ESC Hot Comment丨Professor Ma Aiqun's interpretation of VANISH: HCM treatment strategy transformation-early intervention

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Editor's note: 2021 European Society of Cardiology (ESC) Annual Meeting Late Breaking Science in Heart Failure announced three latest scientific studies. This journal specially invites the team of Professor Ma Aiqun from the Department of Cardiology, the First Affiliated Hospital of Xi’an Jiaotong University, to comment on the topic and learn in-depth with you.

One research background

Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary cardiomyopathy, with an incidence of about 1/500 ^[1] , with obvious genetic tendency ^[2] Most of the inheritance is autosomal dominant. At present, more than 1500 mutations in at least 29 genes have been found to cause HCM ^[3] , most of which are located on the gene encoding sarcomere structural protein ^[4] can cause left ventricular hypertrophy (LVH), myocardial fibrosis, etc., increase the risk of heart failure, atrial fibrillation and sudden cardiac death. The penetrance and phenotype of sarcomere gene mutations are highly heterogeneous and age-dependent, and are often difficult to diagnose in the early stages of HCM disease. With the advancement of genetic testing technology, HCM high-risk sarcomere gene mutations can be identified early before clinical symptoms and irreversible changes in the myocardium occur.

Animal experiments show that the activation of transforming growth factor β (TGF-β) plays an important role in the early pathogenesis of HCM ^[5] ,The binding of angiotensin Ⅱ and its type 1 receptor can activate typical and atypical TGF-β signal transduction pathways, stimulate collagen synthesis and inhibit collagen degradation ^[6] , ARB can inhibit angiotensin Ⅱ and its type 1 Receptor binding inhibits TGF-β from activating ^[2] , thereby inhibiting the progression of HCM disease ^[7] (Figure 1). Before the emergence of LVH, ARB treatment can slow down the progression of LVH and fibrosis .

Figure 1 Model of HCM caused by sarcomere gene mutations and the potential impact of ARB on it

In the early stage of HCM disease, sarcomeric gene mutations increase contractility and calcium sensitivity, that is, the pathways that promote fibrosis before myocardial hypertrophy occurs Activated, abnormally activated TGF-β signaling pathway, leading to myocardial hypertrophy and fibrosis, while ARB can inhibit TGF-β activation and slow down the progression of LVH and fibrosis

previous ARB clinical trials are all For adult patients with confirmed HCM, no obvious clinical benefit was found ^[8-13] . Can early application of ARB be clinically beneficial?

VANISH trial purpose: aims to verify whether ARB can slow the progression of HCM in patients with HCM with sarcomere gene mutations in the early stage of disease without LVH or obvious clinical symptoms.

Two research methods

The VANISH study is a multi-center, randomized, placebo-controlled, double-blind clinical trial. The included patients all carry HCM-causing or possibly pathogenic sarcomere gene mutations, and there are two cohorts, namely the main analysis cohort (HCM early disease stage) and the exploratory cohort (HCM preclinical stage).

The main analysis cohort: consists of 8 to 45-year-old muscular segment gene mutation carriers,Accompanied by LVH, asymptomatic or mild symptoms (NYHA I-II), it is the early stage of the disease.

exploratory cohort: consists of 10 to 25-year-old sarcomere gene mutation carriers, the subject's left ventricular wall thickness is normal (HCM not diagnosed), but accompanied by impaired diastolic function (tissue Doppler E Peak rate reduction), abnormal ECG (Q wave or ST segment change), etc.

Subjects in the two cohorts were randomly divided into valsartan group (80-320mg/d, dose depends on age and body weight) and placebo group, treated for 24 months; the primary endpoint is to reflect myocardial structure, function and injury / Stress and other aspects of 9 different detection indicators.

The specific inclusion and exclusion criteria are shown in Table 1, and the specific experimental design and experimental plan are shown in Figure 2.

Table 1 Inclusion and exclusion criteria

Figure 2 Experimental design and protocol

Three study results

1, A total of 212 subjects with an average age of 22.2±9.7 years, female 40.6 %, NYHA Ⅰ level accounted for 93.4%. Among them, 178 (84%) with LVH were included in the main analysis cohort, and 34 (16%) with normal left ventricular wall thickness were included in the exploratory cohort. The baseline data of the two groups of subjects are shown in Table 2;

Table 2 The baseline data of the two groups

2, In the main analysis cohort, valsartan improved the primary endpoint of the patient compared with placebo. There are statistics Significance ( P = 0.001) (Table 3);

3, Compared with placebo, valsartan has an effect on subjects’ NT-proBNP level, tissue Doppler peak E velocity, and left ventricular end-diastole Volume has the greatest impact ( P =0.025, 0.017, 0.047) (Table 3);

Table 3 Comparison of primary endpoint results

4. Valsartan is safe and well tolerated.No adverse events (Figure 3);

Figure 3 The safety of valsartan

5. Compared with previous HCM clinical trials, all subjects in the VANISH trial carried pathogenic or may be pathogenic The sarcomere gene mutation is ’s first trial to include preclinical HCM (no LVH) subjects, and is also ’s first HCM trial to include children and adolescents, , and its number of subjects is even greater. Many and come from many countries and centers, and the research time is longer.

