Fourteen RCTs met our eligibility criteria. The largest improvement in ppFEV1 favouring treatment was observed for ivacaftor (IVA) in G551D individuals (≥6 years old). Both tezacaftor-ivacaftor (TEZ-IVA) and lumacaftor-ivacaftor (LUM-IVA) also improved ppFEV1 in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo. IVA also significantly improved ppFEV1 in a sub-group of individuals ≥18 years old with an R117H mutation. No significant improvements in ppFEV1 were observed for IVA, LUM, or TEZ in F508del homozygous individuals, LUM or LUM-IVA in F508del heterozygous individuals, or ataluren in individuals with a nonsense mutation. Significant improvements in ppFEV1 and other clinical outcomes were observed for IVA in G551D individuals, TEV-IVA and LUM-IVA in F508del homozygous individuals, and IVA in adults with a R117H mutation.Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV This results in thick and sticky secretions involving a range of epithelial tissues such as the airways and pancreatic ducts, eventually culminating in end-organ damage and failure. Since the discovery of the CFTR gene in 19892, significant progress has been made in the understanding of how CFTR gene mutations alter protein structure and function leading to reduced CFTR activity3.Cystic fibrosis (CF) is a genetic condition caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is located at the apical surface of epithelial cells and the absence of CFTR activity leads to loss of chloride secretion and deficient fluid transport4. Another class of CFTR mutations, referred to as “nonsense” mutations, leads to a premature termination codon and reduced synthesis and hence delivery of CFTR to the cell surface5. In contrast, “gating” mutations are missense mutations that lead to CFTR proteins that are sufficiently synthesized, processed and trafficked to the cell surface but once they arrive they have defective channel opening leading to diminished chloride secretion6.Although over 2000 variants in the CFTR gene have been identified to date, F508del accounts for most CFTR alleles in patients with CF. This particular mutation leads to abnormal CFTR folding and trafficking causing reduced delivery of CFTR to the cell surface11. For example, CFTR “potentiators” are small molecules capable of increasing the amount of time the CFTR channel is spent in the open position and thus targets CFTR mutations with defective “gating”10. CFTR “correctors” are small molecules that can target mutations such as F508del as they can improve CFTR trafficking or transport to the cell surface by stabilizing the 3D conformation of the protein, even if misfolded11. Other CFTR modulators, including CFTR “amplifiers” and “translational read-through” agents increase the amount of CFTR protein produced, the latter being specific to mutations leading to a premature termination codon13.With advances in our understanding of CFTR biology, a new class of small molecule therapies, referred to as CFTR modulators, have been identified using high-throughput small molecule screening; these drugs are unique as they directly target molecular defects in the CFTR protein to increase CFTR activity8. The primary objective of this systematic review was to evaluate the impact of CFTR modulators on lung function and other clinically important outcomes including pulmonary exacerbations, hospitalizations, respiratory symptoms, nutritional status, and adverse events in individuals with CF.In recent years, several placebo-controlled clinical trials have been conducted investigating the efficacy and safety of CFTR modulators but the results have varied depending on the specific CF genotype and therapy under investigation14. A systematic search of online databases using key phrases was conducted to identify randomized, placebo-controlled trials published from January 1, 2005 to March 31, 2018. Online databases searched included: MEDLINE, EMBASE, ACP Journal Club, Cochrane Central Register for Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Cochrane Methodology Register (CMR), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), and NHS Economic Evaluation Database (NHSEED). For comprehensiveness, clinical trial registries such as the European Medicines Agency, U.S. National Institute of Health, and the World Health Organization records were accessed and screened. We used the following key phrases which were designed to maximize sensitivity for detecting therapeutic trials in CF: (“cystic fibrosis” OR “CFTR”) AND .Our search strategy was developed in accordance with PRISMA guidelines14. The level of agreement in the articles selected for full text review and then for inclusion in the review by the two investigators were reported and discrepancies were resolved by the principal investigator (B.S.Q).The literature search and abstracts were reviewed for eligibility independently by two investigators (A.R.H and M.K.). Randomized controlled trials (RCTs) with a parallel design comparing CFTR modulators  to placebo in patients with CF were included. Study inclusion/exclusion were summarized in a PRISMA flow diagram14. Two reviewers (A.R.H. and M.K.) independently extracted data. The level of agreement in the data extracted broken down by study characteristics, risk of bias, and effects of the intervention by the two investigators were reported and discrepancies were resolved by the principal investigator (B.S.Q).The review protocol used in this study is available in the Appendix and was developed in accordance with the PRISMA statement15. A detailed review of the randomization process, blinding, and allocation sequence concealment was performed.Risk of bias was assessed using the Cochrane Risk of Bias tool1) was our primary outcome. Secondary efficacy outcomes included protocol-defined pulmonary exacerbations (PEx), hospitalization due to PEx, respiratory symptoms  Respiratory domain), and nutritional status . Adverse events with a prevalence of >10% (and involving >2 subjects) from either experimental or control groups, serious adverse events (including deaths) leading to treatment discontinuation, and the prevalence of elevated liver function tests (LFTs) were evaluated.Change in percent-predicted forced expiratory volume in one second . For the primary outcome, ppFEV1, sub-group analyses were planned based on age and baseline ppFEV1.The statistical analysis was performed using ReviewManager  in accordance with the Cochrane HandbookThe search yielded a total of 789 potentially relevant articles and abstracts. Following full-text review, thirteen articles  met the inclusion and exclusion criteria   in results between studies  Fig.  with no ies Fig. 20,21.Fig1 significantly improved with LUM-IVA and TEZ-IVA compared to placebo  19. No significant treatment effect was observed with IVA or TEZ alone, and there was a trend toward worsening in ppFEV1 for F508del homozygous individuals treated with higher doses of LUM  Fig. 17,24. FoLUM Fig. 22,24,25.1 on LUM or LUM-IVA 27. For individuals with a nonsense mutation on at least one allele, ataluren did not result in a significant relative improvement in ppFEV1 compared to placebo18.For individuals with the R117H mutation on at least one allele, IVA did not lead to an overall improvement in ppFEVprotocol-defined PEx as described in Appendix Table 20. LUM-IVA and TEZ-IVA also significantly reduced the risk of PEx compared to placebo in F508del homozygous individuals (≥12 years old) but the risk reduction was less than that observed with IVA in G551D : Eight studies examined 17. TEZ-IVA also significantly reduced the rate of PEx leading to hospitalization compared to placebo  but a risk ratio could not be calculated23. Individuals with the G551D mutation on at least one allele treated with IVA also experienced a reduction in the risk of PEx requiring hospitalization but this was not statistically significant  requiring hospitalization: LUM-IVA reduced the risk of PEx requiring hospitalization in F508del homozygous individuals 27, and for LUM-IVA treated F508del heterozygous individuals ≥18 years old   with the G551D mutation on at least one allele 24. In a small phase 2 study involving individuals with F508del/G551D, TEZ-IVA did not lead to significant improvement in the CFQ-R Respiratory domain compared to IVA alone22. For individuals with a nonsense mutation on at least one allele, ataluren did not modify CFQ-R Respiratory domain score compared to placebo18.There was worsening of the CFQ-R Respiratory domain score for F508del homozygous and heterozygous individuals (≥18 years old) on LUM alone , a clinically modest but statistically significant increase in BMI was observed for both doses of LUM-IVA compared to placebo , LUM-IVA did not result in significant improvement in weight or BMI compared to placebo26. There were no significant improvements in BMI compared to placebo among IVA treated individuals with an R117H mutation  or ataluren treated individuals with a nonsense mutation (data not shown)27.Nutritional outcomes (BMI and weight): For individuals with at least one G551D mutation (≥6 years old), significant improvements in weight were observed on IVA compared to placebo  . For studies involving F508del homozygous and heterozygous individuals, those assigned to LUM had increased dyspnea and “abnormal respiration” compared to placebo  resulting in higher rates of treatment discontinuation18.Adverse event reporting: CFTR modulators were generally well tolerated compared to placebo  were observed for G551D patients on IVA and ALT or AST (>3X ULN) in F508del homozygous children aged 6–11 on LUM-IVA compared to placebo  on IVA compared to placebo (3.6% vs 0%) (Appendix Table Level of agreement for study selection and data extraction: There was a strong level of agreement (95%) for the articles selected between the two reviewers for full text review and 100% agreement between the two reviewers for the articles meeting eligibility criteria for inclusion in this review. The level of agreement for data extraction were as follows: study characteristics , risk of bias , and effects of the intervention .29. No prior systematic review has compared all investigational CFTR modulators from phase 2 and 3 RCTs in specific CF genotypes32.This study represents the most comprehensive systematic review of the efficacy and safety of CFTR modulators performed to date. While evidence-based recommendations for the use of CFTR modulators were recently published and provides a valuable resource for practicing clinicians, this review provides a more concise and up-to-date synthesis of all the placebo-controlled clinical trial data33. Furthermore, unpublished phase 2 data evaluating TEZ-IVA in combination with “next-generation” corrector molecules have demonstrated significant improvements in ppFEV1 in subjects with F508del and a minimal CFTR function mutation, some of whom have nonsense mutations.As this review highlights, patients with gating mutations such as G551D benefit the most from current CFTR modulators and those that are F508 homozygous have moderate benefit in comparison. Based on published parallel design trials, CFTR modulators have not been effective in F508 heterozygotes or those with nonsense mutations. However, in a