HCM UPDATE

Pietro GiulianoU. O. Cardiologia

ARNAS CIVICO PALERMO

Paradossi:HCM in assenza di ipertrofia cardiaca: ( G+ / F- )

Antinomie: Quadri clinici ed ecocardiografici tipici della HCM che non sono HCM ( fenocopie).

LAMP2 cardiomyopathy, aphenocopy of HCM. A, From 14-year-oldboy with SD and septal thickness of65 mm (heart weight, 1425 g). B, Clustersof myocytes with vacuolated sarcoplasm(stained red) embedded in area ofscar (stained blue; Masson trichrome). C,Disorganized arrangement of myocytesmost typical of sarcomeric HCM. D,Intracardiac electrogram. ICD elicited 5defibrillation shocks that failed to interruptVF (280 bpm).

2.2.2. Clinical Definition and Differential Diagnosis

The generally accepted definition of HCM, it is a disease state characterized by unexplained LV hypertrophy associated with nondilated ventricular chambers in the absence of another cardiac or systemic disease that itself would be capable of producing the magnitude of hypertrophy evident in a given patient (6,7,9–12),

With the caveat that patients who are genotype positive may be phenotypically negative without overt hypertrophy.

Clinically, HCM is usually recognized by maximal LV wall thickness 15 mm, with wall thickness of 13 to 14 mm considered borderline, particularly in the presence of other compelling information (e.g.,family history of HCM), based on echocardiography.

However, it should be underscored that in principle, any degree of wall thickness is compatible with the presence of the HCM genetic substrate and that an emerging subgroup within the broad clinical spectrum is composed of family members with diseasecausing sarcomere mutations but without evidence of thedisease phenotype (i.e., LV hypertrophy).

These individuals are usually referred to as being “genotype positive/phenotype negative” or as having “subclinical HCM.”

2.1. PrevalenceHCM is a common genetic cardiovascular disease. In addition, HCM is a global disease , with epidemiologicalstudies from several parts of the world reporting a similarprevalence of left ventricular (LV) hypertrophy, the quintessentialphenotype of HCM, to be about 0.2% (i.e., 1:500) inthe general population, which is equivalent to at least 600,000people affected in the United States.This estimated frequency in the general population appears to exceed therelatively uncommon occurrence of HCM in cardiologypractices, implying that most affected individuals remainunidentified, probably in most cases without symptoms orshortened life expectancy.

HCM 1 persona ogni 500

Secondo l’ultimo sondaggio ISTAT, che conta tra Palermo e provincia 1.200.000 abitanti….

almeno 6000 pazienti sono affetti da HCM

80%75%

80%75%

25%

5. DiagnosisThe clinical diagnosis of HCM is conventionally made with cardiac imaging, at present most commonly with 2-dimensional echocardiography and increasingly with CMR.

5.1. Genetic Testing Strategies/Family Screening—Recommendations

CLASS I1. Evaluation of familial inheritance and genetic counseling is recommended as part of the assessment of patients with HCM. (Level of Evidence: B)

2. Patients who undergo genetic testing should also undergo counseling by someone knowledgeable in the genetics of cardiovascular disease so that results and their clinicalsignificance can be appropriately reviewed with the patient. (Level of Evidence: B)

3. Screening (clinical, with or without genetic testing) is recommended in first-degree relatives of patients with HCM. (Level of Evidence: B)

4. Genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy is recommended in patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause (Level of Evidence: B)

CLASS IIa1. Genetic testing is reasonable in the index patient to facilitate the identification of first-degree family members at risk for developing HCM (17,95,102). (Level of Evidence: B)CLASS IIb1. The usefulness of genetic testing in the assessment of risk of SCD in HCM is uncertain (107,108). (Level of Evidence: B)

MYH7 esordio precoce,Ipertrofia severa e alta incidenza di SD

MYBPC3, ipertrofia modesta, esordio tardivo,, fenotipia variabile.

TNNT2Ipertrofia lieve, alta incidenza di SD

HCM is caused by an autosomal dominant mutation in genes that encode sarcomere proteins or sarcomere associated proteins. The most vigorous evidence indicatesthat 8 genes are known to definitively cause HCM: beta myosin heavy chain, myosin binding protein C, troponin T, troponin I, alpha tropomyosin, actin, regulatory light chain,and essential light chain (11,12,30,40–42). In addition, actinin and myozenin are associated with less definitive evidence for causing HCM.

