKGROUND: The number of patients with adult congenital heart disease (ACHD) is rapidly increasing. To optimize patient management, there is a great need to accurately identify high-risk patients. Still, no biomarker has been firmly established as a clinically useful prognostic tool in this group. We studied the association of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitive troponin-T, and growth-differentiation factor 15 with cardiovascular events in ACHD. METHODS: Clinically stable patients with ACHD who routinely visited the outpatient clinic between April 2011 and April 2013 underwent clinical assessment, electrocardiography, echocardiography, and biomarker measurement (NT-proBNP, high-sensitive troponin-T, and growth-differentiation factor 15) at the time of study inclusion. Patients were prospectively followed for the occurrence of cardiovascular events (death, heart failure, hospitalization, arrhythmia, thromboembolic events, and reintervention). Survival curves were derived by the Kaplan-Meier method, and Cox regression was performed to investigate the relation between biomarkers and events with adjustment for multiple clinical and echocardiographic variables. RESULTS: In total, 595 patients were included (median age, 33 years; interquartile range, 25-41 years; 58% male; 90% New York Heart Association class I). Patients were followed during a median of 42 (interquartile range, 37-46) months. Of the 3 evaluated biomarkers, NT-proBNP in the upper quartile (>33.3 pmol/L) was most strongly associated with cardiovascular events (n=165, adjusted hazard ratio, 9.05 [3.24-25.3], P<0.001) and with death or heart failure (n=50, adjusted hazard ratio, 16.0 [2.04-126], P<0.001). When NT-proBNP was analyzed as a continuous variable, similar findings were retrieved. The cumulative proportion of patients with death and heart failure was only 1% in the lowest 2 NT-proBNP quartiles. Elevated NT-proBNP (>14 pmol/L), elevated high-sensitive troponin-T (>14 ng/L), and elevated growth-differentiation factor 15 (>1109 ng/L) identified those patients at highest risk of cardiovascular events (log-rank P<0.0001). CONCLUSIONS: NT-proBNP provides prognostic information beyond a conventional risk marker model in patients with ACHD and can reliably exclude the risk of death and heart failure. Elevated levels of NT-proBNP, high-sensitive troponin-T, and growth-differentiation factor 15 identify patients at highest risk of cardiovascular events. These biomarkers therefore may play an important role in the monitoring and management of patients with ACHD.

The prevalence of pulmonary arterial hypertension before and after atrial septal defect closure at adult age: A systematic review.

BACKGROUND: The development or persistence of pulmonary arterial hypertension (PAH) after atrial septal defect (ASD) closure at adult age is associated with a poor prognosis. The objective of this review was to investigate the prevalence of PAH before and after ASD closure and to identify factors that are associated with PAH. METHODS: EMBASE and MEDLINE databases were searched for publications until March 2017. All studies reporting the prevalence of PAH or data on pulmonary artery pressures both before and after surgical or percutaneous ASD closure in an adult population (≥16 years of age) were included. Papers were methodologically checked and data was visualized in tables, bar charts and plots. RESULTS: A total of 30 papers were included. The prevalence of PAH ranged from 29% to 73% before ASD closure and from 5% to 50% after closure; being highest in older studies, small study cohorts, and studies with high rates of loss to follow-up. The pooled systolic pulmonary artery pressure (PAP) was 43±13 before ASD closure and 32±10 after closure. The overall mean PAP was 34±10 before closure and 28±8 after closure. Studies with a higher mean PAP before closure and a higher mean age of the study cohort reported greater PAP reductions. CONCLUSIONS: The prevalence of PAH and mean pulmonary pressures decreased in all studies, regardless of the mean age or pulmonary pressures of the cohort. The reported prevalence of PAH after ASD closure is substantial, although widely varying (5%-50%), which is likely affected by selection of the study cohort.

In-depth echocardiographic analysis of left atrial function in healthy adults using speckle tracking echocardiography and volumetric analysis.