recent phase 3 cross-over study evaluating IVA and TEZ-IVA in individuals ≥12 years old with F508del and a residual CFTR function mutation, improvements in ppFEV1 of 4.7% and 6.8%, respectively, were observed compared to placebo1, CF individuals (≥6 years old) with the G551D mutation on at least one allele receiving IVA experienced the largest benefit21. F508del homozygous subjects receiving TEZ-IVA (≥12 years old) and LUM-IVA (≥6 years old) also had improvements in ppFEV1 compared to placebo but the effect sizes were modest compared to IVA in G551D24. Individuals (≥18 years old) with the R117H mutation on at least one allele treated with IVA experienced similar improvement in ppFEV1 to F508del homozygous subjects treated with TEZ-IVA and LUM-IVA.When comparing the efficacy of CFTR modulators across all genotypes for ppFEV1, the effect of CFTR modulators on PEx risk and respiratory symptoms were most pronounced with IVA in G551D adolescents and adults (≥12 years old), with a 60% reduction in PEx risk and a 7-point improvement in the CFQ-R Resp domain21. F508del homozygous adolescents and adults also had a 40–45% reduction in PEx risk on TEZ-IVA and LUM-IVA. While F508del homozygous subjects experienced improvements in the CFQ-R Resp domain on both TEZ-IVA and LUM-IVA, this was not clinically significant for LUM-IVA. Individuals with a R117H mutation also experienced improvements in the CFQ-R Resp domain on IVA, with a magnitude of change in the adults comparable to that observed with IVA in G551D. The effect of CFTR modulators on weight were most significant with IVA in G551D individuals (≥6 years old). While F508del homozygous individuals (≥12 years old) had improvement in BMI with LUM-IVA, the effect size was modest.Similar to ppFEV34. There was also increased reporting of acute kidney injury for nonsense mutation patients assigned to ataluren compared to placebo. The long-term safety of CFTR modulator therapies beyond one year could not be assessed in this review and therefore the detection of infrequent or long-term side effects will require ongoing post-marketing surveillance36.Most of the CFTR modulator therapies examined in this review were well tolerated with the exception of increased reporting of respiratory adverse events (e.g. dyspnea) leading to higher rates of treatment discontinuation in patients randomized to LUM and LUM-IVA. The molecular mechanism responsible for the adverse respiratory effects  for patients on LUM remain unclear but appears to be an off-target effect specific to LUM, as opposed to being related to F508del CFTR correction per se, as similar adverse effects have not been observed with F508del CFTR correction with TEZ-IVA2.5) given the lack of clinical trials utilizing this outcome measure19.There are several potential limitations of this review. We excluded cross-over, open-label, and observational studies to avoid carryover effects and to ensure we incorporated the highest level of evidence. We also limited our inclusion to full-text studies which could have resulted in publication bias. We focused on pre-defined clinically important outcomes but did not include multiple-breath washout measurement , individuals colonized/infected with bacteria associated with rapid lung function decline , and individuals with very frequent pulmonary exacerbations requiring continuous or near continuous systemic antibiotics by virtue of requiring clinical stability and no systemic antibiotics 4 weeks prior to randomization and therefore the efficacy and safety of CFTR modulators in these sub-groups remain unclear. For example, based on observational data, F508del homozygous individuals with advanced lung disease started on LUM-IVA have increased respiratory-related adverse events leading to treatment discontinuation; therefore, closer monitoring following treatment initiation is recommended40.There remain several gaps in the placebo-controlled evidence base for CFTR modulators. RCTs to date have excluded young children (<6 years old) and therefore the earliest age of safe use of CFTR modulators remains uncertain. However, small open-label 24-week studies have demonstrated a similar safety profile of IVA in children 1–5 years old with CFTR gating mutations compared to older age groups studied35. Furthermore, based on combined data from an open-label extension trial and U.S. CF patient registry data, the rate of lung function decline over 3 years was lower in G551D patients treated with ivacaftor compared to propensity-matched controls from the CF registry, suggestive of a disease-modifying effect over the longer term.Most placebo-controlled RCTs to date have been limited to a maximum duration of 48 weeks and therefore the long-term placebo-controlled effects of these therapies remain unclear. However, an open-label extension trial evaluating the long-term effects of ivacaftor up to 144 weeks has demonstrated sustained clinical benefits of ivacaftor on lung function, weight, patient-reported respiratory symptoms and PEx risk reduction with no new safety concerns1 and PEx risk reduction but TEZ-IVA is safer and leads to greater improvement in respiratory symptoms.In conclusion, based on randomized placebo-controlled parallel design trials, CFTR potentiation with IVA in individuals with a G551D mutation is safe, and results in robust clinical benefits compared to placebo and to date is superior to the effects observed with CFTR modulators in other CF genotypes. The effects of TEZ-IVA and LUM-IVA in F508del homozygous individuals are comparable with respect to the magnitude of change in ppFEVOnline Appendix


Investigation of the myocardial strain characteristics of the left ventricular non-compaction (LVNC) phenotype with cardiovascular magnetic resonance (CMR) feature tracking.n = 25) and healthy subjects (n = 34) with normal LV volumetrics, and with healthy subjects (n = 18) meeting at least one LVNC diagnostic criteria.CMR cine balanced steady-state free precession data sets of 59 retrospectively identified LVNC phenotype patients  and 36 healthy subjects  were evaluated for LV volumes, systolic function and mass. Hypertrabeculation in patients and healthy subjects was evaluated against established CMR diagnostic criteria. Global circumferential strain (GCS), global radial strain (GRS) and global longitudinal strain (GLS) were evaluated with feature-tracking software. Subgroup analyses were performed in patients (2 (100% vs. 41.7%). LVNC phenotype patients demonstrated reduced GRS , GCS  and GLS  compared to healthy subjects, with statistically significant differences persisting on subgroup comparisons of LVNC phenotype patients with healthy subjects meeting diagnostic criteria. GCS also demonstrated independent and incremental diagnostic value beyond each of the morphology-based CMR diagnostic criteria.All LVNC phenotype patients, as well as a significant proportion of healthy subjects, met morphology-based CMR diagnostic criteria: non-compacted (NC): compacted myocardial diameter ratio > 2.3 (100% vs. 19.4%), NC mass > 20% (100% vs. 44.4%) and > 25% (100% vs. 13.9%), and NC mass indexed to body surface area > 15 g/mLVNC phenotype patients demonstrate impaired strain by CMR feature tracking, also present on comparison of subjects with normal LV volumetrics meeting diagnostic criteria. The high proportion of healthy subjects meeting morphology-based CMR diagnostic criteria emphasizes the important potential complementary diagnostic value of strain in differentiating LVNC from physiologic hypertrabeculation. Left ventricular non-compaction cardiomyopathy (LVNC) is a rare cardiomyopathy that can occur in isolation or in association with other congenital and acquired cardiac pathologies . It is cPreviously considered a rare anomaly, the widespread availability and advances in image quality of echocardiography and cardiovascular magnetic resonance (CMR) imaging and increased awareness have led to increasingly frequent recognition of the LVNC phenotype . HoweverMultiple validated morphology-based echocardiographic diagnostic criteria have evolved since the early descriptions of LVNC , 6–8 witIn order to expand beyond pure morphologic features and global volumetric parameters of cardiac function in the diagnosis and assessment of ischemic and non-ischemic cardiomyopathies, quantitative assessment of myocardial deformation by strain analysis has developed over recent years. Speckle-tracking echocardiography (STE) has demonstrated abnormal patterns of LV myocardial strain and torsion in LVNC including decreased radial, circumferential and longitudinal strain, decreased LV twist and abnormal patterns of ventricular rotation –18. Straclinicaltrials.gov: NCT02306538) and MAFIO  studies were included as a healthy control population [This single centre retrospective cohort study identified patients with isolated LVNC phenotype from heart failure and adult congenital cardiac disease clinic databases, as well as a Boolean search of CMR reports between June 2008 and July 2017. The keyword search of CMR reports included the terms ‘non-compaction’ and/or ‘hypertrabeculation’, and returned cases were qualitatively reviewed by two readers (JGD and BJW) to confirm findings consistent with the LVNC phenotype. Patient exclusion criteria included age < 18 years, incomplete cine bSSFP coverage of the LV, CMR studies with limited image quality, and any concurrent congenital or acquired heart disease with the exception of idiopathic dilated cardiomyopathy with hypertrabeculation. Patient identification and study inclusion is summarized in Fig. pulation . LVNC phfit/Verio (3 T) or Avanto/Avantofit (1.5 T) . All studies included retrospectively gated LV 2-, 3- and 4-chamber long-axis (LAX) single-slice and short-axis oblique (SAO) base-to-apex stack cine bSSFP sequences with 6–8 mm slice thickness, 2 mm slice gap, pixel size ≤1.8 × 1.8 mm2, and a temporal resolution < 50 ms.CMR scans were performed on one of four scanners: Magnetom Skyra42, Circle Cardiovascular Imaging, Calgary, Canada) by a single cardiac-fellowship trained radiologist with 2 years of cardiac imaging experience (JGD) blinded to pre-existing clinical and radiological information.Analysis of LV volumes, systolic function, mass and strain was performed using commercially post-processing software  < 55 and < 54%; LV hypertrophy as a MASSi (mass indexed to BSA) > 83 g/m2 and > 67 g/m2.Abnormality of LV volumetrics  was assessed against gender-specific reference ranges validated for cine bSSFP sequences . Definit2 [The following validated CMR diagnostic criteria for LVNC were assessed in all patients and volunteers: non-compacted (NC): compacted (C) myocardium diameter ratio > 2.3 in end-diastole , NC > 202 .Measurements of NC and C thickness for the calculation of the NC:C ratio were performed on end-diastolic SAO and/or LAX cine images with the myocardium orthogonal to the plane of measurement.A previously validated technique was employed to measure the NC myocardial mass , 11. A sMethods of assessment of the NC myocardium are illustrated in Fig. Radial and circumferential strain were measured across the full thickness of the myocardium from the SAO cine bSSFP stack following application of end-diastolic endo- and epicardial