Hypertrophic cardiomyopathy

1. Hypertrophic cardiomyopathy Frank and Mehta

2. Definition • The term cardiomyopathy is purely descriptive, meaning disease of the heart muscle • Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick — or hypertrophied. This thickened heart muscle can make it harder for the heart to pump blood. Hypertrophic cardiomyopathy may also affect the heart's electrical system • In most people, hypertrophic cardiomyopathy doesn't cause severe problems and they're able to live a normal life. In a small number of people with hypertrophic cardiomyopathy, the thickened heart muscle can cause symptoms such as shortness of breath, problems in the heart's electrical system resulting in life-threatening arrhythmias and sudden cardiac death. Hypertrophic cardiomyopathy is the most common cause of heart-related sudden death in people under 30

3. The myocardial disarray • Microscopic examination of the heart muscle shows that it is abnormal. The normal alignment of muscle cells is absent and this abnormality is called myocardial disarray. This disarray can contribute to an irregular heartbeat (arrhythmia) in some people.

4. Synonyms: HOCM, IHSS and muscular sub-aortic stenosis • 1 in 500 of the UK population suffers from the disease • Note that thickening of LV wall resembling HCM occurs in other disease states: Noonan’s syndrome, Mitochondrial myopathies, Friedreich ataxia,metabolic disorder,Anderson-Fabry disease,LV-non compaction and cardiac amyloidoses.

5. Hypertrophy

6. Differential diagnosis HCM Athletic heart Concentric & regresses < 15 mm < 40 mm > 45 mm Normal • Can be asymmetric • Wall thickness: > 15 mm • LA: > 40 mm • LVEDD : < 45 mm • Diastolic function: always abnormal

7. Stimulus • Unknown • Disorder of intracellular calcium metabolism • Neural crest disorder • Papillary muscle malpositioned and misoriented

8. Genetics and molecular diagnosis • Mandelian autosomal dominant trait. • Mutations in any of the 10 genes, each encoding protein component of cardiac sarcomere • Beta-myosin heavy chain(first identified) chromosome 14. Myosin-binding protein C and cardiac troponin T comprise more than half genotyped patients to date. Regulatory and essential myosin light chains, titin, alpha-tropomyosin, alpha-actin, cardiac troponin I and alpha –myosin heavy chain account for fewer cases. http://genepath.med.harvard.edu/~seidman/cg3/

9. genetic basis

10. Phenotypic expression of HCM(LVH) is product not only of casual mutation, but also of modifier genes and environmental factors. • Increased risk of atrial fibrillation in HCM identified with beta-myosin heavy chain Arg 663 His mutation. Not all the individuals harbouring the gene defects will express clinical features of HCM.(note silent mutations). • Substantial LV modelling with spontaneous LVH occurs associated with accelerated body growth and maturation(adolescence )

11. Pedigree • autosomnal dominant • passed on from affected males and females • The disease does not skip generations

12. Variants of HCM Most common location: subaortic , septal, and ant. wall. • Asymmetric hypertrophy (septum and ant. wall): 70 %. • Basal septal hypertrophy: 15- 20 %. • Concentric LVH: 8-10 %. • Apical or lateral wall: < 2 % (25 % in Japan/Asia): characteristic giant T-wave inversion laterally & spade-like left ventricular cavity: more benign.

13. The major abnormality of the heart in HCM is an excessive thickening of the muscle. Thickening usually begins during early adolescence and stops when growth has finished, ie late teens to early twenties. It is uncommon for thickening to progress after this age • The left ventricle is almost always affected, and in some patients the muscle of the right ventricle also thickens. • It can be seen from Figure that the hypertrophy is usually greatest in the wall separating the left and right chambers of the heart (the septum). The muscle thickening in this region may be sufficient to narrow the outflow tract . In some patients this thickening is associated with obstruction to the flow of blood out of the heart into the major blood vessel, the aorta.

14. In some cases of asymmetric septal hypertrophy, obstruction to the outflow of blood from the heart may occur, as shown here. The mitral valve touches the septum, blocking the outflow tract. Some blood is leaking back through the mitral valve (mitral regurgitation)

15. The variants

17. Pathophysiology of HCM • Dynamic LV outflow tract obstruction • Diastolic dysfunction • Myocardial ischemia • Mitral regurgitation • Arrhythmias

18. Pathophysiology • Left ventricular outflow tract gradient • ↑ with decreased preload, decreased afterload, or increased contractility. • Venturi effect: anterior mitral valve leaflets & chordae sucked into outflow tract → ↑ obstruction, eccentric jet of MR in mid-late systole.

