In this cross-sectional analysis, each data point represents a unique patient. E indicates early mitral inflow velocity; E’, early diastolic tissue Doppler myocardial velocity.
eTable. Lipid Profile and Glucose Metabolism
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Prakash A, Gordon LB, Kleinman ME, et al. Cardiac Abnormalities in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA Cardiol. 2018;3(4):326–334. doi:10.1001/jamacardio.2017.5235
What is the natural history of cardiac disease in children with Hutchinson-Gilford progeria syndrome, an ultrarare premature aging disorder?
In this case-series study of 27 patients with Hutchinson-Gilford progeria syndrome, diastolic dysfunction was the most prevalent cardiac abnormality, appearing early in life with age-related decline, a finding mirroring those seen with normal aging. Other abnormalities, such as valve dysfunction and left ventricular hypertrophy, were less prevalent and appeared during the second decade of life.
Diastolic dysfunction was the most prevalent cardiac abnormality in patients with Hutchinson-Gilford progeria syndrome and may be a potential end point in future clinical trials.
Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare disorder associated with premature death due to cardiovascular events during the second decade of life. However, because of its rarity (107 identified living patients), the natural history of cardiac disease remains uncharacterized. Therefore, meaningful cardiac end points for clinical trials have been difficult to establish.
To examine the course of appearance of cardiac abnormalities in patients with HGPS to identify meaningful cardiac end points for use in future clinical trials.
Design, Setting, and Participants
In this prospective, cross-sectional, observational study, 27 consecutive patients with clinically and genetically confirmed classic HGPS were evaluated at a single center for 1 visit from July 1, 2014, through February 29, 2016, before initiation of treatment.
Main Outcomes and Measures
Echocardiography was used to assess ventricular and valve function using standard techniques. Diastolic left ventricular (LV) function was assessed using tissue Doppler imaging. Previously published normative data were used to adjust findings to age and body size.
This study included 27 patients (median age, 5.6 years; age range, 2-17 years; 15 [56%] male). Among echocardiographic indicators, LV diastolic dysfunction, defined as a tissue Doppler septal or lateral early velocity z score less than −2, was the most prevalent abnormality, seen in 16 patients (59%). Diastolic dysfunction was seen in all age groups, and its prevalence increased with age, mirroring findings seen during normal aging. Indicators of LV diastolic function were more abnormal in older patients. The z scores for lateral and septal early velocities were lower (r = −0.77, P < .001; and r = −0.66, P < .001, respectively), whereas those for the ratio of early mitral inflow velocity to early diastolic tissue Doppler myocardial velocity were higher (r = 0.80, P < .001; and r = 0.72, P < .001, respectively) in older patients. Other echocardiographic findings, including LV hypertrophy, LV systolic dysfunction, and valve disease, were less prevalent in the first decade and were seen more frequently in the second decade.
Conclusions and Relevance
In this largest-to-date cohort of patients with HGPS, LV diastolic dysfunction was the most prevalent echocardiographic abnormality and its prevalence increased with aging. Echocardiographic indicators of LV diastolic function may be useful end points in future clinical trials in this patient population.
Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, sporadic, autosomal dominant, segmental, premature aging disease with a prevalence of 1 in 20 million.1 The disorder occurs because of aberrant splicing of the LMNA gene (OMIM 150330) resulting in accumulation of a permanently farnesylated, uncleaved lamin A isoform called progerin.2,3 Accumulation of progerin causes abnormalities in nuclear morphologic features and function as well as cellular stiffening.4,5 Clinical manifestations include extreme short stature, low body weight, total alopecia, lipodystrophy, sclerodermoid skin, decreased joint mobility, skeletal dysplasia, and strokes.6 Premature death usually occurs in the second decade of life after premature atherosclerosis leads to myocardial infarction.6 Cardiovascular findings at autopsy include loss of vascular smooth muscle cells in large and small arteries with replacement by fibrous tissue,7,8 thickening and calcification of the aortic and mitral valves,9 and interstitial myocardial fibrosis and infarction.9 However, because of the rarity of the condition (107 known living patients worldwide), limited information is available regarding the natural history of cardiovascular abnormalities.10 Therefore, meaningful cardiac end points for clinical trials have been difficult to establish. Echocardiography is a widely available noninvasive technique that can accurately identify anatomical and functional cardiac abnormalities in children.11,12 We performed a cross-sectional study of the largest-to-date cohort of children with HGPS to examine the prevalence and natural history of cardiac abnormalities to identify indicators that may serve as end points in future clinical trials.