contours with superior and inferior insertion point markers to three selected slices at representative basal, mid-ventricular and apical levels. The selected basal slices included circumferentially complete myocardium throughout the cardiac cycle, the selected apical slices avoided obliquely oriented myocardium, and the selected mid-ventricular slices were equidistant between the selected basal and apical slices at the level of the papillary muscles. Global radial strain (GRS) and global circumferential strain (GCS) were calculated from the average of the peak strain of the three selected SAO slices.Longitudinal strain was measured across the full thickness of the myocardium from the LV 2-, 3- and 4-chamber cine bSSFP single-slice images by applying end-diastolic endo- and epicardial contours with a T-bar defining the mitral valve plane and LV apex. Global longitudinal strain (GLS) was calculated from the average of the peak strain of the three LAX slices.Twist was measured as the rotational circumferential displacement (measured in degrees) at the selected basal and apical SAO slices. Torsion was calculated as the difference between basal and apical rotation (i.e. twist) divided by the distance between the two slices along the long axis of the LV.p-value of < 0.05. Categorical variables are described as number and percentage and continuous variables are presented as median and interquartile range (IQR). Testing for normal distribution was performed using the Shapiro-Wilk test. Comparison of categorical variables was performed using Fisher’s exact test, normally distributed continuous variables with the independent samples t-test, and non-normally distributed continuous variables with the Wilcoxon rank sum test. Global strain values were evaluated with receiver operating characteristic (ROC) analyses.All statistical analysis was performed using STATA v14.1  and statistical significance was defined as a two-tailed To assess whether strain parameters are independent of EF in the subgroup A vs. D comparison, individual bivariable logistic regression models were fitted with respective strain measures and EF, and to assess for incremental diagnostic value, the likelihood ratio test was used to compare nested models with EF alone versus a model with GCS added. To assess the independence and incremental diagnostic value of GCS against each of the morphologic CMR diagnostic criteria for LVNC in differentiating all healthy volunteers and LVNC phenotype patients, individual bivariable logistic regression models were fitted with GCS and each diagnostic criteria, and the likelihood ratio test was used to compare nested models with each diagnostic criteria alone versus models with GCS added.p = 0.673), age (p = 0.866) or BSA (p = 0.863) between all healthy subjects and LVNC phenotype patients. All healthy subjects (n = 36/36) were scanned at 1.5 T. Of the LVNC phenotype patients, 61% (n = 36/59) were scanned at 1.5 T and 39% (n = 23/59) at 3.0 T.One hundred fifty-five study candidates were identified from the clinical databases and 1720 exams from the CMR report database. A total of 59 LVNC phenotype patients were included following elimination of duplicate patients and CMR reports using keywords in the negative (e.g. “no evidence of non-compaction”), application of exclusion criteria, and review of CMR data sets studies by the two readers. All 59 (100%) of the patients met each of the four CMR diagnostic criteria for LVNC. LVNC phenotype patients included 30 males (51%) with a median age of 40 years (IQR: 28–50 years). The control group of 36 healthy subjects included 16 males (44%) with a median age of 39 years (IQR: 30–47 years). Demographic characteristics are detailed in Table Subgroups of subjects with normal LV volumetrics included 25 LVNC phenotype patients (subgroup A) and 34 healthy subjects (subgroup B); of the two healthy subjects excluded, both had borderline LV dilation and one had borderline impaired EF. Among the healthy subjects 16 met none of the CMR diagnostic criteria for LVNC (subgroup C) and 18 met one or more criteria (subgroup D).n = 25) and healthy suybjects (n = 34) with normal LV volumetrics revealed no statistically significant differences in sex (p = 0.598), age (p = 0.089), or BSA (p = 0.118).Comparison of LVNC phenotype patients (n = 25) and healthy subjects with normal LV volumetrics not meeting any LVNC criteria (n = 16) revealed a significant difference in age (p = 0.017) but no statistically significant differences in sex (p = 0.513), or BSA (p = 0.527).Comparison of LVNC phenotype patients with normal LV volumetrics (n = 25) and healthy subjects with normal LV volumetrics meeting one or more LVNC criteria (n = 18) revealed a significant difference in BSA (p = 0.045) but no statistically significant differences in sex (p = 0.130) or age (p = 0.588).Comparison of LVNC phenotype patients with normal LV volumetrics (n = 16) and those meeting one or more criteria (n = 18) revealed significant differences in sex (p = 0.045) and age (p = 0.012), but no statistically significant difference in BSA (p = 0.198).Comparison between healthy subjects with normal LV volumetrics not meeting any of the LVNC criteria (p = 0.036), ESV (p < 0.001), ESVi (end-systolic volume indexed to BSA) (p < 0.001) and EF (p < 0.001). The remaining LV volumetric parameters showed no statistically significant difference.Results for LV volumetrics are detailed in Table p < 0.001), mass (p = 0.018), MASSi (p = 0.012) and SVi (stroke volume indexed to BSA) (p = 0.033).Statistically significant differences were demonstrated in EF (p < 0.001), ESV (p = 0.019) and ESVi (p = 0.002).Statistically significant differences were demonstrated in EF (p < 0.004), SV (p = 0.046), SVi (p = 0.008), mass (p = 0.011) and MASSi (p = 0.007).Statistically significant differences were demonstrated in EF (p < 0.023), EDVi (p = 0.032), ESV (p = 0.027) and ESVi (p = 0.019).Statistically significant differences were demonstrated in EF .Results for CMR diagnostic criteria for LVNC are detailed in Table For subgroup comparisons A vs. B, A vs. C and A vs. D, statistically significant differences persisted across all LVNC diagnostic criteria and measures of NC myocardium. On comparison of healthy subjects with normal LV volumetrics meeting one or more LVNC criteria and those meeting none (subgroup C vs. D), only the maximum NC:C ratio did not show statistically significant difference. Of the diagnostic criteria for LVNC met by 18 (53%) healthy subjects with normal LV volumetrics, 5 healthy subjects (28%) met four criteria, 1 (6%) met three criteria, 6 (33%) met two criteria, and 8 (44%) met one of the four criteria.Results for strain analysis and torsion are detailed in Table .Reduced radial, circumferential and longitudinal strain in LVNC phenotype patients was observed compared to healthy subjects, with statistically significant differences at both global and slice specific levels . Comparisons between all LVNC phenotype patients and healthy subjects, as well as the subgroups, are illustrated with box plots in Fig. 4p = 0.031, likelihood ration test χ2(df = 1) = 6.49, p = 0.011); NC mass > 20%  = 18.15, p < 0.001); NC mass > 25%  = 6.89, p = 0.009); NC mass > 15 g/m2  = 13.39, p < 0.001).Comparing all healthy subjects and LVNC phenotype patients, GCS had independent and incremental diagnostic value beyond each of the CMR diagnostic criteria for LVNC: NC:C > 2.3 . In a nested logistic regression model with EF, model fit was significantly improved by the addition of GCS (χ2(df = 1) = 4.55, p = 0.033). No significant differences were demonstrated in global strain between healthy subjects with normal LV volumetrics meeting one or more LVNC criteria and those meeting none (subgroup C vs. D).Statistically significant differences in GRS, GCS and GLS remained when LVNC phenotype patients were compared to healthy subjects with normal LV volumetrics (subgroup A vs. B) with AUCs of 0.80 for GCS, 0.78 for GRS and 0.69 for GLS, as well as when compared to healthy subjects not meeting any CMR diagnostic criteria for LVNC (subgroup A vs. C) with AUCs of 0.86 for GCS, 0.84 for GRS and 0.75 for GLS. Among subjects with normal LV volumetrics comparing LVNC phenotype patients with healthy subjects meeting at least one of the LVNC diagnostic criteria (subgroup A vs. D), statistically significant differences persisted for GCS (AUC 0.72) and GRS (AUC 0.69), but not GLS. However, only GCS remained significant in a bivariable logistic regression model after adjusting for EF  when compared to healthy subjects with ‘physiologic’ hypertrabeculation (meeting one or more diagnostic criteria). Importantly, there were no significant differences between healthy subjects with and without physiologic hypertrabeculation. The AUCs for global strain values in differentiating LVNC phenotype patients from healthy subjects with ‘physiologic’ hypertrabeculation are reasonable considering the important limitations of morphology-based diagnostic criteria and GCS provides significant incremental value in addition to EF. GCS also adds significant incremental value when added to any of the four morphologic diagnostic criteria for LVNC among all healthy subjects and LVNC phenotype patients. No significant differences in LV torsion, however, were demonstrated by CMR FT analysis.The significant proportion of healthy subjects meeting CMR diagnostic criteria for LVNC has previously been observed by larger studies. In the TASCFORCE (Tayside Screening for Cardiovascular Events) study 14.8% of subjects met at least one of the diagnostic criteria assessed, including an NC:C diameter ≥ 2.3 measured on end-diastolic LAX images 12.6%), ≥3 on end-diastolic SAO images (7.2%), ≥2 on end-systolic SAO images (4.4%), and NC > 20% of global LV mass (4.1%) .6%, ≥3 o. This stAlthough there are multiple studies describing the strain characteristics of LVNC assessed by STE –18, CMR Among the healthy subjects GRS values were slightly higher, and GCS and GLS slightly lower, compared to a meta-analysis of CMR FT derived strain values in normal subjects . AlthougTo the best of the authors’ knowledge, this study represents the largest group of LVNC phenotype patients assessed by CMR FT strain analysis. The findings of impaired myocardial strain among LVNC phenotype patients are consistent with previous smaller studies , 27. A sThe absence of a significant difference in LV twist and torsion is inconsistent with previous STE studies demonstrating significantly decreased twist in LVNC phenotype patients compared to healthy subjects , 18. A dLVNC is a rare cardiomyopathy with a variety of clinical manifestations and growing number of genetic associations described in recent years that demonstrate phenotypic overlap with other cardiomyopathies . Due to LVNC phenotype patients demonstrate impaired radial, circumferential and longitudinal strain by CMR FT, persistent on comparison of subjects with normal LV volumetrics meeting at least one diagnostic criteria for LVNC. The high proportion of healthy subjects meeting morphology-based CMR diagnostic criteria emphasizes the important potential complementary diagnostic value of strain in differentiating LVNC from physiologic hypertrabeculation.


