Most genetically determined cardiomyopathies have an autosomal dominant inheritance pattern with variable penetrance. This means that:

• Being a carrier of 1 gene with a pathological mutation may be sufficient to develop cardiomyopathy.
• Anyone who is a carrier of a mutated gene has a 50% chance of passing it on to a child.
• Due to the variable penetrance, the severity of the cardiomyopathy with the same mutation can vary greatly from person to person. A carrier of the same mutation can therefore sometimes not develop cardiomyopathy. Another person may develop a mild form and another person in the same family may develop a severe cardiomyopathy.

Genetic research is sometimes indicated if a familial cardiomyopathy is suspected. However, a negative genetic test does not rule out a genetic cause for the cardiomyopathy. Good cardiological follow-up of family members remains indicated. If a pathological mutation is found, genetic testing can be done within the family to demonstrate or rule out carrier status of this mutation. This then has an important impact on the need for good cardiological follow-up and possible inheritance of the mutation to children.

Before genetic testing, the patient is best referred to a cardiogenetics consultation so that correct counseling can take place in advance.

Indications for genetic research:

• Unexplained hypertrophic cardiomyopathy.
• Unexplained dilated cardiomyopathy in a young patient or a patient with a family history of heart failure, sudden death, ICD or heart transplant at a younger age.
• Arrhythmogenic cardiomyopathy (ARVC,...).
• Suspicion of a syndromic condition or muscular disease (for example Duchenne or Becker's disease ).
• Cardiac ATTR amyloidosis upon initiation of tafamidis (TTR gene).

A non-thickened, normotrophic heart muscle with a dilated LV (end-diastolic diameter > 50 mm) causes reduced contraction of the myocardium, usually leading to heart failure with mildly reduced or reduced LVEF ( HFmrEF or HFrEF).

A non-thickened, normotrophic heart muscle with regional or diffuse hypokinesia of the LV, but without dilation of the LV, with an increased risk of ventricular arrhythmias and usually a picture of heart failure with mildly reduced or reduced LVEF (HFmrEF or HFrEF ).

Dilation and/or dysfunction of the right ventricle (RV) with increased risk of ventricular arrhythmias and/or right heart failure. Sometimes there may be biventricular involvement with also LV dysfunction.

A non-thickened, normotrophic and non-dilated heart muscle with normal systolic contractility and a picture of heart failure with preserved LVEF ( HFpEF ). Classically this is caused by a stiffened endocardium .

It is very important that the diagnosis is made at the earliest possible stage to enable rapid treatment of the cause and slow down further disease progression. Sometimes an image suspicious for cardiac amyloidosis is accidentally seen on a bone scan that was done for another indication . These patients must then be referred quickly for further diagnosis and therapy.

Amyloidosis can be caused by different types of proteins with different underlying disease processes that cause these proteins.

• Protein that precipitates as amyloid :
  • Transthyretin (TTR)
  • Present in everyone and produced by the liver.
  • The TTR protein is normally a tetramer (4 smaller proteins form a stable large protein). In this disease, these tetramers break down into 4 small proteins (monomers) that precipitate as amyloid fibrils, typically almost exclusively in the heart.
• There are 2 forms:

1. 1. ATTRwt ('wild type'):
      • acquired disease, no genetic cause
      • most frequently
   2. ATTRv ('variant'), hATTR : hereditary cardiac amyloidosis :
      • caused by a mutation in the TTR gene
      • autosomal dominant
      • rare

• The disease mainly occurs in older people (> 60 years) and much more frequently in men.
• It is estimated that 5-10% of patients with HFpEF have cardiac ATTR amyloidosis ! Cardiac ATTR amyloidosis also often occurs simultaneously in elderly people with aortic stenosis .

• Protein that precipitates as amyloid :
  • Free light chains of immunoglobulins ('light chain disease ').
  • Normally not present.
  • A consequence of an underlying hematological disease due to a monoclonal gammopathy (from MGUS to multiple myeloma ( Kahler 's disease )).
• Also in younger patients.
• Poor prognosis with rapid progression without correct diagnosis and therapy.

