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People genetically predisposed to hypertrophic cardiomyopathy (HCM) could slow down their disease progression by taking an inexpensive, widely available medication, the VANISH trial suggested.

Among asymptomatic young individuals harboring pathogenic sarcomeric gene variants, those randomized to valsartan showed better overall cardiac structure at 24 months compared with peers getting placebo (adjusted mean change of composite Z-score +0.136 vs -0.095, adjusted P=0.001), according to Carolyn Ho, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston.

The benefit of the angiotensin receptor blocker (ARB) was driven by significant improvements in NT-proBNP, LV end diastolic volume index, and E' velocity, Ho told the audience during a late-breaking scientific session at this year's .

"The VANISH trial suggests there is an opportunity to attenuate disease progression in sarcomeric HCM with a widely available and well-tolerated medication," she concluded.

Moreover, study participants with a baseline left ventricular (LV) wall thickness below the median were the ones who derived the most benefit (P=0.04 for interaction).

"This supports the hypothesis that disease-modifying therapy may be most effective if given early in disease and to individuals with less pronounced remodeling," Ho said.

She noted that early manifestations of sarcomeric HCM are marked by profibrotic genetic pathways centered around transforming growth factor (TGF)-β activation. Over time -- with age, lifestyle, genetic modifiers, and other comorbidities -- this can progress to clinically overt HCM.

"I really like the fact than an inexpensive, generic, familiar medication such as an ARB was able to have an effect. But is an ARB the best way to inhibit TGF-beta?" asked panelist Lars Lund, MD, PhD, of Karolinska Institute in Sweden, during the ESC session discussion.

Ho acknowledged that this question cannot be answered for the time being: "It's the most available and the easiest reach in terms of being safe and well known. It's not what the ARBs were designed for. There are certainly more potent TGF-β inhibitors, but none to my knowledge currently in clinical review. They're largely in development," she said.

"It's been a big challenge for the field trying to find these specific TGF-β inhibitors that have tissue-specific effects but not wider effects, given the wide variety of functions that TGF-β performs," she added.

was a phase II, double-blind trial that included asymptomatic children and adults classified as having New York Heart Association (NYHA) Class I or II symptoms. All were required to have a pathogenic (or likely pathogenic) sarcomeric variant and non-obstructive physiology. A small proportion of participants were taking beta-blockers and even fewer were on calcium channel blockers. None were on mineralocorticoid receptor antagonists, according to Ho.

After an active run-in period that titrated adults to 320 mg/d of valsartan (and children to lower doses according to weight), 178 patients were randomized to valsartan or placebo for the primary analysis.

Mean age was 23 years, and 39% of the cohort were women. White people represented nearly all participants. Over 90% of people were categorized as NYHA Class I.

The valsartan and placebo groups were fairly well balanced, with the exception of the former having a slightly larger maximal LV wall thickness at baseline.

In line with valsartan's safety profile, the results showed that people receiving the ARB in VANISH had no excess adverse events, and there were no instances of hypotension, hyperkalemia, or renal insufficiency either, Ho added.

She explained that her group opted to show moderate effects of valsartan in nine metrics of cardiac structure (e.g., markers of myocardial injury and stress, cardiac morphology, and cardiac function on echocardiography) given that the study couldn't feasibly detect a large clinical benefit.

Lund said he liked this nine-metric component endpoint since it is difficult to have conventional endpoints in such a difficult syndrome with a long disease progression.

Another ESC panelist, Mitja Lainscak, MD, PhD, of General Hospital Murska Sobota in Slovenia, asked why the VANISH investigators didn't consider antifibrotic markers in their composite endpoint.

"Fibrosis is for sure a very interesting and important component of HCM. It's just hard to interrogate in the early stages," Ho replied.

"Younger patients tend to be less likely to have late gadolinium enhancement [LGE], and we weren't able to perform [cardiac MRIs] on all our trial participants because of preexisting primary prevention [implantable cardioverter-defibrillators] or other issues. We were skeptical as to whether we would be able to see regression of LGE," she explained.

She noted that cardiac MRI substudies of VANISH are currently in progress.

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