PURPOSE: Left atrial (LA) dilatation is predictive for complications in a multitude of cardiac diseases; therefore, adequate assessment is essential. Technological advances have made it possible to quantify LA function with Speckle Tracking Echocardiography (STE); however, there are currently no recommendations for normal values with regard to LA function. We aimed to assess LA myocardial and volumetric function in a healthy cohort and investigate correlations with baseline characteristics. METHODS: This prospective cohort study included 147 (aged 20-72) healthy individuals and assessed LA volumetric function using maximum, minimum and pre-a-wave volumes and myocardial function using reservoir function using peak strain in LA relaxation (LA-strain), conduit function using peak strain rate in early LA contraction (LA-SRe) and pump function using peak strain rate in late LA contraction (LA-SRa). RESULTS: Mean LA-strain was 39.7 ± 6.2%, LA-SRe -2.78 ± 0.62 s-1 and LA-SRa -2.56 ± 0.62 s-1 . Subjects were divided into 5 age decades (each 50% female). LA-strain and LA-SRe were lower in the oldest groups, whereas LA-SRa was higher. LA-SRa was higher in males(-2.69 ± 0.68 s-1 vs -2.42 ± 0.52 s-1 ). Age-specific values are provided. Age proved to be an independent predictor for LA-SRa after correction for blood pressure and heart rate. LA expansion index and passive emptying fraction decreased with age, while active emptying fraction increased with age. LA maximum volume did not increase with age. CONCLUSION: This study provides normal values for the three phasic functions of the LA, assessed with STE and volumetric function. Our results suggest the need for age-specific reference ranges, and normal values for this cohort have been calculated.

Adverse outcome of coarctation stenting in patients with Turner syndrome.

OBJECTIVES: This study examines the outcome and procedural outcomes of percutaneous stent angioplasty for aortic coarctation in patients with Turner syndrome (TS). BACKGROUND: TS occurs in 1 in 2,500 live-born females and is associated with aortic coarctation. METHODS: In this multicenter, retrospective cohort study, all patients with TS and a coarctation of the aorta, treated with percutaneous stent implantation were included. The procedural strategies were dictated by local protocols. Adverse events at short- and long-term follow-up and qualitative parameters concerning the stent implantation were assessed. RESULTS: In the largest study to date of TS patients receiving aortic stents, a total of 19 patients from 10 centers were included. Twelve patients were treated for native and 7 for recurrent coarctation. Age at intervention was 16.9 (7-60) years (median; min-max). The coarctation diameter increased significantly from 8.0 mm (2-12) pre-intervention to 15.0 mm (10-19) post-intervention (P < 0.001). Three (15.8%) adverse events occurred within 30 days of the procedure, including two dissections despite the use of covered stents, one resulting in death. At long-term follow-up (6.5 years, min-max: 1-16), two additional deaths occurred not known to be stent-related. CONCLUSIONS: Though percutaneous treatment of aortic coarctation in TS patients is effective, it is associated with serious morbidity and mortality. These risks suggest that alternative treatment options should be carefully weighed against percutaneous stenting strategies. © 2016 Wiley Periodicals, Inc.

Matrix metalloproteinases as candidate biomarkers in adults with congenital heart disease.

Context Matrix metalloproteinases (MMPs) are associated with diastolic dysfunction and heart failure in acquired heart disease. Objective To investigate the role of MMPs as novel biomarkers in clinically stable adults with congenital heart disease. Methods We measured serum MMP-2, -3, -9 and tissue inhibitor of matrix metalloproteinase-1 in 425 patients and analysed the association with cardiac function and exercise capacity. Results MMP-2 was significantly associated with exercise capacity, ventilatory efficiency and left ventricular deceleration time, independently of age, sex, body surface area and NT-proBNP. Conclusion MMP-2 may provide new information in the clinical evaluation of adults with congenital heart disease.

Normal myocardial strain values using 2D speckle tracking echocardiography in healthy adults aged 20 to 72 years.

AIMS: Evaluation of left ventricular (LV) myocardial deformation by speckle tracking echocardiography (STE) is useful for clinical and research purposes. However, strain measurements depend on the used software. Normative data for QLAB 10 (Philips) are scarce. Additionally, little is known about the influence of anthropometric factors. We aimed to establish normal adult STE-derived strain and strain rate values and to evaluate associations with anthropometrics. METHODS: One hundred fifty-five healthy subjects aged 20 to 72 years (≥28 subjects per decile) were prospectively gathered and examined with electrocardiography and two-dimensional echocardiography. With STE, we assessed peak systolic LV global longitudinal strain (GLS), segmental longitudinal strain, and strain rate from the three standard apical views. RESULTS: We included 147 healthy subjects (age 44.6±13.7 years, 50% female, GLS -20.8±2.0%). Men had significantly lower GLS than women (-20.1±1.8% vs -21.5±2.0%, P<.001). GLS was significantly lower in subjects with age above 55 years (P=.029), higher blood pressure (P<.001), higher body surface area (BSA, P<.001), larger LV end-systolic and end-diastolic volumes (both P<.001), lower LV ejection fraction (P<.001), and some indices of diastolic function. After multivariable regression analysis, the correlation with systolic blood pressure, E-wave, and LV end-systolic volume remained significant. The systolic strain rates of most segments correlated with BSA. CONCLUSIONS: Our study resulted in normative LV GLS values assessed with QLAB 10. Male sex, higher BSA, and higher blood pressure negatively influence GLS. Therefore, these factors should be taken into account for strain interpretation in clinical practice.