Patients with clinically and genetically confirmed c.1824 C>T, p. Gly608Gly classic HGPS who enrolled in a clinical trial at Boston Children’s Hospital were evaluated prospectively at a single visit from July 1, 2014, through February 29, 2016. All reported data were obtained at the baseline visit, before initiation of treatment with the protein farnesylation inhibitor lonafarnib. All patients had not previously received treatment at evaluation. Patients with nonclassic forms of progeria were excluded. Written informed consent was obtained from parents, and all data were deidentified. The study was approved by Boston Children’s Hospital’s Committee on Clinical Investigation.
Transthoracic echocardiography was performed using commercial scanners (iE33, Philips Healthcare) and standard imaging techniques recommended by the American Society of Echocardiography.13,14 Left ventricular (LV) volumes and mass were quantified using the area-length method as recommended by the American Society of Echocardiography.13 Body surface area (BSA) was calculated using the Haycock formula,15 and LV volume and mass were adjusted to the BSA by calculating z scores using previously published normative data from the echocardiography laboratory at Boston Children’s Hospital.16,17
Mitral valve inflow velocity during early (E) and late (A) diastole were measured using pulsed wave Doppler imaging, and the E/A velocity ratio was calculated. Pulsed wave tissue Doppler evaluation of LV diastolic function was performed by measuring the lateral and septal early (E′) and late (A′) diastolic myocardial velocities. The E:E′ and E′:A′ velocity ratios were calculated using standard guidelines13,18 and were adjusted for age by using published normative data from our echocardiography laboratory to calculate z scores for each value.16,17 Patients with a septal or lateral E′ velocity z score less than −2 were classified as having LV diastolic dysfunction.
The mitral valve and aortic valves were assessed from apical 4-chamber and parasternal long- and short-axis views using standard techniques.14 A qualitative assessment for valve calcification was performed based on increased echogenicity visible from multiple imaging planes. Mitral and aortic regurgitation were graded semiquantitatively as mild, moderate, or severe, as previously described.14,19 Patients with a mitral valve mean inflow pressure gradient greater than 3 mm Hg measured using continuous wave Doppler imaging were classified as having mitral stenosis. Aortic stenosis was defined as a maximum instantaneous pressure gradient greater than 15 mm Hg measured using continuous wave Doppler imaging.
Twelve-lead electrocardiography was performed using a standard technique. Heart rate z scores were calculated using normative data from our laboratory.17 Electrocardiographic intervals were corrected for heart rate using the Bazett formula.20
Blood pressure (BP) was recorded in both arms after 5 minutes of rest with the patient seated with feet flat on the floor using a standard auscultation technique and size-appropriate cuffs.21 The BP measurements were taken twice in the arm, with the higher initial systolic BP reading and the mean of the 3 measurements in this arm used for final analysis. To account for the severe growth restriction in this patient population, height-age was substituted for chronologic age while calculating age- and sex-specific BP percentiles.22 As previously described, height-age was determined by calculating the median age in the general population of a child with the height of each patient with HGPS using the US Centers for Disease Control and Prevention sex-specific pediatric growth charts (http://www.cdc.gov/growthcharts/cdc_charts.htm).22 Similar to a prior report23 of patients with HGPS, for height-age calculations, segmental whole-body length was used instead of standing height, because joint contractures inherent to HGPS can result in an underestimation of true height. Patients who satisfied standard pediatric criteria (for patients <18 years of age, systolic and/or diastolic BP≥95th percentile for age, sex, and height-age) were classified as being hypertensive.21 Carotid-femoral pulse wave velocity (CFPWV) was determined using a previously described ultrasound technique.22,24
The statistical significance of differences between continuously distributed indicators was assessed using the Wilcoxon rank sum test. Associations between outcome and indicator variables were examined using simple linear regression and multivariable linear regression to adjust for potential confounders. The statistical significance level was set at P < .05 (2-sided). Statistical analysis was performed using SAS software, version 9.4 or higher (SAS Institute Inc).
Characteristics of the 27 study patients (median age, 5.6 years; age range, 2-17 years; 15 [56%] male) are given in Table 1. Patients were evaluated before entry into an open-label drug trial of protein farnesylation inhibitors. Of 29 screened patients, 2 were excluded: one was ineligible for therapy because of liver dysfunction, and the other was excluded because of technical reasons. As previously reported,25 patients demonstrated severe growth failure with severe reduction in weight-for-age, height-for-age, and weight-for-height z scores and a reduced body mass index (BMI), findings suggesting that their body composition included a higher proportion of lean body mass compared with healthy individuals. Systemic hypertension was common, as previously reported.22 With use of height-age to calculate BP percentiles, 13 of 26 patients (50%) were hypertensive.
