Reduced global longitudinal strain at rest and inadequate blood pressure response during exercise treadmill testing in male heterozygous familial hypercholesterolemia patients.

BACKGROUND: Heterozygous familial hypercholesterolemia (heFH) is a genetic disorder leading to premature coronary artery disease (CAD). We hypothesized that the subclinical pathophysiologic consequences of hypercholesterolemia may be detected before the occurrence of clinically overt CAD by stress testing and myocardial strain imaging. PATIENTS-METHODS: We evaluated the treadmill tests (ETTs) of 46 heFH men without known arterial hypertension/diabetes mellitus/vasculopathy like CAD and of 39 healthy men matched for age, baseline systolic/diastolic blood pressure (BP) and heart rate (HR), using Bruce protocol. Global longitudinal strain (GLS) of the left ventricle (LV) additionally to ejection fraction was obtained. RESULTS: heFH men reached a significantly higher peak systolic and diastolic BP compared to controls (p = 0.002 and p < 0.001, respectively). Mean rate pressure product was significantly higher in heFH patients (p = 0.038). Both duration of the ETT and workload in metabolic equivalents was lower in the heFH group (p < 0.001 and p < 0.001, respectively). Baseline to peak rise of systolic and diastolic BP in heFH men was higher (p = 0.008 and p < 0.001 for systolic and diastolic BP, respectively). Furthermore, heFH men had higher rise of HR from baseline to peak, compared to controls; (p = 0.047). GLS in heHF men was slightly decreased (p = 0.014), although the ejection fraction was similar in both groups. CONCLUSION: heFH men have a higher rise in systolic/diastolic BP during ETT, which may reflect early, preclinical hypertension. Furthermore, slight impairment of LV GLS is present, despite the absence of apparent myocardial dysfunction in conventional 2D echocardiography.

Correlation between non-invasive myocardial work indices and main parameters of systolic and diastolic function: results from the EACVI NORRE study.

AIMS: The present study sought to evaluate the correlation between indices of non-invasive myocardial work (MW) and left ventricle (LV) size, traditional and advanced parameters of LV systolic and diastolic function by 2D echocardiography (2DE). METHODS AND RESULTS: A total of 226 (85 men, mean age: 45 ± 13 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. Global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE) were estimated from LV pressure-strain loops using custom software. Peak LV pressure was estimated non-invasively from brachial artery cuff pressure. LV size, parameters of systolic and diastolic function and ventricular-arterial coupling were measured by echocardiography. As advanced indices of myocardial performance, global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were obtained. On multivariable analysis, GWI was significantly correlated with GLS (standardized beta-coefficient = -0.23, P < 0.001), ejection fraction (EF) (standardized beta-coefficient = 0.15, P = 0.02), systolic blood pressure (SBP) (standardized beta-coefficient = 0.56, P < 0.001) and GRS (standardized beta-coefficient = 0.19, P = 0.004), while GCW was correlated with GLS (standardized beta-coefficient = -0.55, P < 0.001), SBP (standardized beta-coefficient = 0.71, P < 0.001), GRS (standardized beta-coefficient = 0.11, P = 0.02), and GCS (standardized beta-coefficient = -0.10, P = 0.01). GWE was directly correlated with EF and inversely correlated with Tei index (standardized beta-coefficient = 0.18, P = 0.009 and standardized beta-coefficient = -0.20, P = 0.004, respectively), the opposite occurred for GWW (standardized beta-coefficient =--0.14, P = 0.03 and standardized beta-coefficient = 0.17, P = 0.01, respectively). CONCLUSION: The non-invasive MW indices show a good correlation with traditional 2DE parameters of myocardial systolic function and myocardial strain.

Echocardiographic reference ranges for normal left ventricular layer-specific strain: results from the EACVI NORRE study.