A Novel 13-Segment Standardized Model for Assessment of Right Ventricular Function Using Two-Dimensional iRotate Echocardiography.

AIMS: The aim of this study was to evaluate the feasibility of transthoracic two-dimensional (2D) iRotate, a new echo modality, to assess the whole right ventricle (RV) from a single transducer position based on anatomic landmarks. METHODS AND RESULTS: The anatomic landmarks were first defined based on three-dimensional echocardiographic datasets using multiplane reconstruction analyses. Thereafter, we included 120 healthy subjects (51% male, age range 21-67 years). Using 2D iRotate, four views of the RV could be acquired based on these landmarks. The anterior, lateral, inferior wall (divided into three segments: basal-mid-apical), and right ventricular outflow tract (RVOT) anterior wall of the RV were determined. The feasibility of visualization of RV segments and tricuspid annular plane systolic excursion (TAPSE) and tissue Doppler imaging (TDI) measurements were assessed. To evaluate this model for diseased RVs, a small pilot study of 20 patients was performed. In 98% of healthy subjects and 100% of patients, iRotate mode was feasible to assess the RV from one single transducer position. In total, 86% and 95%, respectively, of the RV segments could be visualized. The visualization of the RVOT anterior wall was worse 23% and 75%, respectively. TAPSE and TDI measurements on all four views were feasible 93% and 92%, respectively, of the healthy subjects and in 100% of the patients. CONCLUSION: With 2D iRotate, a comprehensive evaluation of the entire normal and diseased RV is feasible from a fixed transducer position based on anatomic landmarks. This is less time-consuming than the multiview approach and enhances accuracy of RV evaluation. Imaging of the RVOT segment remains challenging.

Unnatural history of tetralogy of Fallot: prospective follow-up of 40 years after surgical correction.

BACKGROUND: Prospective data on long-term survival and clinical outcome beyond 30 years after surgical correction of tetralogy of Fallot are nonexistent. METHODS AND RESULTS: This longitudinal cohort study consists of the 144 patients with tetralogy of Fallot who underwent surgical repair at <15 years of age between 1968 and 1980 in our center. They are investigated every 10 years. Cumulative survival (data available for 136 patients) was 72% after 40 years. Late mortality was due to heart failure and ventricular fibrillation. Seventy-two of 80 eligible survivors (90%) participated in the third in-hospital investigation, consisting of ECG, Holter, echocardiography, cardiopulmonary exercise testing, N-terminal pro-brain natriuretic peptide measurement, cardiac magnetic resonance (including dobutamine stress testing), and the Short Form-36 questionnaire. Median follow-up was 36 years (range, 31-43 years). Cumulative event-free survival was 25% after 40 years. Subjective health status was comparable to that in the normal Dutch population. Although systolic right and left ventricular function declined, peak exercise capacity remained stable. There was no progression of aortic root dilation. A previous shunt operation, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality (hazard ratio, 2.9, 1.1, and 2.5, respectively). An increase in QRS duration and a deterioration of exercise tolerance and ventricular dysfunction did not predict mortality. Insertion of a transannular patch was a predictor for late arrhythmias (hazard ratio, 4.0; 95% confidence interval, 1.2-13.4). CONCLUSIONS: Although many patients needed a reoperation or developed arrhythmias, late mortality was low, and the clinical condition and subjective health status of most patients remained good. Previous shunt, low temperature during surgery, and early postoperative arrhythmias were found to predict late mortality.

The natural and unnatural history of the Mustard procedure: long-term outcome up to 40 years.

AIMS: To describe long-term survival, clinical outcome and ventricular systolic function in a longitudinally followed cohort of patients after Mustard repair for transposition of the great arteries (TGA). There is serious concern about the long-term outcome after Mustard repair. METHODS AND RESULTS: This longitudinal single-centre study consisted of 91 consecutive patients, who underwent Mustard repair before 1980, at age <15 years, and were evaluated in-hospital every 10 years. Survival status was obtained of 86 patients. Median follow-up was 35 (IQR 34-38) years. Cumulative survival was 84% after 10 years, 80% after 20 years, 77% after 30 years, and 68% after 39 years. Cumulative survival free of events (i.e. heart transplantation, arrhythmias, reintervention, and heart failure) was 19% after 39 years. Reinterventions were mainly required for baffle-related problems. Supraventricular and ventricular arrhythmias occurred in 28 and 6% of the patients, respectively. Pacemaker and/or ICD implantation was performed in 39%. Fifty survivors participated in the current in-hospital investigation including electrocardiography, 2D-echocardiography, cardiopulmonary-exercise testing, NT-proBNP measurement, Holter monitoring, and cardiac magnetic resonance. Right ventricular systolic function was impaired in all but one patient at last follow-up, and 14% developed heart failure in the last decade. NT-proBNP levels [median 31.6 (IQR 22.3-53.2) pmol/L] were elevated in 92% of the patients. Early postoperative arrhythmias were a predictor for late arrhythmias [HR 3.8 (95% CI 1.5-9.5)], and development of heart failure [HR 8.1 (95% CI 2.2-30.7)]. Also older age at operation was a predictor for heart failure [HR 1.26 (95% CI 1.0-1.6)]. CONCLUSION: Long-term survival after Mustard repair is clearly diminished and morbidity is substantial. Early postoperative arrhythmias are a predictor for heart failure and late arrhythmias.