Interpretation of four studies

"China Cardiovascular Health and Disease Report 2020 Summary" ^[14] shows that the crude rate of HCM in the Chinese population is 0.16%, and there are more than 1 million adult HCM patients ^[15] , my country The annual incidence of cardiovascular death in HCM patients is about 1.7% ^[16] , which is the most common cause of sudden cardiac death in patients under 35 years of age. HCM is already a common cardiovascular disease that endangers the health of Chinese residents.

HCM is a progressively developing disease. It is not easy to be diagnosed before the relevant signs and symptoms appear, but genetic testing technology can identify it early. Vigorously promoting genetic testing of HCM patients and their blood relatives is an effective way to improve the early diagnosis rate of HCM Method is also an important prerequisite for HCM prevention and treatment.

Can drug treatment slow down the progression of HCM or improve its clinical outcome? Which treatment is more effective? It is a problem that has plagued the clinic for many years and needs to be solved urgently.

VANISH test confirmed for the first time that ARB is used in the early stages of HCM carrying pathogenic or possibly disease-causing sarcomere gene mutations, which can slow down the progression of HCM and promote the improvement of its condition not only answers that early treatment can Slow down the progress of HCM and may improve its clinical outcome,It also provides an important theoretical basis for the prevention and treatment of HCM, especially early diagnosis and early treatment.

But are other drugs such as beta blocker , calcium antagonists that mainly act on the heart, other RAS system antagonists, etc. effective? Which method is better? do not know yet.

VANISH is currently the first HCM trial involving children and adolescents of HCM, providing an early and effective treatment option for HCM young patients. It must be emphasized that the results of this test are from patients with asymptomatic or mild symptoms in the early stage of HCM. It is not clear whether this result can be extended to people with clinical symptoms of HCM.

Limitations of the trial: First, the evolution of HCM pathophysiology usually takes years to decades, requiring long-term follow-up of a large number of patients, while the trial is currently followed up for only 2 years and the number of subjects is small, with an average age Smaller, the expected end-point event results may be biased; secondly, the main end point of the trial is 9 clinical indicators that reflect cardiac structure and function, but its relationship with the clinical prognosis of HCM is still unclear; thirdly, the goal of valsartan It is difficult to choose the effective dose. The theoretical basis of the experimental research comes from animal experiments, and it is difficult to convert the effective dose into the effective dose required by humans. Therefore, we look forward to a more comprehensive and longer follow-up study in the later stage of the trial, to observe the long-term effects of its treatment, and to observe more clinical indicators and primary endpoint events.

▼References

1.Maron, BJ; Gardin, JM; Flack, JM; Gidding, SS; Kurosaki, TT; Bild, DE, Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation 1995, 92 (4), 785-9.

2.Alfares, AA; Kelly, MA; McDermott, G.; Funke, BH ; Lebo, MS; Baxter, SB; Shen, J.; McLaughlin, HM; Clark, EH; Babb, LJ; Cox, SW; DePalma, SR; Ho, CY; Seidman, JG; Seidman, CE; Rehm, HL, Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet. Med. 2015, 17 (11), 880-8.

3.Wilcox, JE; Hershberger, RE, Genetic cardiomyopathies. Curr . Opin. Cardiol. 2018, 33 (3), 354-362.

4.Seidman, CE; Seidman, JG, Identifying sarcomere gene mutations in hyp ertrophic cardiomyopathy: a personal history. Circ. Res. 2011, 108 (6), 743-50.

5. Kim, JB; Porreca, GJ; Song, L.; Greenway, SC; Gorham, JM; Church, GM ; Seidman, CE; Seidman, JG, Polony multiplex analysis of gene expression (PMAGE) in mouse hypertrophic cardiomyopathy. Science 2007, 316 (5830), 1481-4.

6.Lopez, B.; Gonzalez, A.; Diez , J., Circulating biomarkers of collagen metabolism in cardiac diseases. Circulation 2010, 121 (14), 1645-54.

7.Teekakirikul, P.; Eminaga, S.; Toka, O.; Alcalai, R.; Wang , L.; Wakimoto, H.; Nayor, M.; Konno, T.; Gorham, JM; Wolf, CM; Kim, JB; Schmitt, JP; Molkentin, JD; Norris, RA; Tager, AM; Hoffman, SR ; Markwald, RR; Seidman, CE; Seidman, JG, Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-beta. J. Clin. Invest. 2010, 120 (10), 3520-9.