Given the tremendous progress in interventional cardiology over the last decade, a growing number of older patients, who have more comorbidities and more complex coronary artery disease, are being considered for technically challenging and high-risk percutaneous coronary interventions (PCI). The success of performing such complex PCI is increasingly dependent on the availability and improvement of mechanical circulatory support (MCS) devices, which aim to provide hemodynamic support and left ventricular (LV) unloading to enable safe and successful coronary revascularization. MCS as an adjunct to high-risk PCI may, therefore, be an important component for improvement in clinical outcomes. MCS devices in this setting can be used for two main clinical conditions: patients who present with cardiogenic shock complicating acute myocardial infarction (AMI) and those undergoing technically complex and high-risk PCI without having overt cardiogenic shock. The current article reviews the advancement in the use of various devices in both AMI complicated by cardiogenic shock and complex high-risk PCI, highlights the available hemodynamic and clinical data associated with the use of MCS devices, and presents suggestive management strategies focusing on appropriate patient selection and optimal timing and support to potentially increase the clinical benefit from utilizing these devices during PCI in this high-risk group of patients. Recent advances in percutaneous coronary intervention (PCI) technologies, including mechanical circulatory support (MCS) devices, have facilitated treatment of high-risk patients with complex coronary artery disease (CAD) and low left ventricular (LV) systolic function as well as patients with acute myocardial infarction (AMI) complicated by cardiogenic shock. These high-risk patients would otherwise be poor candidates for coronary artery bypass grafting (CABG) due to high surgical morbidity and mortality risks, and the ability to provide adequate hemodynamic support using MCS devices would potentially enable safer PCI and improve outcomes as compared to unprotected PCI strategy, surgical revascularization, or medical therapy alone . HoweverIn light of the development of new generation MCS devices with greater hemodynamic support and lower device-associated complications combined with careful planning and optimal timing of device utilization, a growing body of data is suggestive of improvement in procedural success and clinical outcomes ,8, and tOver the last few decades, there has been a tremendous progression in coronary interventional techniques that enables performance of PCI in complex coronary lesions  that would previously not have been amenable to intervention. This includes improved guide catheters and wires, mother-child guide catheters, low-profile balloons, coronary atherectomy devices, dedicated chronic total occlusion devices and algorithms, and superior stent designs that enhance deliverability to achieve complete multivessel revascularization including those involving chronic totally occluded coronary vessels. However, each aspect of PCI, beginning from guide catheter engagement and ending with balloon inflation and stent deployment, is associated with potential risk of vascular damage and impairment of myocardial perfusion. For instance, patients at advanced age, with increased comorbidities, and underlying left ventricular dysfunction, may pose a clinical challenge, as complex PCI among these patients may incur a substantial risk that overweighs any benefit achieved from revascularization . On the Among high-risk patients with active ischemia, the need and the type of revascularization should be discussed by Heart Team in an individual base. The recommendation with respect to the type of revascularization (PCI versus CABG) should be generally guided by important criteria including the predicted surgical mortality (based on the Society of Thoracic Surgeons (STS) score), the anatomical complexity of CAD (based on the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score), and the anticipated completeness of revascularization. The risks of periprocedural complications should be weighed up against the anticipated improvement in quality of life and long-term freedom from death, MI, and repeat vascularization for electing whether conservative therapy, PCI, or CABG is the recommended strategy. According to the current ESC guidelines , when suAs high-risk PCI is associated with increased risk of myocardial ischemia and hemodynamic compromise that may lead to circulatory collapse, the purpose of MCS is to diminish myocardial oxygen consumption and provide adequate cardiac output and myocardial perfusion during the procedure. Use of appropriate MCS devices allows adequate time to safely perform complex PCI with optimal results in these high-risk patients who would not otherwise tolerate complete revascularization . It is c2 with hemodynamic support or <1.8 L/min/m2 without support, pulmonary capillary wedge pressure (PCWP) >15 mmHg, and evidence of end-organ damage  .,18.11,18Several percutaneous MCS devices are currently available to assist interventional cardiologists during high-risk PCIs both for patients undergoing a complex PCI and for those requiring PCI in the setting of cardiogenic sock complicating AMI. Types of available percutaneous MCS devices and comparisons of their characteristics and hemodynamic impact are presented in Since its introduction in the 1960s, IABP remains the most widely used device for temporary support in hemodynamically unstable patients due to its greater availability and ease of insertion as compared to other temporary devices . It is tThe complications associated with IABP use are mainly vascular, including limb ischemia, vascular injury, and stroke . AlthougThe Impella pumps are continuous nonpulsatile microaxial flow devices that are deployed into the LV across the aortic valve and unload the LV by pumping blood from the LV cavity to the ascending aorta. The Impella 2.5 and CP pumps  can be placed percutaneously and provide maximal flow rates of 2.5 and 3.0–4.0 L/min, respectively, while the Impella 5.0 and Impella LD  devices are larger LV assist axial-flow pumps that require surgical cutdown and provide up to 5.0 L/min of cardiac output ,37,38. SUnlike IABP, Impella (as other percutaneous ventricular assist devices) functions independently of the remaining LV function and does not require synchronization with the cardiac cycle. Therefore, Impella devices are more helpful than IABP in patients with severely depressed LV function who present with significant arrhythmias. Impella results in effective LV unloading thus resulting in decreased LV filling pressures (LVEDP) and myocardial oxygen consumption, while improving cardiac output, mean arterial pressure, and coronary perfusion . All theDespite the improvement in hemodynamic parameters, device-related complications are not rare and can be clinically meaningful, thereby contradicting the potential hemodynamic benefits that can be achieved with the use of Impella devices in some cases. As with any mechanical support device, common complications associated with Impella include vascular trauma, limb ischemia, and bleeding requiring blood transfusion. Moreover, hemolysis is frequently encountered during Impella support due to mechanical erythrocyte shearing, but usually improves after repositioning the device. Based on the Impella EUROSHOCK Registry , utilizaImpella should not be used in patients with a mechanical aortic valve or LV thrombus as well as in those with severe peripheral arterial disease or who cannot tolerate systemic anticoagulation therapy. Although severe aortic stenosis and regurgitation are considered relative contraindication, the use of Impella in this setting has been shown to be feasible and may be considered in selected high-risk patients with severe aortic stenosis and cardiogenic shock or those with severe LV dysfunction and CAD who require high-risk PCI and/or balloon aortic valvuloplasty as well as in selected patients who develop hemodynamic collapse during transcatheter aortic valve replacement (TAVR) .The TandemHeart (CardiacAssist) system is an extracorporeal, centrifugal, continuous flow pump, which is available on the market for left, right, and biventricular failure. For LV support, TandemHeart device is percutaneously inserted to pump blood extracorporeally from the left atrium through a transseptal cannula back into the femoral/iliac artery through an arterial cannula using a centrifugal pump that provides 3 to 5 L/min of continuous flow at 3000 to 7500 rpm, respectively ,37. The By propelling blood from the left atrium directly to the arterial system, TandemHeart results in a significantly reduced LV preload, filling pressures, and myocardial oxygen demand, while cardiac output and mean arterial pressures are improved. However, because LV output through the aortic valve competes with the retrograde flow from the device, LV afterload increases as the device support is augmented, which may ultimately result in aortic valve closure requiring LV venting ,45.Similar to other percutaneous MCS devices, TandemHeart use may infrequently cause limb ischemia and vascular injury . AdditioBased on the Extracorporeal Life Support Organization (ELSO) registry data, the number of ECMO devices and the number of centers utilizing ECMO are markedly increasing ,48. VA-EVA-ECMO support results in a remarkable increase in cardiac output and mean arterial pressure. However, its use is limited by retrograde blood flow leading to LV afterload mismatch, inadequate LV decompression, and high myocardial oxygen