5.1.1. Genotype-Positive/Phenotype-Negative PatientsRecommendation

CLASS I1. In individuals with pathogenic mutations who do not express the HCM phenotype, it is recommended to perform serial electrocardiogram (ECG), TTE, and clinical assessment at periodic intervals (12 to 18 months in children and adolescentsand about every 5 years in adults), based on the patient’s age and change in clinical status (16,120 –122).(Level of Evidence: B)

The 12-lead ECG is abnormal in 75% to 95% of patients with HCM (9,131,132). These abnormalities do not correlate with severity or pattern of hypertrophy as determined by echocardiography

5.2. Electrocardiography—RecommendationsCLASS I1. A 12-lead ECG is recommended in the initial evaluation ofpatients with HCM. (Level of Evidence: C)2. Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring

Crypts were found in 70% (30/43) of carriers and in 12% (31/252) of controls (P , 0.001).

G+/F-

Results of DDD Pacing. Initial cohort studies of the results of dual-chamber pacing in patients with obstructive HCM and limiting symptoms showed symptomatic improvement in almost 90% of patients, accompanied by an improvement in exercise time and a reduction in gradient.However, there have been 3 randomized crossover trials in which patients received 2 to 3 months of continuous DDD pacing but also underwent a back-up AAI mode (no pacing) as a control arm (283,284,367).Although symptomatic improvement was reported by the majority of patients following continuous DDD pacing, a similar frequency of improvement was reported by patients during the AAI mode (control mode without pacing).These findings suggest a placebo effect as well as a “training effect” contributing to the initial symptomatic improvement of patients undergoing dual-chamber pacing (283,284,372)

Il futuro: trattamento farmacologico malattia e paziente specifico.

La CMI resta una malattia orfana dal punto divista della terapia. I farmaci nei pazienti conCMI sono necessari per il controllo dei sintomi.

Tuttavia,le strategie terapeutiche si basano sulleevidenze di un piccolo numero di studi di piccoledimensioni, o, più spesso, su indicazioniempiriche o estrapolazioni dalle evidenze ottenutein altre cardiopatie.

Pertanto, le linee guida esistenti sul trattamentodella CMI offrono raccomandazioni che sonoraramente basate su solide evidenze.

Esistono dati preclinici ottenuti in laboratorio su modelli animali di CMI o tessuto miocardico umano.

Questi comprendono:

la prevenzione dello sviluppo di fenotipo nei soggetti genotipo-positivi (ottenuta in animali transgenici con statine e sartani).

la correzione dei meccanismi di disfunzione e scompenso, legati prevalentementealle mutazioni sarcomeriche, volte a prevenire la progressione della malattia verso la cosiddetta“end-stage”.

la correzione dei meccanismi cellulari di aritmogenesi peculiari dellaCMI.

È verosimile che molecole in grado di interferire positivamente con ciascuno di questiaspetti siano in grado di svolgere un’azione positiva anche sugli altri due.

Il caso di un’ipotetica terapia antiaritmica specifica per la CMI rappresenta un buon paradigma di questo concetto. La genesi di aritmie nei pazienti con CMI è estremamente complessa, ed è spesso stata attribuita ad alterazioni extracellulari quali il disarray, l’ischemia microvascolare e la fibrosi miocardica.

Tuttavia, le conseguenze elettriche delle mutazioni sarcomeriche a livello cardiomiocitario giocano un ruolo di sicuro rilievo, verosimilmente anche più importante di quello degli altrimeccanismi citati.

La CMI è infatti associata a un rimodellamento elettrofisiologico moltocomplesso, caratterizzato da molteplici modificazionidel metabolismo del calcio intracellularee da profonde modificazioni delle correntitransmembrana.

Una iper-attivazione della corrente lenta del sodio è stata descrittarecentemente in cardiomiociti ventricolari isolati.Tale iperattivazione era all’origine di un sovraccarico di calcio intracellulare,con conseguente alterazione delmetabolismo energetico cellulare; la stessa alterazionesi associava inoltre a un marcato prolungamentodel potenziale di azione cardiomiocitario e ad aumento spiccato di early after depolarizations(EAD), indicatori riconosciutidi instabilità elettrica ed aritmogenesi.

Seguendo un approccio transazionale, sulla base di questi dati è stato progettato uno studio pilota multicentrico internazionale, randomizzato e in doppio cieco, per valutare l’effetto di ranolazina sulla tolleranza allo sforzo, le aritmie e la funzione diastolica nei pazienti con CMI (EUDRA-CT 2011-004507-20).

In modo analogo, la perexilina, una molecola che aumenta il consumo di carboidrati dei cardiomiociti migliorandone il profilo metabolico, ha recentemente dimostrato in uno studio randomizzato di svolgere un effetto favorevole sulla funzione diastolica e sulla capacità funzionale dei pazienti con CMI.

Grazie