8.Araujo, AQ; Arteaga, E.; Ianni, BM; Buck, PC; Rabel lo, R.; Mady, C., Effect of Losartan on left ventricular diastolic function in patients with nonobstructive hypertrophic cardiomyopathy. Am. J. Cardiol. 2005, 96 (11), 1563-7.

9.Kawano, H. ; Toda, G.; Nakamizo, R.; Koide, Y.; Seto, S.; Yano, K., Valsartan decreases type I collagen synthesis in patients with hypertrophic cardiomyopathy. Circ. J. 2005, 69 (10), 1244 -8.

10.Penicka, M.; Gregor, P.; Kerekes, R.; Marek, D.; Curila, K.; Krupicka, J.; Candesartan use in, H.; Non-obstructive Cardiomyopathy Estate Study , I., The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study. J. Mol. Diagn. 2009, 11 (1), 35-41.

11.Shimada, YJ; Passeri, JJ; Baggish, AL; O'Callaghan, C.; Lowry, PA; Yannekis, G.; Abbara, S.; Ghoshhajra, BB; Rothman, RD; Ho, CY; Januzzi, JL; Seidman, CE; Fifer , MA, Effects of losartan on left ventricular hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy. JACC Heart Fail 2013, 1 (6), 480-7.

12.Yamazaki, T.; Suzuki, J.; Shimamoto, R.; Tsuji, T.; Ohmoto-Sekine, Y. ; Ohtomo, K.; Nagai, R., A new therapeutic strategy for hypertrophic nonobstructive cardiomyopathy in humans. A randomized and prospective study with an Angiotensin II receptor blocker. Int. Heart J. 2007, 48 (6), 715-24.

13.Axelsson, A.; Iversen, K.; Vejlstrup, N.; Ho, C.; Norsk, J.; Langhoff, L.; Ahtarovski, K.; Corell, P.; Havndrup, O.; Jensen , M.; Bundgaard, H., Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial. The Lancet Diabetes & Endocrinology 2015, 3 (2), 123- 131.

14. China Cardiovascular Health and Disease Report Compilation Group, Summary of China Cardiovascular Health and Disease Report 2020. Chinese Journal of Circulation 2021, 36 (276), 521-544.

15.Zou, Y.; Song , L.; Wang, Z.; Ma, A.; Liu, T.; Gu, H.; Lu, S.; Wu, P.; Zhang dagger, Y.; Shen dagger, L.; Cai, Y. ; Zhen double dagger, Y.; Liu, Y.; Hui, R., Prevalence of idiopathic hypertrophic cardiomyopathy in China: a population-based echocardiographic analysis of 8080 adults. Am. J. Med. 2004, 116 (1), 14-8.

16.Wang, J.; Wang, Y.; Zou, Y.; Sun, K.; Wang, Z.; Ding, H.; Yuan, J.; Wei, W.; Hou, Q.; Wang , H.; Liu, X.; Zhang, H.; Ji, Y.; Zhou, X.; Sharma, RK; Wang, D.; Ahmad, F.; Hui, R.; Song, L., Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. Eur. J. Heart Fail. 2014, 16 (9), 950-7.

Doctor of Medicine,Doctoral supervisor, second-level professor/first-level chief physician, key teacher of the Ministry of Education, "35" talent in Shaanxi Province, and "215" talent in Shaanxi Provincial Department of Health.

is currently the director of the Shaanxi Provincial Key Laboratory of Molecular Cardiology, the director of the Shaanxi Provincial Cardiovascular Disease Quality Control Center, the chairman of the Shaanxi Provincial General Practice Association, the standing committee member of the General Practice Branch of the Chinese Medical Association, "Chinese Journal of Molecular Cardiology" Deputy Editor-in-Chief, Deputy Editor-in-Chief of Chinese Journal of Heart Failure and Cardiomyopathy.

's main research direction is the application research of heart failure, cardiovascular ion channel disease and precision medicine for cardiovascular disease.

successively presided over 1 science and technology benefiting people plan of the Ministry of Science and Technology, 1 international science and technology cooperation project of the Ministry of Science and Technology, 4 National Natural Science Foundation of China (1 key project, 3 general projects), 4 scientific research funds of the Ministry of Health, and the Ministry of Education 3 projects and 4 from the Natural Science Foundation of Shaanxi Province;

published more than 300 papers, including more than 130 papers (H factor 24) included in SCI, edited 9 monographs, and edited the National Clinical (Assistant) Physician Qualification Examination Series There are 6 series of books, 1 monograph in chief translation, 5 monographs participated in editing;

has obtained 1 national utility model patent and 2 software copyrights.

successively won 2 first prizes, 1 second prize of Shaanxi Science and Technology Award, 1 third prize of China Medical Science and Technology Award and 4 other department-level scientific and technological achievements awards;

successively guided graduate doctoral students 65 There are 70 postgraduates.

(Source: "International Circulation" editorial department)

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