demand. The concurrent use of IABP or Impella can add further support by direct unloading of the LV and reducing ventricular wall stress ,52. ReceOne of the recent advancements in the percutaneous extracorporeal life support (ECLS) technology is the development of the Lifebridge B2T “bridge to therapy” system , which is a miniaturized and portable heart-lung support system similar in design to standard ECMO systems with an ability to provide cardiovascular stabilization and sufficient end-organ perfusion immediately after circulatory arrest. The Lifebridge system enables rapid application within 5 min due to its automated set-up and portable design in addition to less cumbersome transportation of the patient than standard ECMO equipment due to its smaller size and suitcase configuration. Other technical features include a battery life of 2 h, an overall weight of 18 kg (39.6 lb.), and a maximal blood flow of 6 L/min. Real-world clinical data of the German Lifebridge Registry involving 444 patients from 60 tertiary cardiovascular centers has been recently published  showing Adverse events related to VA-ECMO include bleeding (with excessive anticoagulation), thromboembolic events in the circuit or systemically (if anticoagulation is inadequate), cannula-induced vascular injuries, infection, stroke (ischemic or hemorrhagic), hemolysis, and limb ischemia . To reduPercutaneous LV MCS pumps under investigation include the pulsatile iVAC 2L , which has been recently evaluated prospectively in a pilot study of 14 patients undergoing high-risk PCI demonstrating 100% angiographic success . The AorApart from LV support, RV failure refractory to medical therapy is increasingly becoming a clinical challenge, thereby prompting the development of devices to specifically provide RV support. Large inferior AMI may cause predominant RV failure with cardiogenic shock with or without severe LV dysfunction. When cardiogenic shock is persistent despite maximal medical therapy, the options for MCS in this setting include VA-ECMO, surgical implantation of RVAD or total artificial heart (TAH), and heart transplantation . The recThe most recent clinical practice guidelines regarding the use of percutaneous MCS for PCI and management of ACS recommend consideration of the use of these devices in the setting of high-risk PCI and AMI complicated by cardiogenic shock . HoweverIn the setting of PCI with cardiogenic shock complicating AMI, a previous retrospective study has suggested a potential benefit with early IABP support placed prior to PCI showing decreased rates of in-hospital mortality and cardiac adverse events compared with IABP placed only following PCI . In a meAmong patients undergoing PCI without evident cardiogenic shock, IABP use was tested in the CRISP-AMI  trial ; a 30-ceGiven these conflicting results and the controversy surrounding its benefit, the use of IABP in the setting of STEMI complicated with cardiogenic shock is decreasing and its routine use has been recently downgraded to class III (harm) by the ESC  and to cp = 0.01) and 6-month  mortality [There are currently limited available data to establish a significant clinical benefit of Impella use in patients with cardiogenic shock undergoing PCI. Impella devices provide greater hemodynamic support with a more pronounced cardiac output augmentation and LV unloading than IABP. In 2008, the ISAR-SHOCK (Impella LP 2.5 versus IABP in Cardiogenic SHOCK) trial  was the ortality . More reortality . There wortality . Finallyortality . It is iThe effectiveness and safety of Impella support for planned high-risk coronary interventions have been investigated in small studies showing encouraging results. In the AMC MAC1 study , 19 consp = 0.227 in the intention-to-treat population, and 34.3% versus 42.2%, p = 0.092 in the per-protocol population). Impella did provide greater hemodynamic support and at 90-day follow-up there was a trend towards a decreased incidence of adverse events with Impella in the intention-to-treat population  and significantly decreased events in the per-protocol population  [The largest prospective randomized clinical study to examine the effect of hemodynamic support with Impella in patients undergoing high-risk PCI was the PROTECT II trial . In this= 0.023) . A more = 0.023) . Interes2), PCWP (decreased from 31 to 17 mmHg), and mixed venous oxygen saturation (increased from 49 to 69%), as well as improvement in kidney function (urine output increased from 70 to 1200 mL/day and creatinine decreased from 1.5 to 1.2 mg/dL) and lactic acid level (decreased from 11 to 1.5 mg/dL). However, overall mortality (40.2% at 30 days and 45.3% at 6 months) and bleeding complications remained high [Small studies have shown a significant improvement in hemodynamics with TandemHeart use, but were underpowered to show improvement in survival. In an observational study by Kar et al. , TandemHned high . In a smned high . Similarned high .Data on the use of TandemHeart in high-risk PCI is limited to observational studies. A study from the Mayo Clinic summarized data on 54 consecutive patients undergoing high-risk PCI using a TandemHeart device for support, demonstrating feasibility and safety of this device to allow performance of high-risk and complex intervention . All patWhile ECMO provides excellent cardiopulmonary support with a relative ease of implementation, its use in the setting of AMI and shock is limited by the need for specialized perfusion expertise and nursing as well as the possibility for increased LV stroke work and myocardial oxygen demand, which can precipitate further myocardial ischemia. Additionally, there is need for large bore cannulas and aggressive antithrombotic therapy which increase the risk of bleeding. A recent single-center study  reportedA suggested algorithmic approach to MCS use during PCI for cardiogenic shock complicating AMI and high-risk PCI without cardiogenic shock is depicted in For prophylactic percutaneous MCS use in the setting of high-risk PCI, great emphasis should be on identifying the patient’s anatomic, hemodynamic, and procedural features that indicate adjunctive MCS support may be necessary and also determine the optimal device to utilize . The curThe majority of studies involving the new MCS devices for cardiogenic shock and high risk PCI have demonstrated superior hemodynamic improvement as compared to IABP but these studies were largely underpowered to find mortality benefit and therefore should be regarded as feasibility trials and a basis for larger clinical trials in the future. The DanGer Shock study  is an onDespite the lack of current evidence, we believe that advanced MCS devices may improve clinical outcomes, including survival, in a selected group of patients and in specific circumstances. Future studies should largely focus on three major considerations when examining the clinical benefit of MCS. First, the optimal MCS device design and amount of support needed to achieve hemodynamic as well as metabolic improvement is unclear. For instance, in the IMPRESS in Severe Shock trial, one third of the patients died due to refractory cardiogenic shock and lactate levels remained high in many patients while being on Impella CP support, suggesting that the actual level of support was not sufficient ,73. SecoThird, the timing of MCS device insertion in relation to primary PCI among patients with AMI and cardiogenic shock can be critical to achieve survival benefit and future studies should focus on determining the optimal timing of MCS, which remains elusive. Recent studies have shown in an animal model that mechanical support with LV unloading reduces infarct size and favorably mediates key biological pathways associated with inflammation and maladaptive cardiac remodeling when mechanical support is initiated prior to coronary reperfusion compared with early reperfusion without support ,97,98,99Based on these promising retrospective data, and after the FDA’s approval of Impella for cardiogenic shock complicating AMI, investigators have organized the construct of a multicenter national shock protocol now referred to as the “National Cardiogenic Shock Initiative” (NCSI) emphasizing invasive hemodynamic monitoring and rapid initiation of percutaneous MCS support. The analysis of the first 171 patients enrolled in NCSI was recently published .Another field of future research is the percutaneous LV unloading strategy using Impella in combination with VA-ECMO (ECMELLA) to improve outcomes in patients with refractory cardiogenic shock ,104. In The use of MCS devices is expanding and several MCS devices are currently available and can provide varying magnitude of hemodynamic support during high-risk and complex PCIs. Small randomized controlled trials have provided conflicting results regarding survival benefit using these devices despite substantial hemodynamic and metabolic benefit. However, given the high morbidity and mortality burden among patients undergoing high-risk and complex PCI, detailed hemodynamic assessment and careful patient selection is mandatory to achieve incremental benefit over early revascularization and pharmacologic therapy with utilizing these devices. Furthermore, the optimal timing and magnitude of hemodynamic support during PCI as well as prevention of device-related complications are all important considerations in future research in this field. Until adequate data supporting MCS use in a broader patient population is available, MCS devices during PCI should be individualized based on multiple factors with a recommended use in patients with the greatest potential benefit and a relatively low risk of device-related complications.


