HCM slides

1. HCM UPDATE
Pietro Giuliano
U. O. Cardiologia
ARNAS CIVICO PALERMO

7. Paradossi:
HCM in assenza di ipertrofia cardiaca: ( G+ / F- )
Antinomie:
Quadri clinici ed ecocardiografici tipici della HCM che
non sono HCM ( fenocopie).

8. LAMP2
cardiomyopathy, a
phenocopy of HCM. A,
From 14-year-old
boy with SD and septal
thickness of
65 mm (heart weight,
1425 g). B, Clusters
of myocytes with
vacuolated sarcoplasm
(stained red)
embedded in area of
scar (stained blue;
Masson trichrome). C,
Disorganized
arrangement of
myocytes
most typical of
sarcomeric HCM. D,
Intracardiac
electrogram. ICD
elicited 5
defibrillation shocks
that failed to interrupt
VF (280 bpm).

13. 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 the
disease phenotype (i.e., LV hypertrophy).
These individuals are usually referred to as being “genotype positive/
phenotype negative” or as having “subclinical HCM.”

14. 2.1. Prevalence
HCM is a common genetic cardiovascular disease.
In addition, HCM is a global disease , with epidemiological
studies from several parts of the world reporting a similar
prevalence of left ventricular (LV) hypertrophy, the quintessential
phenotype of HCM, to be about 0.2% (i.e., 1:500) in
the general population, which is equivalent to at least 600,000
people affected in the United States.
This estimated frequency in the general population appears to exceed the
relatively uncommon occurrence of HCM in cardiology
practices, implying that most affected individuals remain
unidentified, probably in most cases without symptoms or
shortened life expectancy.

15. 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

16. 80%

18. 80%
25%

20. 5. Diagnosis
The 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 I
1. 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 clinical
significance 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 IIa
1. 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 IIb
1. The usefulness of genetic testing in the assessment of risk of SCD in HCM is
uncertain (107,108). (Level of Evidence: B)

21. MYH7 esordio
precoce,
Ipertrofia severa e
alta incidenza di SD
MYBPC3, ipertrofia modesta,
esordio tardivo,, fenotipia variabile.
TNNT2
Ipertrofia
lieve, alta
incidenza
di SD
HCM is caused by an autosomal dominant mutation in genes that encode sarcomere proteins or sarcome
associated proteins. The most vigorous evidence indicates
that 8 genes are known to definitively cause HCM: beta myosin heavy chain, myosin binding protein C, troponin
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.

22. 5.1.1. Genotype-Positive/Phenotype-Negative Patients
Recommendation
CLASS I
1. 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 adolescents
and about every 5 years in adults), based on the patient’s age and change in clinical
status (16,120 –122).
(Level of Evidence: B)

23. 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—Recommendations
CLASS I
1. A 12-lead ECG is recommended in the initial evaluation of
patients with HCM. (Level of Evidence: C)
2. Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring

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

30. 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)

34. Il futuro: trattamento farmacologico malattia e paziente specifico.
La CMI resta una malattia orfana dal punto di
vista della terapia. I farmaci nei pazienti con
CMI sono necessari per il controllo dei sintomi.
Tuttavia,le strategie terapeutiche si basano sulle
evidenze di un piccolo numero di studi di piccole
dimensioni, o, più spesso, su indicazioni
empiriche o estrapolazioni dalle evidenze ottenute
in altre cardiopatie.
Pertanto, le linee guida esistenti sul trattamento
della CMI offrono raccomandazioni che sono
raramente basate su solide evidenze.

35. 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 prevalentemente
alle mutazioni sarcomeriche, volte a prevenire la progressione della malattia verso la
cosiddetta“end-stage”.
 la correzione dei meccanismi cellulari di aritmogenesi peculiari della
CMI.
È verosimile che molecole in grado di interferire positivamente con ciascuno di questi
aspetti siano in grado di svolgere un’azione positiva anche sugli altri due.

36. 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 molto
complesso, caratterizzato da molteplici modificazioni
del metabolismo del calcio intracellularee da profonde modificazioni delle correnti
transmembrana.
Una iper-attivazione della corrente lenta del sodio è stata descritta
recentemente in cardiomiociti ventricolari isolati.
Tale iperattivazione era all’origine di un sovraccarico di calcio intracellulare,
con conseguente alterazione del
metabolismo energetico cellulare; la stessa alterazione
si associava inoltre a un marcato prolungamento
del potenziale di azione cardiomiocitario e ad aumento spiccato di early after
depolarizations(EAD), indicatori riconosciuti
di instabilità elettrica ed aritmogenesi.

37. 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.

52. Grazie