AIMS: To obtain the normal range for 2D echocardiographic (2DE) measurements of left ventricular (LV) layer-specific strain from a large group of healthy volunteers of both genders over a wide range of ages. METHODS AND RESULTS: A total of 287 (109 men, mean age: 46 ± 14 years) healthy subjects were enrolled at 22 collaborating institutions of the EACVI Normal Reference Ranges for Echocardiography (NORRE) study. Layer-specific strain was analysed from the apical two-, three-, and four-chamber views using 2DE software. The lowest values of layer-specific strain calculated as ±1.96 standard deviations from the mean were -15.0% in men and -15.6% in women for epicardial strain, -16.8% and -17.7% for mid-myocardial strain, and -18.7% and -19.9% for endocardial strain, respectively. Basal-epicardial and mid-myocardial strain decreased with age in women (epicardial; P = 0.008, mid-myocardial; P = 0.003) and correlated with age (epicardial; r = -0.20, P = 0.007, mid-myocardial; r = -0.21, P = 0.006, endocardial; r = -0.23, P = 0.002), whereas apical-epicardial, mid-myocardial strain increased with the age in women (epicardial; P = 0.006, mid-myocardial; P = 0.03) and correlated with age (epicardial; r = 0.16, P = 0.04). End/Epi ratio at the apex was higher than at the middle and basal levels of LV in men (apex; 1.6 ± 0.2, middle; 1.2 ± 0.1, base 1.1 ± 0.1) and women (apex; 1.6 ± 0.1, middle; 1.1 ± 0.1, base 1.2 ± 0.1). CONCLUSION: The NORRE study provides useful 2DE reference ranges for novel indices of layer-specific strain.

Echocardiographic reference ranges for normal non-invasive myocardial work indices: results from the EACVI NORRE study.

AIMS: To obtain the normal ranges for 2D echocardiographic (2DE) indices of myocardial work (MW) from a large group of healthy volunteers over a wide range of ages and gender. METHODS AND RESULTS: A total of 226 (85 men, mean age: 45 ± 13 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. Global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE) were estimated from left ventricle (LV) pressure-strain loops. Peak LV systolic pressure was non-invasively derived from brachial artery cuff pressure. The lowest values of MW indices in men and women were 1270 mmHg% and 1310 mmHg% for GWI, 1650 mmHg% and 1544 mmHg% for GCW, and 90% and 91% for GWE, respectively. The highest value for GWW was 238 mmHg% in men and 239 mmHg% in women. Men had significant lower values of GWE and higher values of GWW. GWI and GCW significantly increased with age in women. CONCLUSION: The NORRE study provides useful 2DE reference ranges for novel indices of non-invasive MW.

Echocardiographic reference ranges for normal left atrial function parameters: results from the EACVI NORRE study.

Aims: To obtain the normal ranges for echocardiographic measurements of left atrial (LA) function from a large group of healthy volunteers accounting for age and gender. Methods and results: A total of 371 (median age 45 years) healthy subjects were enrolled at 22 collaborating institutions collaborating in the Normal Reference Ranges for Echocardiography (NORRE) study of the European Association of Cardiovascular Imaging (EACVI). Left atrial data sets were analysed with a vendor-independent software (VIS) package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire data sets. The lowest expected values of LA function were 26.1%, 48.7%, and 41.4% for left atrial strain (LAS), 2D left atrial emptying fraction (LAEF), and 3D LAEF (reservoir function); 7.7%, 24.2%, and -0.53/s for LAS-active, LAEF-active, and LA strain rate during LA contraction (SRa) (pump function) and 12.0% and 21.6% for LAS-passive and LAEF-passive (conduit function). Left atrial reservoir and conduit function were decreased with age while pump function was increased. All indices of reservoir function and all LA strains had no difference in both gender and vendor. However, inter-vendor differences were observed in LA SRa despite the use of VIS. Conclusion: The NORRE study provides contemporary, applicable echocardiographic reference ranges for LA function. Our data highlight the importance of age-specific reference values for LA functions.

Echocardiographic reference ranges for normal left ventricular 2D strain: results from the EACVI NORRE study.