Metabolic profiles were similar to those in a prior report.22 As seen in the eTable in the Supplement, 13 patients (48%) had hyperinsulinemia, and 9 (33%) were insulin resistant. Lipid abnormalities were notable for abnormally low high-density lipoprotein cholesterol level in 17 (63%).
Echocardiographic indicators of LV size, function, and mass are summarized in Table 2. Compared with normative data from our laboratory, z scores for LV end-diastolic volume, end-systolic volume, mass, mass to volume ratio, and ejection fraction were elevated. Because of the unusual body habitus, characterized by low BMI and weight-for-height z scores, we repeated these analyses using ideal body weight instead of actual body weight to calculate the BSA. We found that these adjusted z scores for LV size and mass were closer to normal values. Systolic dysfunction, defined as an LV ejection fraction less than 55%, was not seen in any patient. Left ventricular hypertrophy (LVH), defined as both LV mass and LV mass-to-volume z scores greater than 2, was present in 7 patients (25%). The presence of LVH was associated with older age at evaluation but not with sex, systemic hypertension, or CFPWV.
As indicated in Table 3, all echocardiographic indicators of diastolic LV function were abnormal compared with normative values from the echocardiography laboratory at Boston Children’s Hospital. Left ventricular diastolic function indicators are insensitive to body composition; therefore, these z scores were not recalculated using ideal body weight.17 Left ventricular diastolic dysfunction, defined as a tissue Doppler septal or lateral E′ velocity z score less than 2, was present in 16 patients (59%), and its prevalence steadily increased with age (Table 4). As seen in the Figure, LV diastolic function indicators were worse in older patients. Specifically, z scores for lateral and septal E’ velocities were lower (r = −0.77, P < .001; and r = −0.66, P < .001, respectively), whereas those for the E:E′ ratio were higher in older patients (r = 0.80, P < .001; and r = 0.72, P < .001, respectively). Diastolic indicators were not significantly different between hypertensive and normotensive patients.
As indicated in Table 4, the most common mitral valve abnormalities were annular and chordal calcification, occurring in roughly one-fourth of patients. Significant mitral stenosis and regurgitation were less common. As indicated in Table 4, the prevalence of mitral valve abnormalities was higher in older patients.
As indicated in Table 4, annular calcification was the most common abnormality, occurring in more than one-third of patients. Valvar aortic stenosis and regurgitation were less common. As seen in Table 4, the prevalence of aortic valve abnormalities was higher in older patients.
Assessed qualitatively, an unusually increased echo brightness of the aortic root wall was noted in 19 of the 27 patients (70%). Patients with an abnormally bright aortic root had lower lateral and septal E’ velocity z scores and higher lateral and septal E:E′ velocity z scores. Aortic root brightness was not associated with age.
The results of 12-lead electrocardiography were normal in 25 patients (93%). One 12-year-old patient’s electrocardiogram showed LVH, biatrial enlargement, and right axis deviation. Echocardiography revealed aortic and mitral stenosis and LVH. A 16-year-old patient’s electrocardiogram showed LVH with strain. Echocardiography showed LVH.
Among electrocardiographic measurements, heart rate was elevated for age (median z score, 1.8; range, 0.17-3.07), but the z score did not vary with age. The PR, QRS, and QT intervals (all corrected for heart rate) did not vary with age.
As reported previously,22,26 CFPWV was elevated compared with prior published normative values in children (median, 9.1 m/s; range, 7.3-13.0 m/s). A higher CFPWV was associated with a lower lateral E′ z score (r = −0.41, P = .05). No associations were found between CFPWV and other indicators of diastolic LV function or with LVH.
As indicated in Table 4, all patients were asymptomatic, and none had documented cardiac arrhythmia, congestive heart failure, or myocardial infarction.
In this cohort of patients with HGPS, representing approximately 25% of the world’s population with HGPS, we found that LV diastolic dysfunction was the most prevalent echocardiographic abnormality, seen in all age groups, but its prevalence increased with age. Other cardiac abnormalities, including mitral and aortic valve stenosis or regurgitation and LVH, were less common and seen only during the second decade of life.