19. Left ventricular outflow tract gradient • Approximately 25% of patients with HCM have a dynamic systolic pressure gradient in the leftventricularoutflowtract caused by contact between the mitral valve leaflet(s) and the interventricular septum under resting conditions • Outflowtractgradient in excess of 30 mmHg is an important cause of symptoms. • Some authors believe that the gradient is simply a consequence of high velocity flow through the aortic valve, and hence does not represent a real obstruction to cardiac output. • However, if the gradient is greater than 50 mmHg, the percentage of systolic volume ejected before the beginning of SAM is greatly reduced and this is probably responsible for patients' symptoms when severe, outflowtractgradient can cause dyspnoea, chest pain, syncope, and predisposes to the development of atrial arrhythmias ; it is also an independent predictor of disease progression and adverse outcome, including sudden death

20. Physical examination Maneuvers that ↓ end-diastolic volume (↓ venous return & afterload, ↑ contractility) • Vasodilators • Inotropes • Dehydration • Valsalva • Amyl nitrite • Exercise → ↑ HCM murmur

22. General considerations for natural history and clinical course • Clinical presentation in any phase from infancy to old age.variable clinical course 25 % of cohort achieve normal longevity. • Course of many patients may be punctated by adverse clinical events: sudden cardiac death, embolic stroke, and consequences of heart failure • Progressive symptoms largely of exertional dyspnea, chest pain, impaired conciousness, syncope near-syncope or pre-syncope: depending on functionality of LV systole, progression to advanced congestive heart failure(end-stage phase!) with LV remodelling and systolic dysfunction, complications attributable to AF, including embolic stroke. • Triad: DOE(per exclusionem), angina, presyncope/syncope • Sustained V-Tach and V-Fib: most likely mechanism of syncope/ sudden death. • Dependant on atrial kick: CO ↓ by 40 % if A. Fib present. • Note poor prognosis in case of male patient, yonger age family Hx. For sudden death, Hx. Of syncope, exercise induced hypotention(worst)

25. Brockenbrough response • In PVC: augmented preload, increased contractibility, in HCM worsening of LVOT obstruction increase in pressure gradient. • Normal subjects following PVC shows a proportional increase in Ao systolic and LV systolic pressures.

27. Management • The first step in developing a treatment plan is to demonstrate whether or not a dynamic left ventricular outflow tract obstruction is present. • Physical examination should reveal a dynamic outflow tract murmur often accompanied by a bifid carotid impulse. • The treatment of hypertrophic obstructive cardiomyopathy has been divided into pharmacologic therapy versus more invasive procedures (dual-chamber pacing, catheter-based septal ablation, and septal myectomy)

28. Pharmacologic Therapy • the goal of medications in hypertrophic cardiomyopathy is to blunt these catecholamine-induced phenomena • Drugs, which suppress contractility (negative inotropic agents) and suppress heart rate (negative chronotropic agents), have been the mainstays of therapy. • Beta-adrenergic receptor blockers, calcium entry blockers, and disopyramide have been the drugs of choice. • Since most patients have symptoms only with exertion, the resting gradient should not be used as assessment of efficacy of medical therapy. The calcium channel blockers are a good alternative if a beta-blocker cannot be tolerated.

29. Dual-Chamber Pacing • In the patient with sinus rhythm, the normal activation and contraction sequence of the left ventricle results in the base of the heart commencing contraction prior to the apical portion. • This results in septal contraction which projects into the left ventricular outflow tract with subsequent left ventricular outflow obstruction. • Pacing the ventricle from the right ventricular apical lead position allows the apical segments to contract prior to the basal segments and helps with ventricular emptying before the outflow obstruction can occur. • Chronic pacing may result in remodeling of the ventricle, such that there is widening of the left ventricular outflow tract to further decrease the gradient. • Dual-chamber pacing of both the atrium and the ventricle is necessary for synchronization of atrial and ventricular contraction

30. The gold standard for symptomatic relief in patients with hypertrophic obstructive cardiomyopathy is septal myectomy. Via an aortotomy, the ventricular septum is debulked at the basal and mid-ventricular levels. Additional muscle is usually removed from the anterior wall as well. This results in immediate enlargement in left ventricular outflow tract and abolishment of the gradient in most cases . In addition, if mitral regurgitation is secondary to the distortion of the mitral valve leaflets from the systolic anterior motion, the mitral regurgitation is also abolished. All of this results in a significant decrease in filling pressures and a significant improvement in diastolic filling of the heart.

