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Observational Study
. 2018 Apr 1;3(4):326-334.
doi: 10.1001/jamacardio.2017.5235.

Cardiac Abnormalities in Patients With Hutchinson-Gilford Progeria Syndrome

Ashwin Prakash  1   2 , Leslie B Gordon  3   4 , Monica E Kleinman  3   5 , Ellen B Gurary  6 , Joseph Massaro  6 , Ralph D'Agostino Sr  6 , Mark W Kieran  7 , Marie Gerhard-Herman  8 , Leslie Smoot  1   2
Affiliations
Observational Study

Cardiac Abnormalities in Patients With Hutchinson-Gilford Progeria Syndrome

Ashwin Prakash et al. JAMA Cardiol. .

Abstract

Importance: 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.

Objective: 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.

Exposure: Classic HGPS.

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.

Results: 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.

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Conflict of interest statement

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.

Figures

Figure.
Figure.. Association Between Tissue Doppler Indicators of Diastolic Left Ventricular Function and Age
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.
See this image and copyright information in PMC

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References

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