Although cardiovascular disease is the most frequent cause of death in patients with HGPS, studying the course of cardiac abnormalities in HGPS has been difficult because of the rarity of the syndrome (prevalence of 1 in 20 million living individuals).1 Until recently, description of the phenotype has relied on the review of isolated case reports.6,9 A more recent prospective report included 15 patients, most during the first decade of life, but did not include assessment of diastolic LV function.10 Our study includes the largest-to-date cohort that underwent comprehensive echocardiographic evaluation to assess for abnormalities in LV systolic and diastolic function, LVH, and LV valve abnormalities.
The BSA-adjusted end-diastolic and end-systolic LV volumes were elevated in patients with HGPS compared with normative data from our laboratory. Left ventricular volume measurements in patients with HGPS have not been previously reported. It has been previously reported that cardiac output and LV volumes in healthy children are linearly related to BSA.16 These associations assume a normal body composition and BMI. Patients with HGPS have a markedly abnormal body composition, with reduced subcutaneous and visceral fat and low BMI values. As a result, the proportion of lean body mass to less metabolically active fatty tissue in patients with HGPS is higher compared with that in healthy children. Therefore, it may be expected that BSA-corrected cardiac output would be higher in patients with HGPS and could be responsible for the higher than normal LV volume z scores in our study. The confounding effect of body composition is supported by our finding that when ideal body weight was used to calculate BSA, LV volume z scores were similar to normative values. However, LV mass z scores remained significantly higher than normative values despite this correction, suggesting that elevated LV mass observed in patients with HGPS is independent of body composition abnormalities.
No patients had LV systolic dysfunction. The LV ejection fraction was on average higher than normal in our cohort, consistent with a prior report.10
In contrast to normal systolic function in most patients, LV diastolic dysfunction was highly prevalent, with a higher prevalence in older patients. Although this finding is not surprising in the context of a premature aging disorder, it had not been previously reported; therefore, the course and severity of abnormalities were not known. The largest previous report10 of patients with HGPS did not include assessment of diastolic function. The inverse association between age and diastolic tissue Doppler velocities observed in our cohort mirrors the changes seen during the normal process of aging.27,28 However, the pathogenesis of LV diastolic dysfunction in HGPS remains unknown. Systemic hypertension is known to be associated with diastolic LV dysfunction. In our cohort, although hypertension and diastolic dysfunction were common, they were not significantly associated. It could be speculated that diffuse myocardial fibrosis, endocardial fibrosis, or subclinical coronary ischemia may play a role in the pathogenesis of cardiac disease in HGPS. Prior pathologic case reports found myocardial interstitial fibrosis6 and endocardial thickening,8 both of which could contribute to diastolic dysfunction. In the future, quantification of myocardial extracellular volume fraction by cardiac magnetic resonance may help evaluate the role of diffuse fibrosis in the etiology of diastolic dysfunction.29-31 The identification of LV diastolic dysfunction as an early abnormality in patients with HGPS raises the possibility of its use as an noninvasive marker to assess progression of disease and response to therapy in future studies.
The most common valve abnormalities were calcification involving the mitral valve annulus and chords and the aortic valve annulus. These findings were most prevalent in the second decade of life. Similarly, valve dysfunction, including stenosis or regurgitation, was late and seen only in the second decade of life. These findings are similar to those reported by Merideth et al10 in a smaller cohort.
Electrocardiographic abnormalities were rare in our cohort and were seen only during the second decade of life. In contrast to a prior report,32 we did not find significant repolarization abnormalities. In the prior report,32 several patients with repolarization abnormalities had T-wave inversion in the right precordial leads, which is a normal finding in children. Misclassification of this normal finding likely led to an overestimation of abnormalities. It is also possible that some of the older patients in the prior report32 with ST-T–wave abnormalities had hemodynamically significant valve disease, resulting in pressure and/or volume overload of the left ventricle, contributing to the echocardiographic abnormalities. In our cohort, the prevalence of hemodynamically significant valve disease was low. Furthermore, in contrast to the bradycardia and PR, QRS, and QTc prolongation reported in progeroid mice, the patients in our cohort had higher than average heart rates, normal electrocardiographic intervals, and no documented arrhythmia. Given the discrepancy between preclinical and clinical data, this area deserves further investigation.
Despite a high prevalence of diastolic dysfunction and a small but significant number of patients with mitral and/or aortic valve abnormalities, no patients reported cardiac symptoms, congestive heart failure, documented arrhythmias, or myocardial infarction. However, further longitudinal research is needed to determine whether some patients develop symptoms with further progression of valve disease or with development of coronary artery disease.