AIMS: To obtain the normal ranges for 2D echocardiographic (2DE) measurements of left ventricular (LV) strain from a large group of healthy volunteers accounting for age and gender. METHODS AND RESULTS: A total of 549 (mean age: 45.6 ± 13.3 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. 2DE data sets have been analysed with a vendor-independent software package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire the data sets. The lowest expected values of LV strains and twist calculated as ± 1.96 standard deviations from the mean were -16.7% in men and -17.8% in women for longitudinal strain, -22.3% and -23.6% for circumferential strain, 20.6% and 21.5% for radial strain, and 2.2 degrees and 1.9 degrees for twist, respectively. In multivariable analysis, longitudinal strain decreased with age whereas the opposite occurred with circumferential and radial strain. Male gender was associated with lower strain for longitudinal, circumferential, and radial strain. Inter-vendor differences were observed for circumferential and radial strain despite the use of vendor-independent software. Importantly, no intervendor differences were noted in longitudinal strain. CONCLUSION: The NORRE study provides contemporary, applicable 2D echocardiographic reference ranges for LV longitudinal, radial, and circumferential strain. Our data highlight the importance of age- and gender-specific reference values for LV strain.

3D echocardiographic reference ranges for normal left ventricular volumes and strain: results from the EACVI NORRE study.

AIM: To obtain the normal ranges for 3D echocardiography (3DE) measurement of left ventricular (LV) volumes, function, and strain from a large group of healthy volunteers. METHODS AND RESULTS: A total of 440 (mean age: 45 ± 13 years) out of the 734 healthy subjects enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study had good-quality 3DE data sets that have been analysed with a vendor-independent software package allowing homogeneous measurements regardless of the echocardiographic machine used to acquire the data sets. Upper limits of LV end-diastolic and end-systolic volumes were larger in men (97 and 42 mL/m2) than in women (82 and 35 mL/m2; P < 0.0001). Conversely, lower limits of LV ejection fraction were higher in women than in men (51% vs. 50%; P < 0.01). Similarly, all strain components were higher in women than in men. Lower range was -18.6% in men and -19.5% in women for 3D longitudinal strain, -27.0% and -27.6% for 3D circumferential strain, -33.2% and -34.4% for 3D tangential strain and 38.8% and 40.7% for 3D radial strain, respectively. LV volumes decreased with age in both genders (P < 0.0001), whereas LV ejection fraction increased with age only in men. Among 3DE LV strain components, the only one, which did not change with age was longitudinal strain. CONCLUSION: The NORRE study provides applicable 3D echocardiographic reference ranges for LV function assessment. Our data highlight the importance of age- and gender-specific reference values for both LV volumes and strain.

Two-dimensional transthoracic echocardiographic normal reference ranges for proximal aorta dimensions: results from the EACVI NORRE study.

AIMS: To report normal reference ranges for echocardiographic dimensions of the proximal aorta obtained in a large group of healthy volunteers recruited using state-of-the-art cardiac ultrasound equipment, considering different measurement conventions, and taking into account gender, age, and body size of individuals. METHODS AND RESULTS: A total of 704 (mean age: 46.0 ± 13.5 years) healthy volunteers (310 men and 394 women) were prospectively recruited from the collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. A comprehensive echocardiographic examination was obtained in all subjects following pre-defined protocols. Aortic dimensions were obtained in systole and diastole, following both the leading-edge to leading-edge and the inner-edge to inner-edge conventions. Diameters were measured at four levels: ventricular-arterial junction, sinuses of Valsalva, sino-tubular junction, and proximal tubular ascending aorta. Measures of aortic root in the short-axis view following the orientation of each of the three sinuses were also performed. Men had significantly larger body sizes when compared with women, and showed larger aortic dimensions independently of the measurement method used. Dimensions indexed by height and body surface area are provided, and stratification by age ranges is also displayed. In multivariable analysis, the independent predictors of aortic dimensions were age, gender, and height or body surface area. CONCLUSION: The NORRE study provides normal values of proximal aorta dimensions as assessed by echocardiography. Reference ranges for different anatomical levels using different (i) measurement conventions and (ii) at different times of the cardiac cycle (i.e. mid-systole and end-diastole) are provided. Age, gender, and body size were significant determinants of aortic dimensions.

