May 4, 2018

Selected publications spring 2018

Posted by: Anonymous

Aalen J, Storsten P, Remme EW, Sirnes PA, Gjesdal O, Larsen CK, Kongsgaard E, Boe E, Skulstad H, Hisdal J, Smiseth OA
Afterload Hypersensitivity in Patients With Left Bundle Branch Block.
JACC Cardiovasc Imaging. 2018 Jan 12. pii: S1936-878X(17)31144-0. doi: 10.1016/j.jcmg.2017.11.025. [Epub ahead of print]
PMID: 29361486


Objective: This study sought to investigate the hypothesis that patients with left bundle branch block (LBBB) are hypersensitive to elevated afterload.

Background: Epidemiological data suggest that LBBB can provoke heart failure in patients with hypertension.

Methods: In 11 asymptomatic patients with isolated LBBB and 11 age-matched control subjects, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were measured by echocardiography. Systolic arterial pressure was increased by combining pneumatic extremity constrictors and handgrip exercise. To obtain more insight into mechanisms of afterload response, 8 anesthetized dogs with left ventricular (LV) micromanometer and dimension crystals were studied during acutely induced LBBB and aortic constriction. Regional myocardial work was assessed by LV pressure-dimension analysis.

Results: Consistent with normal afterload dependency, elevation of systolic arterial pressure by 38 ± 12 mm Hg moderately reduced LVEF from 60 ± 4% to 54 ± 6% (p < 0.01) in control subjects. In LBBB patients, however, a similar blood pressure increase caused substantially larger reduction in LVEF (p < 0.01), from 56 ± 6% to 42 ± 7% (p < 0.01). There were similar findings for GLS. In the dog model, aortic constriction abolished septal shortening (p < 0.02), and septal work decreased to negative values (p < 0.01). Therefore, during elevated systolic pressure, the septum made no contribution to global LV work, as indicated by net negative work, and instead absorbed energy from work done by the LV lateral wall.

Conclusions: Moderate elevation of arterial pressure caused marked reductions in LVEF and GLS in patients with LBBB. This reflects a cardiodepressive effect of elevated afterload in the dyssynchronous ventricle and was attributed to loss of septal function.


Chivulescu M, Haugaa KH, Lie ØH, Edvardsen T, Ginghină C, Popescu BA, Jurcut R
Right ventricular remodeling in athletes and in arrhythmogenic cardiomyopathy.
Scand Cardiovasc J. 2018 Feb;52(1):13-19. doi: 10.1080/14017431.2017.1416158. Epub 2017 Dec 19.
PMID: 29254378


Objective: Changes in right ventricular (RV) structure and function following prolonged endurance training in athletes arise due to its unique anatomy and physiology. Arrhythmogenic cardiomyopathy (AC) should be differentiated from electrical, functional and structural adaptation of the heart in response to repetitive intense physical activity due to the negative contribution of exercise on AC progression and arrhythmic risk.

Design: For this review we performed a systematic search of the PubMed database up to October 2017 using terms and keywords pertaining to RV, athlete’s heart (AH), AC, sudden cardiac death. Results: This review summarizes currently available data on the impact of exercise on cardiac structure and function, discusses the debatable hypothesis of exercise-induced RV remodeling, compares the common features and search for distinctive characteristics between AH and AC.

Conclusion: Exercise has a more profound impact on the structure and function of the RV than of the left ventricle. Differentiating physiologic RV remodeling following prolonged endurance exercise from subclinical cardiac pathology can be challenging. A multimodality approach is recommended to differentiate between exercise-induced physiological adaptations and cardiomyopathy.


Dejgaard LA, Haland TF, Lie OH, Ribe M, Bjune T, Leren IS, Berge KE, Edvardsen T, Haugaa KH
Vigorous exercise in patients with hypertrophic cardiomyopathy.
Int J Cardiol. 2018 Jan 1;250:157-163. doi: 10.1016/j.ijcard.2017.07.015
PMID: 29169752


Background: We aimed to investigate if history of vigorous exercise was associated with changes in left ventricular morphology, left ventricular function and ventricular arrhythmias (VAs) in hypertrophic cardiomyopathy genotype positive, phenotype negative (Genotype+ LVH−) and in phenotype positive (HCM LVH+).

Methods: In this cross sectional study we included 187 subjects (age 49 ± 16 years, 89(48%) female, 121(65%) HCM LVH+ and 66 (35%) Genotype+ LVH-) who answered a questionnaire on physical activity history. Exercise ≥6 metabolic equivalents was defined as vigorous. Subjects with a history of vigorous exercise ≥4 h/week during ≥6 years were defined as athletes. All underwent echocardiography and Holter monitoring. VAs were defined as aborted cardiac arrest, sustained or non-sustained ventricular tachycardia.

Results: In both Genotype+ LVH− and HCM LVH+, lifetime vigorous exercise correlated with larger left ventricular end-diastolic volume (rho 0.44 and 0.38 respectively, both p < 0.001). Lifetime vigorous exercise correlated with increased left ventricular mass in Genotype+ LVH− (rho 0.28, p = 0.03), but not in HCM LVH+ (p = 0.53).