In the test cohort, all single‐point surrogates correlated with RV ejection fraction (p < 0.010), but correlation (R) was higher for SPM‐O  than TAPSE  and SFD , and non‐significantly higher than TAPSE‐F  and SFD‐F . SPM‐O explained more of the observed variance in RV ejection fraction (19%) and predicted it more accurately than any other 2D marker . We conclude that systolic motion of the basal RV freewall predicts global function more accurately than other 2D estimators. However, no markers summarise 3D contractile patterns, limiting their predictive accuracy.Right ventricular (RV) function has prognostic value in acute, chronic and peri‐operative disease, although the complex RV contractile pattern makes rapid assessment difficult. Several two‐dimensional (2D) regional measures estimate RV function, however the optimal measure is not known. High‐resolution three‐dimensional (3D) cardiac magnetic resonance cine imaging was acquired in 300 healthy volunteers and a computational model of RV motion created. Points where regional function was significantly associated with global function were identified and a 2D, optimised single‐point marker (SPM‐O) of global function developed. This marker was prospectively compared with tricuspid annular plane systolic excursion (TAPSE), septum‐freewall displacement (SFD) and their fractional change  in a test cohort of 300 patients in the prediction of RV ejection fraction. RV ejection fraction was significantly associated with systolic function in a contiguous 7.3 cm Right ventricular (RV) function has prognostic value in acute This study was conducted at a single centre and was approved by the Hospital's research ethics committee. Participants were recruited by advertisement and all gave written, informed consent. We did not study patients with cardiovascular disease or pregnancy, or those taking medication for hypertension, diabetes or hypercholesterolaemia. Standard published safety contraindications to MR imaging were applied −1, TE 1.5 ms, TR 3.0 ms, 20 cardiac phases, sensitivity encoding (SENSE) factor 2.0) The CMR examinations were performed on a 1.5 T Philips Achieva system . In order to capture the whole‐heart phenotype, a high‐spatial resolution, 3D balanced, steady‐state, free procession cine sequence was used that assesses the left and right ventricles in their entirety in a single breath‐hold  and performed on a high‐performance server . The method uses prior knowledge by comparing each new set of images with a series of cardiac atlases where the anatomy has been manually defined Segmentation accuracy was confirmed by visual inspection of the segmented images, by voxel concordancy with manual segmentation of the same subjects and by comparison of RV ejection fraction (RVEF) measured by two readers with 2 years’ cardiac MR experience using CMRtools  with RVEF derived from the model. Segmentation reproducibility was confirmed using repeat imaging of the same subjects.In model development, local function was assessed as the distance travelled in 3D space from end‐diastole to end‐systole by each of the 11,262 points representing the RV wall (‘excursion’). Global function was assessed by RVEF using a method previously described. In model validation, ventricular function was assessed by four single‐point measures in clinical use: TAPSE, fractional tricuspid annular plane systolic excursion (TAPSE‐F), SFD and fractional septum‐freewall displacement (SFD‐F) and their measurement followed published methods Test–retest reproducibility was assessed using bias (mean and standard deviation) and intra‐class correlation coefficient (ICC) with a two‐way random model for absolute agreement Adjacent points on the RV wall are likely to have highly correlated function (multicolinearity), increasing the risk of unreliable predictions in new datasets. Principal component analysis (PCA) was used to overcome this problem. ‘Principal components’ are orthogonal modes of variation seen in the data, from which the original dataset can be described with maximal economy. Being orthogonal, principal components are linearly uncorrelated with each other, and are therefore suitable variables for regression analysis and predictive models. The first, largest, principal component (PC1) was retained for subsequent regression. Only one component was retained to ensure estimations of the predictive strength of the 3D model were conservative, and to allow a direct comparison with other ‘single‐variable’ markers, such as TAPSE.2 statistic). A p value of < 0.05 was considered statistically significant.In model validation, each of the five 2D measures was tested by correlation, linear regression and accuracy of RVEF prediction. Correlation with RVEF was assessed using the Pearson product‐moment coefficient. Difference in correlation coefficients was assessed by a method described by Steiger Six hundred and forty adult volunteers successfully completed the imaging protocol. All datasets were used for analysis and there were no failures of the segmentation algorithm. Baseline characteristics of participants included in the study are shown in Table −2, limits of agreement: −6 to + 22 ml.m−2). Intraclass correlation coefficients for test–retest reliability of the model were 0.99 for 3D automated RV volume index and 0.93 for pointwise systolic excursion. Mean ± SD point distance from automated to manual segmentation was 1.46 ± 1.46 mm (95%CI: 1.46–1.47).No significant bias was detected between 3D automated, 3D manual and 2D manual volumetry of the right ventricle  measurement was derived by identifying a sub‐group of voxels within the patch coinciding with conventional scanning planes. Excursion values in the patch were reconstructed using PC1 and correlated with the original excursion value. The highest correlating voxel (R = 0.9) coinciding with a scanning plane was identified at 43% of the distance from base to apex, in the basal freewall of the four‐chamber plane. The displacement of this point from end‐diastole to end‐systole in millimetres was recorded manually from the four‐chamber plane  were evaluated prospectively in 300 subjects. All markers were significantly correlated with RVEF  although differences between median (IQR [range]) were non‐significant . The dashed lines mark the zone in the freewall where global function (right ventricular ejection fraction) and local function (excursion) are significantly associated .Figure S2. Prediction of RVEF in model validation cohort. RVEF, right ventricular ejection fraction; SFD(‐F), septum‐freewall displacement ; TAPSE(‐F), tricuspid annular plane systolic excursion ; SPM‐O, optimised single‐point marker.Click here for additional data file.


Introduction: The current study was sought to assess the immediate effect of percutaneous balloonmitral valvuloplasty (PBMV) on right ventricular (RV) and pulmonary functions using speckle tracking echocardiography (STE) and spirometry respectively.Methods: Two-dimensional speckle tracking and doppler studies for strain and strain rate imaging of RV were performed before PBMV, after 48h and 15 days of PBMV using echocardiography and spirometry. Mitral valve area, peak and mean mitral valve transannular pressure gradients, late filling velocities,Wilkins score, Systolic pulmonary artery pressure, TAPSE, RV end-diastolic and end-systolic areas,RV fractional area change and Tei index were measured.Results: There was a significant rise in peak RV global longitudinal strain (GLS) from baseline to48h post PBMV and at 15 days post PBMV. Segmental RV strain at basal septum, mid septum,apical septum and basal RV free wall showed considerable improvement from baseline to 48h post PBMV and 15 days post PBMV. RV longitudinal strain rate parameters did not show significant improvement after PBMV and remained low at follow-up. Post PBMV all patients showed restrictive features on pulmonary function test. The mean FEV1 (% predicted), mean FVC (% predicted), mean PEFR improved from baseline to 48h PBMV and 15 days post PBMV. Though the mean FEV1/FVC increased post PBMV at 15 days follow-up, but it was statistically insignificant.Conclusion: RV performance in MS was decreased mainly due to increase in RV after load which improves after PBMV. Patients with severe MS have impaired pulmonary function which is of restrictive type and successful PBMV improves pulmonary function. The prevalence rates have been found to be 0.2 to 1.1/1000 populations.3 Rheumatic mitral stenosis (MS) is the most common RHD which includes characteristic changes of the mitral valve include thickening at the leaﬂet edges, fusion of the commissures, chordal shortening and fusion.4 Subsequent scarring leads to valve deformity resulting in a small fish mouth orifice.5Rheumatic heart disease (RHD) is one of the noticeable causes of mortality and morbidity in developing countries across the globe. It has been estimated that 15.6 million people are affected by RHD globally.6Long standing pulmonary arterial hypertension can result in morphological changes in the pulmonary vasculature comprising of endothelial proliferation and medial hypertrophy. This causes secondary right ventricular (RV) overload, dilatation and failure. Pulmonary dysfunction in severe MS is attributed to interstitial and alveolar edema, reactive fibrosis, pleural effusion and decreased lung volumes.7 Among many indices, strain and strain rate are novel to assess RV function. For the evaluation of RV function by strain and strain rate, Tissue Doppler imaging (TDI) is used.8 A new method, Two-dimensional speckle tracking, to quantify strain and strain rate for assessment of global and regional myocardial function. Lack of angle dependency is the main advantage of strain derived by speckle tracking over strain derived by TDI, which may result in more reliable strain measurements.Abnormalities in RV function play vital role in the development of clinical symptoms and prognosis of MS patients.9 whereas only few studies examined the immediate effect of PBMV on RV function using speckle tracking echocardiography (STE).10 The current study was sought to assess the immediate effect of PBMV on RV and pulmonary functions using STE and spirometry respectively.There are studies on long-term improvement in RV and pulmonary functions in patients with MS after percutaneous balloon mitral valvuloplasty (PBMV)This prospective, observational study was conducted between May 2017 and December 2018 which consisted of 52 patients with symptomatic severe Rheumatic mitral stenosis. This study was approved by the institutional ethics committee of our institute [IEC number: 639]. A written informed consent was obtained from all the study participants.1. Patients aged >18 years.2. Patients with severe MS (MVA<1.0 cm²).3. Patients with successful PBMV.1. Patients having severe aortic valve disease associated with mitral stenosis.2. Patients with atrial fibrillation, coronary heart disease, congenital heart disease, mitral regurgitation (MR) grade more than 2+ after PBMV.3. Patients with diabetes and hypertension.4. Pregnant women.5. Patients who refused to give consent.11 and spirometry using American Thoracic Society recommendations.12 Echocardiography was performed by using SIEMENS ACUSON S2000 echocardiography machine with 3.5MHz probe. Spirometry was performed by using Easy One ProTMLab, ndd Medical Technologies Andover, MA, USA.Baseline clinical and demographic characteristics were obtained from all patients. Two-dimensional speckle tracking and doppler studies for strain and strain rate imaging of RV were performed before and 48h after PBMV using American Society of Echocardiography recommendations13 was used to judge mitral leaflet mobility, valvular and subvalvular thickening, and