Echocardiographic reference ranges for normal cardiac Doppler data: results from the NORRE Study.

AIMS: Reference values for Doppler parameters according to age and gender are recommended for the assessment of heart physiology, specifically for left ventricular (LV) diastolic function. In this study, we report normal reference ranges for Doppler parameters obtained in a large group of healthy volunteers. Echocardiographic data were acquired using state-of-the-art cardiac ultrasound equipment following Doppler acquisition and measurement protocols approved by the European Association of Cardiovascular Imaging. METHODS AND RESULTS: A total of 449 (mean age: 45.8 ± 13.7 years) healthy volunteers (198 men and 251 women) were enrolled at the collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. A comprehensive echocardiographic examination was obtained from all subjects following predefined protocols. The majority of the Doppler diastolic parameters (e', E/e') as well as right ventricle systolic s' wave velocity were similar in men and women. Left ventricle s' wave velocity was higher in men than in women. E wave and e' were higher in younger subjects and decreased progressively in the older ones. E/e' ratio increased with ageing. Septal e' <8 cm/s was present in 19.7% of the subjects in the 40-60 year group and in 55% of those in the ≥60 year group. However, the cut-off value of average E/e' or lateral E/e' remained <15 or 13, respectively, in the majority of patients. CONCLUSION: The NORRE study provides the reference values for the most useful Doppler parameters in the evaluation of heart physiology. These data highlight the need of using age-specific reference values especially for the diagnosis of LV systolic and diastolic dysfunction and for the estimation of LV filling pressures.

Echocardiographic reference ranges for normal cardiac chamber size: results from the NORRE study.

AIMS: Availability of normative reference values for cardiac chamber quantitation is a prerequisite for accurate clinical application of echocardiography. In this study, we report normal reference ranges for cardiac chambers size obtained in a large group of healthy volunteers accounting for gender and age. Echocardiographic data were acquired using state-of-the-art cardiac ultrasound equipment following chamber quantitation protocols approved by the European Association of Cardiovascular Imaging. METHODS: A total of 734 (mean age: 45.8 ± 13.3 years) healthy volunteers (320 men and 414 women) were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. A comprehensive echocardiographic examination was performed on all subjects following pre-defined protocols. There were no gender differences in age or cholesterol levels. Compared with men, women had significantly smaller body surface areas, and lower blood pressure. Quality of echocardiographic data sets was good to excellent in the majority of patients. Upper and lower reference limits were higher in men than in women. The reference values varied with age. These age-related changes persisted for most parameters after normalization for the body surface area. CONCLUSION: The NORRE study provides useful two-dimensional echocardiographic reference ranges for cardiac chamber quantification. These data highlight the need for body size normalization that should be performed together with age-and gender-specific assessment for the most echocardiographic parameters.

Complications leading to sudden cardiac death in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a disease of small pulmonary arteries, characterized by vascular proliferation and remodeling. Progressive increase in pulmonary vascular resistance ultimately leads to right ventricular heart failure and death. PAH-specific drug therapy has improved clinical outcomes and survival. While the survival is better, progression of pulmonary vasculopathy contributes to pulmonary artery dilatation. Left main compression syndrome, pulmonary artery dissection, pulmonary artery rupture, and severe hemoptysis are reported as complications leading to sudden cardiac death, an event encountered more often in PAH patients. The advent of PAH-targeted drug therapy has reduced referral for lung transplantation; however, severe complications require rapid diagnosis, decision making, and possible registration on a lung transplantation waiting list. PAH referral centers provide multidisciplinary emergency care and specific therapeutic management, contributing to improved quality of life and survival for PAH patients. We review the complications leading to sudden death in PAH.

Successful epoprostenol withdrawal in pulmonary arterial hypertension: case report and literature review.