Left ventricular systolic function was similar between athletes and non-athletes in Genotype+ LVH− and HCM LVH+. HCM LVH+ athletes had lower E/e' (p = 0.03) and higher e' (p = 0.02) compared to non-athletes, while this difference was not observed in Genotype+ LVH−. Lifetime vigorous exercise was similar among HCM LVH+ with and without VAs (p = 0.89).

Conclusions: Increased lifetime vigorous exercise was associated with larger left ventricular volumes in hypertrophic cardiomyopathy, but correlated to left ventricular mass only in Genotype+ LVH−. Vigorous exercise was associated with favorable diastolic function in HCM LVH+, and was not associated with VAs.


Edvardsen T, Smiseth OA
Evaluation of diastolic function by echocardiography: important progression, but issues to be resolved.
Eur Heart J Cardiovasc Imaging. 2018 Apr 1;19(4):387-388. doi: 10.1093/ehjci/jex319. No abstract available.
PMID: 29236972

This editorial refers to ‘Impact of the 2016 ASE/EACVI recommendations on the prevalence of diastolic dysfunction in the general population’, by J.G. Almeida et al., pp. 380–386.

A joint task force of the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE) published an updated recommendation for evaluation of left ventricular (LV) diastolic function in 2016.1 The primary goal of this update was to simplify the approach and increase the utility of the guidelines in daily clinical practice. This includes need for a more specific algorithm to identify patients with elevated LV filling pressure.

LV diastolic dysfunction is caused by impaired LV relaxation with or without reduced restoring forces (and early diastolic suction), and increased LV chamber stiffness, and when the dysfunction limits filling, LV diastolic pressure becomes elevated as a compensatory mechanism to maintain cardiac output. Therefore, demonstration of elevated LV filling pressure is an important diagnostic target when using echocardiography to evaluate diastolic function.

LV filling pressure refers to the pressure that fills the ventricle, and is used differently depending upon which pressure is available and what is the purpose of the study. When the issue is pulmonary congestion, the most relevant pressure is mean LA pressure which may be approximated as pulmonary capillary wedge pressure (PCWP) and as LV pre-atrial contraction (pre-A) pressure.2 When the issue is LV mechanical function, however, LV end-diastolic pressure (ideally transmural end-diastolic pressure) which represents LV preload, is the preferred parameter of LV filling pressure. All these parameters are valid measures of LV filling pressure although their relationships to Doppler parameters are slightly different.

Since early symptoms of heart failure are often non-specific, an accurate non-invasive method to estimate LV filling pressure would be of great clinical value. The EACVI/ASE task force presented an algorithm for evaluation of LV filling pressure.1 This algorithm was recently tested in two large multicentre studies which used invasive filling pressure as reference method.3,4 Lancellotti et al.3 in the Euro-Filling study investigated 159 patients at nine European centres with simultaneous evaluation of echo estimates of filling pressures and invasive measurements of LV end-diastolic pressure. Additionally, the EACVI/ASE recommendations from 2009 were compared to the 2016 recommendations. They found that the new 2016 recommendations for non-invasive assessment of LV filling pressure were reliable and clinically useful, and importantly, superior to the 2009 recommendations for estimating invasive LV end-diastolic pressure. In the other study, Andersen et al.4 included 450 patients in a multicentre trial with PCWP in 293 patients and LV pre-A pressure in 157 patients as references. They concluded that the EACVI/ASE recommendations for echocardiographic assessment of LV filling pressure are readily available and can be performed with high feasibility and good accuracy. These two studies confirm that the new EACVI/ASE recommendations are clinically valuable and accurate and therefore very helpful in making correct diagnosis of our patients. The algorithm for estimation of LV filling pressure may be applied in patients with normal LV ejection fraction and unexplained exertional dyspnoea, and also in patients with heart failure with reduced ejection fraction when considering adjustment of diuretics or other medication. A limitation of this diagnostics is that patients with heart failure may have normal filling pressure at rest and elevated filling pressure only during exercise. Therefore, further development of a diastolic stress test is needed.


Finsberg H, Xi C, Tan JL, Zhong L, Genet M, Sundnes J, Lee LC, Wall ST
Efficient estimation of personalized biventricular mechanical function employing gradient-based optimization.
Int J Numer Method Biomed Eng. 2018 Mar 9. doi: 10.1002/cnm.2982. [Epub ahead of print]
PMID:  29521015


Individually personalized computational models of heart mechanics can be used to estimate important physiological and clinically-relevant quantities that are difficult, if not impossible, to directly measure in the beating heart. Here, we present a novel and efficient framework for creating patient-specific biventricular models using a gradient-based data assimilation method for evaluating regional myocardial contractility and estimating myofiber stress. These simulations can be performed on a regular laptop in less than 2 h and produce excellent fit between measured and simulated volume and strain data through the entire cardiac cycle. By applying the framework using data obtained from 3 healthy human biventricles, we extracted clinically important quantities as well as explored the role of fiber angles on heart function. Our results show that steep fiber angles at the endocardium and epicardium are required to produce simulated motion compatible with measured strain and volume data. We also find that the contraction and subsequent systolic stresses in the right ventricle are significantly lower than that in the left ventricle. Variability of the estimated quantities with respect to both patient data and modeling choices are also found to be low. Because of its high efficiency, this framework may be applicable to modeling of patient specific cardiac mechanics for diagnostic purposes.

