LV Diastolic Dysfunction Common in HGPS

Nancy A. Melville

March 28, 2018

Patients with Hutchinson-Gilford progeria syndrome (HGPS) show a high prevalence of left ventricular (LV) diastolic function abnormality on echocardiography, with dysfunction often starting early in life, suggest results from the largest cohort to date of patients with the highly rare, fatal disease.

"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," the authors reported.

"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."

The study provides important new insights of HGPS disease progression, first author, Ashwin Prakash, MD, from Boston Children's Hospital Department of Cardiology and Harvard Medical School in Massachusetts, told theheart.org | Medscape Cardiology.

"The clinical implication of the research is that these patients start showing diastolic dysfunction fairly early in life — by the age of 5 or 6 — and by the middle of the second decade almost all of them have it," he said.

"This is a new finding because until now, we thought that their hearts were not diseased until the last second decade. Now we know that we need to be looking at their diastolic function from very early on," he explained. "We can also use the diastolic function parameters as a marker for disease progression. Potentially, it may help us monitor the effects of the treatments we are using."

He cautioned, however, that "all this should be tempered by the fact that these findings are new, and we need to learn more about them as time goes on."

Premature Aging

HGPS, marked by features resembling premature aging, strikes early. Children typically die of heart disease within the first two decades of life, at an average age of 13 years.

Common clinical manifestations of the genetic disease range from extremely short stature, low body weight, and total alopecia to lipodystrophy, sclerodermoid skin, and stroke.

With so few cases in the world — a prevalence of just 1 in 20 million — information on the natural history of cardiovascular abnormalities is limited.

What is known from autopsy cardiovascular findings is that patients show a loss of vascular smooth muscle cells in large and small arteries with replacement by fibrous tissue, thickening and calcification of the aortic and mitral valves, and interstitial myocardial fibrosis and infarction.

For the new study, published February 21 in JAMA Cardiology, researchers with Boston Children's Hospital Department of Cardiology and Harvard Medical School enrolled 27 patients with clinically and genetically confirmed HGPS who were evaluated prospectively in single visits at Boston Children's Hospital from July 2014 through February 2016.

The patients, who had a median age of 5.6 years (range, 2 to 17 years) and were 56% male, were evaluated before entry into an open-label drug trial of protein farnesylation inhibitors.

Echocardiographic evaluation showed that LV diastolic dysfunction, defined as a tissue Doppler septal or lateral early velocity z score of less than −2 was the most prevalent abnormality, seen in 16 patients (59%).

Patients in all age groups showed diastolic dysfunction, with the prevalence increasing with age, consistent with normal aging, and indicators of LV diastolic function became more abnormal in older patients.

Older patients showed lower z scores for lateral and septal early velocities (r = −0.77 and r = −0.66, respectively; both P < .001) and higher ratios of early mitral inflow velocity to early diastolic tissue Doppler myocardial velocity (r = 0.80 and r = 0.72, respectively; both P < .001).

Other echocardiographic findings that were less common in the first decade and frequent in the second decade of life included LV hypertrophy (LVH) and valve disease.

None of the patients showed LV systolic dysfunction, and the LV ejection fraction was on average higher than normal. In addition, electrocardiographic abnormalities were rare and seen only in the second decade of life.

Despite the high rates of diastolic dysfunction, no patients had cardiac symptoms, congestive heart failure, documented arrhythmias, or myocardial infarction.

The study is the largest-to-date cohort of patients with HGPS to undergo comprehensive echocardiographic evaluation assessing for abnormalities in LV systolic and diastolic function, LVH, and LV valve abnormalities.

The largest prior report on patients with HGPS did not include assessment of diastolic function, the authors noted.

While the findings on LV diastolic dysfunction were surprising, they are consistent with normal aging, Prakash noted.

"It makes sense that in a premature aging disorder like progeria (HGPS), we should see diastolic dysfunction," he explained.

"However, it is nice to be able to actually prove it, because progeria is similar to aging, but not exactly like it."

Cardiac output and LV volumes are linearly associated with body surface area (BSA) in healthy children, therefore, the significantly lower fat and low body mass index measures in children with HGPS would seem to result in higher BSA-corrected cardiac output and subsequently higher than normal LV volume z scores, the authors explained.

But importantly, LV mass z scores remained higher than normal even after correcting for the confounding effect of body composition, the authors noted.

This finding "suggests that elevated LV mass observed in patients with HGPS is independent of body composition abnormalities," they write.

Systemic hypertension, known to be linked with diastolic LV dysfunction, was indeed common in the group, but the two were not significantly associated in the study.

Speculating on other factors playing a role in the pathogenesis of cardiac disease in HGPS, the authors suggested diffuse myocardial fibrosis, endocardial fibrosis, or subclinical coronary ischemia may be involved.

"Prior pathologic case reports found myocardial interstitial fibrosis and endocardial thickening, both of which could contribute to diastolic dysfunction," they write.

Meanwhile, the findings highlight a potentially important new marker in the management of HGPS.

"The identification of LV diastolic dysfunction as an early abnormality in patients with HGPS raises the possibility of its use as a noninvasive marker to assess progression of disease and response to therapy in future studies," the authors said.

Useful Marker?

In an editorial published with the study, Diane Fatkin, MD, from the Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia, notes that to be a useful marker, LV diastolic dysfunction would need to be more definitively associated with disease severity.

"The rationale for this strategy would be somewhat stronger if LV diastolic dysfunction was established to be a general marker of overall disease severity and not a potentially nonfatal, albeit frequent, complication of the disease," she writes.

"A related question is why all patients with HGPS with the p.Gly608Gly LMNA variant don't exhibit LV diastolic defects and how these phenotype-negative individuals might be assessed in clinical trials."

Conversely, while LMNA mutations are linked to systolic dysfunction, that also wasn't seen, Fatkin said in commenting on the study for theheart.org | Medscape Cardiology.

"LMNA mutations are an important cause of LV systolic dysfunction (and dilated cardiomyopathy), but none of the patients studied here had systolic defects."

In addition, "LV diastolic dysfunction in older patient populations could cause heart failure with preserved ejection fraction and/or atrial arrhythmias, but this was not seen in the HGPS patients, potentially due to their young age and early death from other causes."

"Hence, the clinical impact of the diastolic defects is uncertain," Fatkin said.

She added that the study provides important insights extending beyond HGPS for people with LV diastolic defects.

"The main point here is that understanding the cause of LV diastolic dysfunction could be very useful not only for the HGPS patients, but also for the large numbers of older people who have LV diastolic defects, as this might lead to new strategies to treat or prevent diastolic dysfunction and its consequences."

Particularly intriguing is the potential role of the cardiomyocyte nucleus, Fatkin said.

"It is unclear why defects in a nuclear lamina protein could result in LV diastolic defects, but it is intriguing to speculate that the cardiomyocyte nucleus might have a central role in sensing and coordinating responses to mechanical stress perturbations within cells."

Prakash said research is ongoing to gain further understanding of the disease — and potential treatments.

"Regarding future plans for these patients, the most important next step is to get data on longitudinal follow-up," he said.

"We are already working on that, and most of these patients have returned for a follow-up visit. Stay tuned for those results in the next year or so. There are also other drug trials planned."

The study was supported by grants the Progeria Research Foundation; the National Heart, Lung, and Blood Institute; and 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). The authors and Fatkin had no disclosures to report.

JAMA Cardiol. Published February 21, 2018. Abstract, Editorial

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