Pulmonary arterial hypertension is a rare and devastating disease characterized by vascular proliferation and remodeling. Epoprostenol, the drug counterpart of the eicosanoid prostacyclin, produced by the vascular endothelial cells, is the drug of choice for this disease. Its capacity to act rapidly and to significantly improve survival prospects in severe pulmonary hypertension patients has been supported by a wealth of evidence. Intravenous epoprostenol was believed to require therapy of indefinite duration. Since 2001, oral drugs have been approved for specific treatment. The availability of newer and less invasive drug therapies for pulmonary arterial hypertension led physicians to withdraw epoprostenol in carefully selected patients. We report a case of successful intravenous epoprostenol interruption in a patient with idiopathic disease. A literature review on epoprostenol withdrawal in pulmonary hypertension in adult patients is also provided.

Normal Reference Ranges for Echocardiography: rationale, study design, and methodology (NORRE Study).

BACKGROUND: Availability of normative reference values for cardiac chamber dimensions, volumes, mass, and function is a prerequisite for the accurate application of echocardiography for both clinical and research purposes. However, due to the lack of consistency in current echocardiographic 'reference values', their use for clinical decision-making remains questionable. AIMS: The aim of the 'Normal Reference Ranges for Echocardiography Study (NORRE Study)' is to obtain a set of 'normal values' for cardiac chamber geometry and function in a large cohort of healthy Caucasian individuals aged over a wide range of ages (25-75 years) using both conventional and advanced echocardiographic techniques. METHODS: The NORRE Study is a large prospective, observational multicentre study in which transthoracic echocardiographic studies will be acquired in 22 laboratories accredited by the European Association of Cardiovascular Imaging and in one laboratory in the USA accredited by ICAEL. The final sample size has been estimated in 1100 normal subjects in whom M-mode, 2D, and 3D imaging, colour Doppler, pulsed-wave Doppler, pulsed-wave tissue Doppler, and colour tissue Doppler imaging data will be obtained. All studies will be sent to a central echocardiographic core laboratory for quantitative analysis. Multiple studies will be performed for reproducibility analysis. CONCLUSION: After completion of the NORRE Study, uniform reference limits according to age, gender, and anthropometric parameters will be available to standardize the quantitative interpretation of echocardiography.

Cardiac resynchronization therapy decreases the mitral coaptation point displacement in heart failure patients.

BACKGROUND: In patients with left ventricular (LV) dysfunction the mitral leaflet coaptation point (CPMA) is displaced towards the LV apex. The aim of our study was to estimate the value of CPMA measurement as a simple index regarding the acute effects of cardiac resynchronization therapy (CRT), which is coming to be an established method of treatment for congestive heart failure (CHF). METHODS: We studied 20 patients with CHF (NYHA III-IV) and LV ejection fraction (LVEF) 22 +/- 4%. All patients received CRT and an echocardiogram was performed within 24-48 hours. The echocardiographic indices LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD), LVEF, mitral annulus diameter (MAD), and the degree of intraventricular desynchronization, were measured at CRT off and CRT on. The CPMA, the distance between the coaptation point of the mitral leaflets and the mitral annulus, was measured from the apical 4-chamber view in end-systole at both CRT on and CRT off. RESULTS: CRT improved both the contractility and dimensional indices in CHF patients. CPMA decreased from 11.3 +/- 2 mm at CRT off to 9.1 +/- 1.8 mm after CRT on (p < 0.001) and MAD from 38.9 +/- 3.9 mm at CRT off to 37.5 +/- 3.7 mm at CRT on (p < 0.002). LVEF improved from 24.5 +/- 5.7% at CRT off to 29.5 +/- 5.1% at CRT on (p < 0.001). There was an improvement in LV synchronization from 88 +/- 7 ms at CRT off to 48 +/- 3 ms at CRT on (p < .001). CPMA was correlated with MAD (r = 0.52, p < 0.05 and r = 0.59, p < 0.05 at CRT off and CRT on, respectively). Moreover, the absolute change in CPMA was correlated with LVESD (r = 0.68) and LVEDD (r = 0.65), both p < 0.05, with the time difference of the basal segments of the septal and lateral wall at CRT on (r = 0.68, p < 0.01), and inversely correlated with LVEF (r = -0.55, p < 0.05). CONCLUSION: In patients with severe LV systolic dysfunction and dilatation CRT was associated with an improvement in both CPMA and MAD.