Left: finite element mesh of a biventricular geometry reconstructed from MR images separated into 3 material regions, namely, left ventricle free wall (blue), septum (green), and right ventricle free wall (right). Right: myocardial fiber orientation are assigned using the LDRB algorithm42 with an angle +α and −α prescribed on the endocardium and epicardium, respectively. Here showing the fiber architecture for α ranging from 30° to 80° with increments of 10°, where the absolute value of the fiber angle is used as color map


Castrini AI, Lie ØH, Leren IS, Estensen ME, Stokke MK, Klæboe LG, Edvardsen T, Haugaa KH
Number of pregnancies and subsequent phenotype in a cross-sectional cohort of women with arrhythmogenic cardiomyopathy.
Eur Heart J Cardiovasc Imaging. 2018 Apr 6. doi: 10.1093/ehjci/jey061. [Epub ahead of print]
PMID: 29659777


Aims: We aimed to assess the relation between number of pregnancies and cardiac structure, function, and arrhythmic events in women with arrhythmogenic cardiomyopathy (AC).

Methods and results: We included female AC patients in a cross-sectional study. Number of pregnancies and pregnancy related symptoms were recorded. Ventricular arrhythmias were defined as aborted cardiac arrest, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator therapy. Right and left ventricular dimensions and function, including strain analyses, were assessed by echocardiography and magnetic resonance imaging. We created a new AC severity score to grade the severity of AC disease. We included 77 women (age 47 ± 16, 43 probands and 34 AC mutation positive female relatives), 19 ± 14 years after last pregnancy. Median number of pregnancies was 2 (0-4); 19 had no previous pregnancies, 16 had 1 pregnancy, 30 had 2, and 12 had ≥3 pregnancies. Presence of a definite AC diagnosis (P = 0.36), severity of AC disease (P = 0.53), and arrhythmic events (P = 0.25) did not differ between groups of pregnancies. Number of pregnancies was related to increased right ventricular outflow tract diameter in single variable analyses [odds ratio (OR) 1.76, 95% confidence interval (CI) 1.08-2.87; P = 0.02], but not when adjusted for body surface area and age (OR 1.56, 95% CI 0.91-2.66; P = 0.11). The number of pregnancies was not associated with any other measures of cardiac structure and function.

Conclusion: Higher number of pregnancies did not seem to relate to a worse phenotype in women with AC.


Hasselberg NE, Haland TF, Saberniak J, Brekke PH, Berge KE, Leren TP, Edvardsen T, Haugaa KH
Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation.
Eur Heart J. 2018 Mar 7;39(10):853-860. doi: 10.1093/eurheartj/ehx596.
PMID: 29095976


Lamin A/C (LMNA) mutations cause familial dilated cardiomyopathy (DCM) with frequent conduction blocks and arrhythmias. We explored the prevalence, cardiac penetrance, and expressivity of LMNA mutations among familial DCM in Norway. Furthermore, we explored the risk factors and the outcomes in LMNA patients.

Methods and results: During 2003-15, genetic testing was performed in patients referred for familial DCM. LMNA genotype-positive subjects were examined by electrocardiography, Holter monitoring, cardiac magnetic resonance imaging, and echocardiography. A positive cardiac phenotype was defined as the presence of atrioventricular (AV) block, atrial fibrillation/flutter (AF), ventricular tachycardia (VT), and/or echocardiographic DCM. Heart transplantation was recorded and compared with non-ischaemic DCM of other origin. Of 561 unrelated familial DCM probands, 35 (6.2%) had an LMNA mutation. Family screening diagnosed an additional 93 LMNA genotype-positive family members. We clinically followed up 79 LMNA genotype-positive [age 42 ± 16 years, ejection fraction (EF) 45 ± 13%], including 44 (56%) with VT. Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had a 9% annual incidence of a newly documented cardiac phenotype and 61% (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up. Ten (32%) had AV block, 7 (23%) AF, and 12 (39%) non-sustained VT. Heart transplantation was performed in 15 of 79 (19%) LMNA patients during 7.8 ± 6.3 years of follow-up.

Conclusion: LMNA mutation prevalence was 6.2% of familial DCM in Norway. Cardiac penetrance was high in young asymptomatic LMNA genotype-positive family members with frequent AV block and VT, highlighting the importance of early family screening and cardiological follow-up. Nearly 20% of the LMNA patients required heart transplantation.

Center for Cardiological Innovation