We subjectively found an unusually high level of echo brightness of the aortic root wall in a subset of patients with HGPS compared with pediatric and adult patients without HGPS. In our cohort, patients with HGPS with increased wall brightness were more likely to have features of diastolic LV dysfunction. The significance of this observation is unclear but may relate to pathologic findings that describe prominent thickening of the aortic adventitial layer.8 Increased carotid artery echo brightness demonstrated by ultrasonography in HGPS also suggests a more diffuse vascular pathologic finding.22 Future studies that use quantitative methods to assess aortic root wall brightness and correlation with pathologic observations may provide greater insight into the significance of this finding.
As previously shown, aortic stiffness assessed using CFPWV measurements was increased in this HGPS cohort. We found an association between higher CFPWV and lateral E’ velocity z score but not with other indicators of diastolic LV function. Although the association is relatively weak, it is consistent with a previously reported association between progressive ventricular and arterial stiffening during the process of normal aging.33 This association requires further investigation during longitudinal follow-up of these patients.
Several limitations of the current study are worth considering. Although we report data on the largest-to-date cohort of patients with HGPS (representing approximately 25% of the world’s population with HGPS), our analyses remain limited by the small sample size inherent in the rarity of this condition. However, because of the small number of patients worldwide, larger studies may not be feasible to conduct. The cross-sectional study design has inherent limitations. In the future, we plan to report longitudinal data from these patients to address these limitations. Because of radiation and procedural risks, our study did not include cardiac catheterization to assess coronary artery stenosis or calcification. The assessment of diastolic dysfunction was based on tissue Doppler techniques, and invasive confirmation of abnormal diastolic compliance was not possible because of ethical considerations. However, the use of tissue Doppler echocardiography for assessment of LV diastolic function is well established. We did not measure other indicators of diastolic function, such as strain and left atrial size, because of the lack of adequate normative data.
In this largest-to-date cohort of patients with HGPS, LV diastolic function was the most prevalent cardiac abnormality, appearing early and affecting almost all patients older than 6 years. Other cardiac abnormalities, including valve abnormalities, were less common and appeared during the second decade of life. Echocardiographic indicators of LV diastolic dysfunction may be useful end points in future clinical trials.
Accepted for Publication: December 4, 2017.
Corresponding Author: Ashwin Prakash, MD, Department of Cardiology, Boston Children’s Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115 (email@example.com).
Published Online: February 21, 2018. doi:10.1001/jamacardio.2017.5235
Author Contributions: Drs Prakash and Gordon had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Prakash, Gordon, Kleinman, D'Agostino, Kieran, Gerhard-Herman, Smoot.
Acquisition, analysis, or interpretation of data: Prakash, Gurary, Massaro, D'Agostino, Smoot.
Drafting of the manuscript: Prakash, Gordon, D'Agostino, Gerhard-Herman.
Critical revision of the manuscript for important intellectual content: Prakash, Gordon, Kleinman, Gurary, Massaro, D'Agostino, Kieran, Smoot.
Statistical analysis: Gurary, Massaro, D'Agostino.
Obtained funding: Gordon, Kieran, Smoot.
Administrative, technical, or material support: Gordon, Kleinman, Kieran, Gerhard-Herman.
Supervision: Prakash, Gordon, Kieran, Smoot.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Prakash reported receiving grants from the Progeria Research Foundation; the National Heart, Lung, and Blood Institute; and the Harvard Clinical and Translational Science Center and other support from Merck Pharmaceuticals during the conduct of the study. Dr Gordon reported receiving support from Boston Children's Hospital during the conduct of the study. Dr Kleinman reported receiving grants from the Progeria Research Foundation and Novartis during the conduct of the study and nonfinancial support from Novartis, Merck, and Eiger Pharmaceuticals outside the submitted work. Dr Massaro reported receiving personal fees from the Progeria Research Foundation during the conduct of the study. Merck Pharmaceuticals supplied the lonafarnib used in the trial. Dr Gordon is the mother of a child with HGPS who participated in this study. No other disclosures were reported.
Funding/Support: This study was supported by grants PRFCLIN2007-02 and PRFCLIN2009-03 from the Progeria Research Foundation (Dr Kieran); grant 1RC2HL101631-0 from the National Heart, Lung, and Blood Institute (Dr Kieran); and grant UL1 TR001102 from the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award).
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We are grateful to the children with progeria who participated in this study and their families. We thank Kyra Johnson, BS (Progeria Research Foundation, Peabody, Massachusetts), for travel and lodging coordination and the Family Inn (Cambridge, Massachusetts) and Devon Nicole House (Boston, Massachusetts) for housing families. Ms Johnson was compensated for her work.