calcification. Systolic pulmonary artery pressure was derived from the tricuspid regurgitant jet peak velocity using the modified Bernoulli equation. The tricuspid annular plane systolic excursion (TAPSE) was determined by the difference in the displacement of the RV base during systole and diastole. RV end diastolic and end-systolic areas were measured from the apical four chamber view to calculate RV fractional area change (RVFAC). The Tei index of RV myocardial performance was calculated as the time between tricuspid valve closure to tricuspid valve opening, divided by the RV ejection time, determined by pulsed Doppler.Mitral valve area (MVA) was determined by planimetry. The peak and mean mitral valve transannular pressure gradients and late filling velocities were measured using continuous wave doppler recordings through mitral inflow. Wilkins score14Two-dimensional images were acquired from the four-chamber view for offline analysis using the two-dimensional strain software. The endocardial borders of the RV were traced manually by point and click approach and tracked by the software. An epicardial surface tracing is then automatically generated by the system. After manual adjustment of the region of interest, software automatically divides the region of interest into 6 segments. The RV free wall and interventricular septum were divided in three segments, basal, mid, and apical, for quantification of regional systolic strain. The GLS was calculated for the entire the right ventricle.12 Patients were instructed to inhale as much as possible and then exhale rapidly and forcefully for as long as flow is maintained. Patient should exhale for at least six seconds. At the end of the forced exhalation, the patient should again inhale fully as rapidly as possible. The following parameters were determined -- Forced vital capacity (FVC), forced expiratory volume in first second (FEV1), FEV1/FVC and peak expiratory flow rate (PEFR) rate. Interpretation of pulmonary function tests: Restriction was defined as FVC< 80% of predicted with normal or increased FEV1/FVC.15 Obstruction was defined low FEV1/FVC ratio (<0.7) and FEV1<80% predicted.16 Mixed restriction and obstruction is defined as low FVC (<80% predicted), FEV1 (<80% predicted) along with reduced FEV1/FVC ratio (<0.7).16Spirometry was performed to evaluate the lung function disturbances, according to the recommendations of American Thoracic Society.2 with no more than 2+ MR. Two-dimensional (2D) speckle tracking, Doppler studies were repeated after 2 weeks to assess immediate changes in parameters. Pulmonary function tests were repeated after 2 weeks to assess immediate changes.Echocardiography was repeated 48 h after the procedure to evaluate the final MVA and to assess the degree of residual MR. Successful PBMV was defined as post valvuloplasty MVA >1.5 cmP value of ≤0.05 was considered as significant.Continuous variables were expressed as mean and standard deviation (SD). Paired Student’s t-test was used to determine the significance among the parameters pre and post PBMV. Statistical Package for Social Sciences (SPSS) version 20.0  was used for the analysis. A This study findings were conceived from 52 symptomatic severe rheumatic MS patients who underwent PBMV. Mean age of the study population was 35.8±9.2 years. Majority of them were female patients (72%). Dyspnea was the presenting symptom in all the cases. Sixty one percent were in NYHA class-III and 39% were in NYHA class-II. Six patients (11%) had undergone prior PBMV and 2 patients (4%) had undergone prior closed mitral valvotomy (CMV). The mean Wilkins score was 6.5±1.2. Demographic and clinical characteristics of the study population at baseline were shown in Comparison of baseline and follow-up echocardiographic characteristics were summarized in Comparison of baseline and follow-up RV longitudinal strain parameters were shown in In our study RV longitudinal strain rate parameters did not show significant improvement after PBMV and remained low at follow-up. Details of RV longitudinal strain rate parameters at baseline, post PBMV 48 hours and post PBMV 15 days follow up were summarized in 1 (% predicted), mean FVC (% predicted), mean PEFR improved from baseline to 48 hours PBMV and 15 days post PBMV. Though the mean FEV1/FVC (108.52±17.21) increased post PBMV at 15 days follow-up, but it was statistically insignificant (In our study 4 patients (7%) had obstructive airway disease and remaining of the 48 patients (93%) had restrictive features on pulmonary function test before PBMV. Post PBMV all patients showed restrictive features on pulmonary function test. The mean FEVnificant .17, Alabaady M et al18 and Kumar V et al19. These findings suggest immediate improvement in RV function following PBMV. Conventionally, for evaluation of procedural success, these echocardiographic parameters are valuable.In our study there was a significant increase in 2D MVA, FAC, TAPSE at 48 hours following PBMV which was maintained post PBMV at 15 days follow-up. We observed a significant decrease in PASP, mean mitral valve gradient and peak mitral valve gradient. Similar findings were observed in studies done by Roushdy et al7In our study RV MPI showed no significant change after PBMV at 48 hours and at 15 days follow-up which shows that immediate improvement of RV function is due to decreased after load of RV. RV MPI is a load independent parameter of RV function. Similar observations were reported by Mohan et al.19 and Alabaady M et al18. Enhanced LV filling and LV contractility following PBMV may be the reasons for improvement of IVS strain than RV free wall strain in our study.In our study there was significant rise in RV GLS at 48 hours after PBMV and at 15 days follow-up. Also found a significant rise in RV segmental strain at basal septum of IVS, mid septum of IVS, apical septum of IVS, basal RV free wall at 48 hours post PBMV and at 15 days follow-up. Statistically insignificant difference was observed in RV segmental strain at mid RV free wall and apical RV free wall at 48 hours post PBMV and lack of improvement at 15 days follow-up. Similar findings were reported by Kumar V et al19 Strain rate is more affected by contractility and is not affected by loading conditions. This means that increased afterload is the main cause of RV systolic dysfunction in severe MS patients. In our study RV GLS has strong correlation with PASP than other conventional echocardiographic parameters. Similar observations were made in previous studies by Roushdy MA et al, Alabaady M et al, and Kumar V et al.19We observed no change in RV segmental strain rates in any of the RV segments. Similar findings were reported by Roushdy et al and Kumar V et al.21 The restrictive features may be due to chronic lung congestion due to increased interstitial fluid, decreased lung compliance and fibrosis from chronic congestion and consequent muscle fatigue.In our study 4 patients (7%) had obstructive type airway disease and remaining 48 patients (93%) had restrictive type of features on pulmonary function test before PBMV. Post PBMV all patients showed restrictive type of features on pulmonary function test. Similar findings were reported by Simkova et al and Khan et al.1 (%predicted), FVC (%predicted) and PEFR. However, the changes in FEV1/FVC were statistically insignificant. Similar observations were reported by Khan et al and Mundhra SH et al.22 All the patients showed improvement of their ventilatory function after PBMV that may be due to reduction in left atrial hypertension, pulmonary venous congestion, resulting in increased lung compliance.In our study, 15 days post PBMV, there was significant improvement in pulmonary function parameters FEVThe number of patients studied were relatively less and study was done in severe MS patients only. Short axis images of RV were not recorded. Doppler strain was not included for comparison. Short duration of follow-up.Right ventricular function can be assessed by global and segmental RV strain using STE comparable with conventional echocardiographic parameters. RV performance in MS is reduced mainly due to rise in RV afterload which improves after PBMV. Patients with severe MS have impaired pulmonary function which is of restrictive type and successful PBMV improves pulmonary function.None.This study was conducted with a prior approval from the institutional ethics committee (IEC number: 639) and an informed consent was obtained from all the study participants prior to the enrolment.None.


Familial lipodystrophy is a rare genetic condition in which individuals have, besides metabolic changes and body fat deposits, a type of cardiomyopathy that has not been well studied. Many of the patients develop cardiovascular changes, the most commonly reported in the literature being the expression of a type of hypertrophic cardiomyopathy. This article, presented as a bibliographic review, reviews the clinical and cardiovascular imaging aspects in this scenario of cardiomyopathy in a rare metabolic disease, based on the latest scientific evidence published in the area. Despite the frequent association of congenital lipodystrophy and ventricular hypertrophy described in the literature, the pathophysiological mechanisms of this cardiomyopathy have not yet been definitively elucidated, and new information on cardiac morphological aspects is emerging in the aegis of recent and advanced imaging methods, such as cardiac magnetic resonance. Due to the absence of energy storage sites, an ectopic deposition of triglycerides occurs in the skeletal muscle and liver.2Lipodystrophy is a rare disease characterized by the loss of adipose tissue, which may be generalized or partial.3 and, recently discovered, cardiomyopathy. Presentations such as left ventricular hypertrophy or even dilated cardiomyopathy have been described in patients with lipodystrophy.The reduced ability to store triglycerides and their ectopic deposition are determinant for the predisposition and severity of complications, such as insulin resistance, diabetes mellitus, hypertriglyceridemia, hepatic steatosisGenetic lipodystrophies can be divided and subdivided into various types, each one with its specific mutation, which determine the most diverse clinical presentations and possible associations with the development of heart disease. Despite that, this condition is extremely rare, with a higher prevalence in populations with high levels of consanguinity.This paper aimed to describe familial lipodystrophy and its association with the development of cardiomyopathies, in the light of the latest scientific evidence.4 Individuals with this alteration have an almost total lack of adipose tissue, leading to prominent skeletal musculature regarding its phenotypic aspect. During childhood, many individuals develop hepatosplenomegaly and umbilical prominence; and during adolescence, complications such as diabetes arise.One of the most frequent types of genetic lipodystrophy is the generalized congenital type, characterized by an autosomal recessive disorder, occurring most often in cases of parental consanguinity. This form is present in all geographical regions and, because of the consanguinity cause, it probably has the highest prevalence reported in some regions of Brazil, such as the Northeast.This syndrome can manifest in many different forms, being related to one of four existing subtypes and, consequently, to the affected chromosome. Among these subtypes, the Berardinelli-Seip syndrome (BSCL) is well-known, described through the scientific collaboration of the great Brazilian researcher W. Berardinelli. Today it is known that this syndrome is identified by a mutation in chromosome 11q13, which encodes the protein seipin, present in the endoplasmic reticulum, being responsible for the formation of lipid droplets and their fusion within adipocytes. Its absence causes a lack of both metabolically active adipose tissue and mechanical adipose tissue since birth, which may lead to mild mental retardation and cardiomyopathies, making it the most severe of the subtypes.This is a type of genetic lipodystrophy, in which the individuals have skeletal abnormalities, such as mandibular and clavicular hypoplasia, associated with skin atrophy, delayed teething, cranial suture closure and joint stiffness. As a common feature of lipodystrophies, MAD leads to metabolic complications such as diabetes, insulin resistance, hypertriglyceridemia, and low HDL-cholesterol levels.5 fat. These patients have normal fat distribution during childhood and begin to have progressive and variable loss of subcutaneous fat during puberty, typically from the extremities, and in varying degrees from the abdomen and chest.Familial partial lipodystrophy is, mostly, an autosomal dominant disorder characterized by loss of upper and lower-limb fat as well as trunk5Many patients, especially females, show fat accumulation in the face, neck and perineal and intra-abdominal regions.  