31. Echocardiographic still frames from the parasternal long-axis. The left images were obtained prior to surgical myectomy, while the right images were obtained after myectomy in the same patient. The bottom images are magnified views of the left ventricular outflow tract. Note the surgical "bite" from the septum and enlargement of the outflow tract. Ao = aortic root, LA = left atrium, LV = left ventricle.

32. It is important to recognize that the ideal patient for septal myectomy has idiopathic hypertrophy localized to the basal ventricular septum.

33. Echocardiographic still frames from the apical long-axis. Note the massively enlarged papillary muscle inserting directly into the anterior mitral leaflet (arrows). The left image is a diastolic frame and the right image is a systolic frame. There is obstruction caused by the hypertrophied papillary muscle at the mid-cavity level in this patient. LA = left atrium, LV = left ventricle, RV = right ventricle.

34. Non-Surgical Septal Ablation Echocardiographic still frames (systole) from the parasternal long-axis. The image on the left is prior to catheter-based septal ablation, while the right image was obtained at follow-up 3 months after the procedure. Note the systolic anterior motion of the mitral valve causing obstruction in the baseline image, which is abolished due to akinesis of the septum at follow-up (arrows). Ao = aortic root, LA = left atrium, LV = left ventricle.

35. Recent interest has been generated with a catheter-based therapy-septal ablation. With this procedure, installation of ethyl alcohol is performed through a PTCA balloon catheter and carefully selected septal perforator branches. This results in a localized myocardial infarction of the basal septum. There have been cases where intractable ventricular fibrillation has occurred during the procedure. Large ventricular septal defects resulting in death have occurred. Also, there have been reported cases where the alcohol diffuses through collateral circulation to involve the entire wall, resulting in a large anteroapical myocardial infarction.

36. HCM Patients Without Obstruction • The activation of the local (myocardial tissue) renin-angiotensin cascade (RAS) has been reported in HCM and other hypertrophic ventricles. Inhibition of the tissue RAS via intracoronary infusions of ACE inhibitor can improve diastolic properties. However, systemic administration has not been widely studied. Caution must be taken prior to commencing therapy with antagonists of RAS (ACE inhibitor, angiotensin receptor blocker, etc.) that the patients have no resting or inducible outflow gradient. The afterload reduction that is produced by these agents can exacerbate the obstructive tendency, and counteract any gains made in diastolic function. Drugs, which slow or blunt the heart rate, can facilitate left ventricular filling by maintaining an adequate diastolic filling period. Additionally, low-dose diuretics can be useful adjuncts in non-obstructive HCM. A novel surgical technique has been developed for patients with severely limiting dyspnea and apical HCM. Debulking of the apical myocardium results in a larger ventricular cavity and improved operating compliance at end-diastole

37. Prevention of Sudden Death in HCM • Patients who have been resuscitated from cardiac arrest or have sustained ventricular tachycardia are clearly at increased risk. • secondary prevention of sudden death with implantable defibrillator appears to be efficacious • Primary prevention of sudden is much more difficult. HCM with one or more first-degree relatives who have had SCD would appear to be a great risk. Those with the most severe forms of hypertrophy have also been reported to harbor increased risk. Other factors such as nonsustained ventricular tachycardia, syncope in young patients, perfusion defects, hypotensive response to exercise, etc., have also been studied in HCM. The approach to place ICDs in patients with prior cardiac arrest, sustained ventricular tachycardia, or a significant family history of sudden death should be considered.

39. References • http://www.cardiovascularultrasound.com/content/6/1/19 • http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/guidelines-HCM-FT.pdf • http://www.mayoclinic.com/health/hypertrophic-cardiomyopathy/DS00948/DSECTION=risk-factors • http://www.mayoclinic.org/hypertrophic-cardiomyopathy/physiciansguide.html