Among other things:

• Heart failure
• Arrhythmia: AF, bradycardia, sinus arrest, AV block
• Hypotension
• CVA
• Peripheral or autonomic neuropathy, polyneuropathy

• Fatigue
• Weight loss and intestinal disorders (diarrhea or constipation)
• Especially in ATTR amyloidosis : bilateral carpal tunnel syndrome, spinal canal stenosis, spontaneous rupture of the biceps tendon
• Especially in AL amyloidosis : macroglossia, periorbital hematomas, progressive renal insufficiency and proteinuria with possibly nephrotic syndrome.

• Treatment of the cause: inhibition of further deposition of transthyretin monomers in the myocardium.
• Tafamidis ( Vyndaqel ) 61 mg 1 per day per os.
  • Reimbursed in Belgium since 10-2021.
  • Very expensive.
  • Can normally be collected from the hospital pharmacy.
  • Mechanism of action:
    
    Tafamidis is an ATTR stabilizer, which prevents ATTR tetramers from breaking down into monomers that then precipitate as amyloid fibrils . Tafamidis aims to slow down the progressive accumulation of transthyretin monomers and thus slow down progressive heart failure. The amyloidosis already present will therefore not disappear.

• • Clinical effects ( ATTR-ACT study)
    • Slower decline in exercise capacity.
    • After a treatment period of longer than approximately 1.5 years:
      • significantly better survival.
      • decrease in hospitalizations due to heart failure.
    • This effect is maintained and increases after almost 5 years of treatment.
    • Ghese effects were only present in patients in NYHA class I and II, not in patients with more advanced disease and already NYHA class III.
  • Refund
    • To be requested by a cardiologist.
    • Conditions:
      • few symptoms, NYHA class I or II. Therapy should therefore be started at the earliest possible stage of the disease. Patients who are already in NYHA class III at baseline are no longer eligible for reimbursement.
      • abnormal bone scintigraphy ( Perugini score 2 or 3).
      • no gammopathy (after blood and urine tests).
      • If there are signs of progressive heart failure (evolution to permanent NYHA class III or more), therapy must be stopped and reimbursement will lapse.
      • genetic research of the TTR gene.
  • Rational use of this very expensive therapy is needed. Since this is primarily a long-term treatment with only prognostic benefits after a treatment period of more than 1.5 years, this therapy should only be given to patients with:
    • a sufficiently good functional and cognitive condition.
    • not too many other comorbidities that negatively affect life expectancy in the short to medium term.
    • not too old an age. This is a relative criterion, whereby the general and functional condition (biological age) must be taken into account.
•  Others
  • Patisiran ( Onpattro ), intravenously.
    • Mechanism of action
      • small interfering RNA ( siRNA ).
      • blocks the production of transthyretin in the liver.
    • Very expensive.
    • Only reimbursed for hereditary ATTR ( hATTR ) with also stage 1 neuropathy.
    • This treatment is only possible through a neurological reference center.

• Specific points of attention for therapy in cardiac amyloidosis :
  • The most important thing is to maintain euvolemia with diuretics, MRA and/or SGLT2 inhibitors.
  • There is usually intolerance and hypotension with therapy with ACE inhibitor, ARB and/or beta blocker . Therapy should be discontinued if blood pressure is less than 120/80 mmHg or bradycardia.
  • There is a high risk of AF with also a very high thromboembolic risk, sometimes even with sinus rhythm.
  • If AF is documented, there is a strict indication for anticoagulants. Sometimes warfarin is also started in patients who still have sinus rhythm to prevent thromboembolic complications.
  • In AF with tachycardia:
    • rate control with a beta blocker and/or amiodarone . High doses should be used with caution due to increased risk of bradycardia or AV block.
    • digoxin is contraindicated due to high risk of toxicity.
  • There is an increased risk of bradycardia and need for pacemaker implantation. Regular monitoring of heart rhythm with an ambulatory Holter monitor if necessary is recommended.
  • Implantation of an ICD to prevent sudden death is not normally recommended in these patients.