Excess f6Five genes may be involved in the pathophysiology of this type of lipodystrophy, all leading to subcutaneous fat loss in the extremities. The most prevalent form of familial lipodystrophy is autosomal dominant type 2, the first familial partial lipodystrophy more formally described: FPLD2 , also referred to as variant or Dunnigan Syndrome. This syndrome has a prevalence of 1 in 15 million people, affecting both genders equally. The patients develop several metabolic complications such as dyslipidemia, hypertriglyceridemia and diabetes. In addition, they may manifest varying degrees of myopathy, cardiomyopathy, and other conduction system abnormalities, thus proving to be a multisystem dystrophy.7 It has been shown that the LMNA R482W mutation is more associated with muscle and cardiac abnormalities, such as muscular atrophy and dystrophy, cardiac hypertrophy and advanced atherosclerosis.8 But the phenotypic differences associated with each specific mutation determinant of FPLD are yet to be elucidated.FPLD2 is characterized by a mutation in the long arm of chromosome 1 (1q21-22) specifically involving lamins A and C or the LMNA gene. Commonly, the mutation that causes FPLD2 affects exon 8 , but other mutations in exon 8 and 11 (codon 644 - R644C) have already been described.9Numerous mutations spread throughout the LMNA protein give rise to diseases commonly called laminopathies that affect muscle, heart, fat, cartilage and bone tissues or lead to early aging syndromes.9 It is believed that the alteration of these proteins weakens the integrity and structure of the nuclear envelope, which would profoundly deteriorate the structure of the adipocyte nucleus, ultimately leading to premature cell death. In addition, it is known that A-type lamin is capable of interacting with transcription factors such as SREBP1 (Sterol Regulatory Element Binding Protein 1), which is involved in the differentiation of adipocytes.9 Furthermore, it has been observed that type A and C-lamins bind to telomeric sequences, having a role in regulating telomere length.A-type lamins include lamins A (LMNA) and C (LMNC) that arise from alternative splicing of RNA from the LMNA gene. These proteins are expressed in most cells, and they are located in the nuclear envelope and nucleoplasm and play a relevant role in directing the transcription of heterochromatin located on the periphery of the nucleus.10The main point common to all types of lipodystrophy is the total or almost total absence of adipose tissue, thus compromising the affected individual's storage of triglycerides and their metabolic activity. Before that, most patients clinically manifest muscular appearance, prominent superficial veins, extremity enlargement, acanthosis nigricans, umbilical prominence or hernia, hyperphagia and accelerated growth, menstrual period irregularity , precocious puberty and menarche, among other signs and symptoms that may include cardiac autonomic changes.10One of the key points possibly related to the occurrence of cardiomyopathies in patients with lipodystrophy and also associated with all the described types is the accumulation of fat in ectopic tissues, such as the liver and skeletal muscle. Also, the lower capacity to oxidize and store fat promotes dyslipidemia, insulin resistance, development of diabetes mellitus and its complications, which may involve the cardiovascular system.11The World Health Organization, together with the International Society and Federation of Cardiology, has defined cardiomyopathy as a myocardial disease associated or not with cardiac dysfunction and can be classified according to morphological and physiological changes, such as dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic left ventricular cardiomyopathy, metabolic cardiomyopathy, among others.12 The condition, known as diabetic cardiomyopathy, is an under classification of metabolic cardiomyopathy and is defined by the presence of myocardial involvement in patients with diabetes, after excluding other causes such as ischemic myocardial disease. In diabetic cardiomyopathy, there may be left ventricular remodeling and dilation, associated with diastolic and, in some cases, systolic dysfunction.13Special attention should be paid, in this context, to metabolic cardiomyopathy, which develops before various pathological conditions associated with systemic metabolic disorders, being characterized by structural and functional changes without concomitant coronary artery disease or hypertension.13 The almost exclusive use of this compound leads to excess lipids, which may be accumulated in the heart muscle or diverted to non-oxidative pathways, disrupting normal cell function and causing organ dysfunction and apoptosis, a fact called lipotoxicity.14 In addition, permanently hyperglycemia can cause damage to the myocardium through proteins modified by advanced glycation end products, as well as oxygen free radicals, leading to their accumulation and myocardial fibrosis, which can result in dysfunction, initially only diastolic.13The glucose metabolism impairment present in diabetes is associated with the higher consumption of fatty acids as an energy source, which is justified by the lack of insulin or resistance to it.10 Early atherosclerosis, especially in patients with familial partial lipodystrophy, may have a prevalence rate of over 60% and manifests before age 45. With such aggressiveness, the pathophysiological mechanisms involved seem not only to be dependent on metabolic changes, but perhaps on a direct effect of gene mutation on endothelial function.15Several cardiac alterations have been described in the literature in patients with lipodystrophy, whether solely morphological alterations or alterations associated with cardiac dysfunction, but the pathophysiological basis involved has not been completely elucidated.16In a collection of case series of lipodystrophy prior to the year 2000, several cases with hypertrophic cardiac changes have been described, with or without systolic obstruction to ventricular ejection, many with cardiomegaly and associated systemic arterial hypertension .1617 can also been found in the literature, even in very young or still infant patients,20 and, in some cases, the progression of ventricular hypertrophy has been documented.21 In some of these cases identified at early ages, the evolution of cardiomyopathy to global systolic dysfunction in childhood or youth has been documented.22After the 2000s, publications on isolated or grouped cases showing an association between lipodystrophy and ventricular hypertrophy23 considered that LMNA mutations are generically expressed with muscular dystrophy, lipodystrophies, bone dysplasias, and cardiovascular disease, and, before that, they reported the case of a family with Chinese ancestors with three generations of heart disease, in which 100% of the relatives older than 40 years had the clinical manifestations. The cardiovascular disease shown by the carriers of this mutation consisted of arrhythmias, atrioventricular blocks and dilated cardiomyopathies. Part of these individuals died because of cardiovascular disease.23Hubert Pan et al.24 reported a group of 22 patients with CGL2, of which 86.4% had a family history of the disease. Most patients had the common metabolic signs associated with the pathology, such as diabetes mellitus, insulin resistance, acanthosis nigricans, hepatosplenomegaly, elevated fasting blood glucose and triglyceride levels and low HDL-cholesterol levels, which contributed to many patients being diagnosed with metabolic syndrome. On cardiovascular examination, part of the patients had arterial hypertension, 50% of the patients had left ventricular concentric hypertrophy and 4.5% had left ventricular eccentric hypertrophy, but all cases had normal patterns in both left ventricular systolic and diastolic function, when evaluated by conventional echocardiography.24In 2010, Rêgo et al.1 studied 44 patients with lipodystrophy, of whom 31 had CGL. The individuals were submitted to genotypic and phenotypic diagnoses, as well as cardiac morphological and geometric analysis. Of the 31 individuals with CGL, 18 had some degree of ventricular hypertrophy, although none of them had LV systolic dysfunction.1  and 5 control subjects with similar characteristics of age and body mass. Parameters such as total cholesterol levels and blood pressure were similar in both groups. Individuals with lipodystrophy, however, had low HDL cholesterol levels, high fasting blood glucose levels, three-fold higher circulating triglyceride content, and detection of pericardial adipose tissue by cardiovascular imaging methods  of lipodystrophy, was designed to elucidate the pathophysiological basis of myocardial aggression in this disease. Genetically modified mice with no gene for seipin, when compared to controls, showed left ventricular hypertrophy associated with both diastolic and systolic ventricular dysfunction. However, in contrast to what was suggested in other studies, they did not have cardiac triglyceride deposits, contradicting the hypothesis of myocardial lipotoxicity. However, myocardial changes induced in this model correlated with altered glucose metabolism. Based on the findings of this study, it cannot be confirmed that cardiac lipotoxicity is the pathophysiological mechanism involved with hypertrophy and ventricular dysfunction in this disease. But it is quite plausible that the metabolic alteration of glycemic control is indirectly related to transcription factors responsible for the regulation of pro-hypertrophic gene activation.27Published in 2017, the study by Joubert et. al.,Familial lipodystrophy is a rare condition where individuals show, besides metabolic and skeletal muscle changes, adipose tissue alterations, a type of cardiomyopathy. Cardiac changes commonly described in the literature, in case series, show a hypertrophic cardiomyopathy phenotype. The evolution to left ventricular systolic dysfunction can happen in a percentage of cases. There is not enough information to conclude on the frequency of cardiac functional impairment, such as the diastolic dysfunction type, or even incipient systolic changes.Still, despite the frequent association of congenital lipodystrophy and ventricular hypertrophy, the pathophysiological mechanisms remain unknown. Hypotheses that the altered glucose metabolism caused by the disease is responsible for activation of pro-hypertrophy genes could explain such association.