Association between N-terminal pro-brain natriuretic peptide and quality of life in adult patients with congenital heart disease.

AIMS: Advances in medical treatment have resulted in increased life expectancy in congenital heart disease. Consequently, the focus of management has shifted from reducing mortality to reducing long-term morbidity with the goal of improving quality of life. A predictor of quality of life might be N-terminal pro-brain natriuretic peptide, a well-established marker for heart failure. We aimed to determine the association between N-terminal pro-brain natriuretic peptide and quality of life in patients with congenital heart disease. METHODS: We collected blood samples from consecutive patients who were initially operated between 1968 and 1980 (47.8% women; mean age 40.2±5.4 years). The 36-item Short-Form Health Survey was completed to assess subjective health status as a measure of quality of life. Analysis was performed for the entire group and for subgroups defined as simple versus complex congenital heart diseases. Median N-terminal pro-brain natriuretic peptide level was 15.2 pmol/L (overall range 1.3-299.3 pmol/L). N-terminal pro-brain natriuretic peptide levels were associated with the subdomain physical functioning (ß=-0.074, p=0.031). This association remained significant after adjustment for age and sex (ß=-0.071, p=0.038) and after adjustment for age, sex, body mass index, left ventricular function, and renal function (ß=-0.069, p=0.048). In complex congenital heart disease, the association between N-terminal pro-brain natriuretic peptide and physical functioning remained significant in multivariable analysis (ß=-0.076, p=0.046). No associations were found in the simple congenital heart disease group or on the other health status subdomains. CONCLUSION: In adults operated for congenital heart disease, N-terminal pro-brain natriuretic peptide is associated with the subdomain physical, primarily in the complex subgroup.

Prognostic value of left atrial strain in patients with tetralogy of fallot.

To demonstrate prognostic utility of left atrial strain (LAS) in adult patients with repaired Tetralogy of Fallot (rTOF). Adults patients with rTOF were prospectively enrolled in this study between years 2011 and 2015. Left atrium (LA) phasic functions were assessed using 2D speckle tracking echocardiography. Association of LA strain (LAS) with primary (any cardiovascular event) and secondary (death, heart failure or arrhythmia) composite endpoints was assessed using Cox regression analysis. Hundred-and-twelve rTOF patients, in whom LAS was feasible and were in sinus rhythm, were included in the final analysis (age 33 ± 10 years, 68[61%] male). Median duration of follow-up was 8.6 [4.2-9.7] years in the study group. Primary composite endpoint was reached in 48 patients (mean event-free survival time: 7.2 [6.6-7.9] years), and secondary composite endpoint was reached in 22 patients (mean event-free survival time: 8.7 [8.1-9.2] years). LA reservoir strain (LAS-r) was defined as tertile groups (1st tertile < 33%, 2nd tertile = 33-44%, 3rd tertile > 44%). Decreasing tertiles of LAS-r was associated with primary and secondary composite endpoints in Kaplan-Meier analysis (p = 0.02 and 0.002, respectively). In univariable Cox-regression, both decreasing LAS-r and LAS-r tertiles were associated with primary and secondary composite endpoints. Adjusted by initial repair age and NT-proBNP quartiles, increased LAS-r was associated with significantly decreased occurrence of experiencing any events (HR = 0.97, CI 0.93-0.99, p < 0.001). Decreasing LAS-r was still associated with primary endpoint when adjusted by left atrium volume index (LAVImax) (HR = 0.96, CI 0.92-0.99, p = 0.01), left ventricle global longitudinal strain (HR = 0.96, CI 0.93-0.99, p < 0.001) or right ventricle free wall longitudinal strain (HR = 0.96, CI 0.93-0.99, p = 0.03). Assessment of LA mechanics with the use of STE has incremental utility in determination of mortality and morbidity in rTOF, and may be implemented in clinical practice.