• Treatment by the hematology department.
• Supportive heart failure therapy via the cardiologist.

• Mutations in one of the proteins in a sarcomere (MYBPC3 and MYH7, troponin , actin, titin ,..).
• Autosomal dominant inheritance.
• See genetic.

• Usually deviant
• LV strain pattern with negative T waves V4-6
• Left anterior hemiblock or left bundle branch block

There is usually an asymmetric LV hypertrophy, most pronounced in certain segments of the myocardium, usually the septum.

Sometimes there is LVOT obstruction (LV outflow tract ) due to hypertrophy of the basal septum and/or systolic anterior movement (SAM) of the anterior mitral valve leaflet . This is then called a hypertrophic obstructive cardiomyopathy. This LVOT obstruction can already be present at rest, but sometimes only during exercise.

There are different patterns of LV hypertrophy:

• Subaortic (basal septum, septum)
• Apical
• Less frequently diffuse, concentric hypertrophy
• …

• Sometimes this is an accidental diagnosis.
• Dyspnea d'effort due to heart failure and/or LVOT obstruction.
• Palpitations due to AF/VT.
• Syncope due to arrhythmia and/or (during exercise) LVOT obstruction.
• Sudden death.
• Angor on exertion (due to small vessel disease due to pronounced LV hypertrophy or LVOT obstruction)

• Succession.
• With symptoms of dyspnea d'effort :
  • Medication
    • Objective: slow down the heart rate and reduce myocardial contraction (and therefore LVOT obstruction).
    • Beta blocker , increasing to the maximum tolerated dose.
    • Calcium blocker with negative inotropic effects ( diltiazem or verapamil ), increasing to the maximum tolerated dose.
    • New therapy for obstructive hypertrophic cardiomyopathy: mavacamten ( Camzyos ) per os, a myosin ATPase inhibitor. Read more
  • If there are signs of fluid retention, a low dose loop diuretic can be started. High doses should be avoided as dehydration may increase LVOT obstruction.
  • Thinning of the basal septum
    • If persistent symptoms of dyspnea NYHA class III or syncope during exercise with LVOT obstruction and a maximum gradient of ≥ 50 mmHg at rest or with stress echocardiography, despite maximum drug therapy.
    • How?
      • Surgical myomectomy ( Morrow procedure).
      • Percutaneous alcoholic septal ablation.

• Prevention of sudden death with implantation of an ICD.
  • In secondary prevention after documented spontaneous sustained VT and/or after successful resuscitation for VT or VF.
  • In primary prevention at an increased risk of sudden death.
    • The estimation of this risk per patient remains very difficult and is done on the basis of risk stratification.
    • This risk of sudden death at 5 years is estimated with the HCM Risk-SCD calculator. For example: AHA HCM SCD Calculator - Professional Heart Daily | American Heart Association .
      • Risk factors here are:
        • age
        • maximum thickness of the LV muscle (in mm)
        • left atrial diameter (in mm)
        • maximum LVOT gradient (in mmHg )
        • family history of sudden death (especially first- line relatives ≤ 50 years)
        • documented non- sustained VT (> 3 beats) at higher risk with frequent or longer episodes of increased heart rate ≥ 200 per minute
        • unexplained syncope
        • LVEF ≤ 50%
        • apical aneurysm
        • extensive LGE (late gadolinium enhancement , a sign of fibrosis or scarring) ≥ 15% of the LV mass on MRI of the heart
      • To be reevaluated every 1-2 years or at any clinical change.
      • Recommendations:
        • 5-year risk ≥ 6%: ICD implantation.
        • 5-year risk 4 - 6%: implantation of an ICD to be considered.
        • 5-year risk < 4%: no implantation of an ICD unless considered after consultation with the patient if LVEF ≤ 50% or extensive LGE ≥ 15% of LV mass on cardiac MRI.