Diagnostic approach and differential diagnosis in patients with hypertrophied left ventricles (Ali Yilmaz, Udo Sechtem, April 30, 2013, BMJ Journals)

• LVH is frequently defined by a left ventricular wall thickness of at least 13 mm.

• The exact diagnosis and differentiation of 'pathological' LVH—which occurs in, for example, hypertensive heart disease (HHD), hypertrophic cardiomyopathy (HCM), myocardial storage/infiltrative disease, or systemic diseases such as mitochondrial myopathy—from 'physiological' LVH (which occurs in athletes) is of paramount therapeutic and prognostic value.

• Non-invasive imaging modalities such as cardiovascular magnetic resonance (CMR) allow a detailed and comprehensive work-up of hypertrophied hearts and enable the non-invasive and safe diagnosis of the underlying origin in various cardiovascular diseases.

• Invasive endomyocardial biopsy (EMB) techniques have been refined and allow a safe and targeted sampling of biopsy specimens from both the LV and right ventricular (RV) myocardium with sophisticated post-procedural techniques, allowing a comprehensive histopathological work-up of such specimens with subsequent exact diagnosis

• The most important key to a straightforward diagnosis is still the patient's history with a major focus on his/her family history. For example, an athlete's heart in an obviously inactive patient with LVH is quite unlikely.

 

HCM & Differential diagnosis of LVH (2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy)

• In up to 60% of adolescents and adults with HCM, the disease is an autosomal dominant trait caused by mutations in cardiac sarcomere protein genes.

Metabolic disorders: The most common metabolic disorders in adults with HCM are Anderson-Fabry disease, with a prevalence of around 0.5–1% in patients older than 35–40 years.

Mitochondrial cardiomyopathies: Primary mitochondrial disorders are caused by mutations in nuclear or mitochondrial DNA that are transmitted as autosomal dominant, autosomal recessive, X-linked and maternally inherited traits. The most frequent are those caused by mutations in genes that code for the respiratory chain protein complexes.

Neuromuscular disease: With the exception of Friedreich's ataxia, HCM is a rare manifestation of neuromuscular disease.

Malformation syndromes: Several malformation syndromes are associated with HCM. The most common are those caused by mutations in genes that code for proteins of the Ras/mitogen activated protein kinase (MAPK) pathway including Noonan, LEOPARD (Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness) and Costello syndromes.

Infiltrative disease/inflammation: Cardiac amyloidosis results in a progressive increase in the thickness of the left and right ventricular myocardium, interatrial septum and AV valves. Light chain (AL) and hereditary transthyretin (TTR)-related amyloidoses can affect the heart in isolation or with multi-organ involvement, whereas wild type (senile) TTR amyloidosis predominantly affects the heart and the carpal tunnel ligament. Myocardial oedema and cellular infiltration in acute myocarditis can mimic HCM, but this is usually a transient phenomenon, accompanied by other clinical and laboratory findings suggestive of the diagnosis.

Endocrine disorders: LVH is reported in association with phaeochromocytoma and acromegaly, but treatment of the underlying endocrine disorder usually results in resolution of hypertrophy.

Drugs: Chronic use of some drugs, including anabolic steroids, tacrolimus and hydroxychloroquine, can cause LVH although they rarely result in a left ventricular wall thickness =1.5 cm.

Diagnosis of HCM:
• The diagnosis of HCM rests on the detection of increased LV wall thickness by any imaging modality, but the disease phenotype also includes myocardial fibrosis, morphologic abnormalities of the mitral valve apparatus, abnormal coronary microcirculatory function and electrocardiographic abnormalities. Due to the diverse aetiology of the disease, detection of increased LV wall thickness that is unexplained by loading conditions should prompt a systematic search for its underlying cause.
• Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased LV wall thickness ≥15 mm in one or more LV myocardial segments that is not solely explained by abnormal loading conditions.
• Genetic and non-genetic disorders can present with lesser degrees of wall thickening (13–14 mm); in these cases, the diagnosis of HCM requires evaluation of other features including family history, non-cardiac symptoms and signs, electrocardiogram (ECG) abnormalities, laboratory tests and multi-modality cardiac imaging.
• Common diagnostic challenges include the following: 1-Presentation in the late phase of the disease with a dilated and/or hypokinetic left ventricle and LV wall thinning. 2-Physiological hypertrophy caused by intense athletic training. 3-Patients with co-existent pathologies. 4-Isolated basal septal hypertrophy in elderly people.
• Counselling is essential before and after testing for genetic disease. Genetic testing is recommended in patients fulfilling diagnostic criteria for HCM to enable cascade genetic screening of their relatives.
• The clinical diagnosis of HCM in first-degree relatives of patients with unequivocal disease (LVH =15 mm) is based on the presence of otherwise unexplained increased LV wall thickness =13 mm in one or more LV myocardial segments.

History and physical examination:
• Age is one of the most important factors to take into account when considering the possible causes for HCM. For example, inherited metabolic disorders and congenital dysmorphic syndromes are much more common in neonates and infants than in older children or adults, whereas wild-type TTR-related amyloidosis is a disease mostly of men over the age of 65 years.
• In patients with LV outflow tract obstruction (LVOTO), a number of typical features may be identified including a rapid up-and-down stroke to the arterial pulse and an ejection systolic murmur at the left sternal edge that radiates to the right upper sternal edge and apex. The intensity of the murmur is increased by manoeuvres that reduce ventricular preload or afterload, such as standing up from the squatting position and forceful attempted exhalation against a closed airway (Valsalva manoeuvre). Most patients with LVOTO also have signs of mitral regurgitation.

ECG in HCM

• The ECG can be normal at presentation (6% of patients in referral cohort studies) but generally shows a variable combination of LVH, ST- and T-wave abnormalities, and pathological Q-waves.
• The frequency of arrhythmias detected during ambulatory electrocardiographic monitoring is age-related. Asymptomatic non-sustained ventricular tachycardia, at a rate between 120 and 200 beats per minute, occurs in 25% of adults with HCM. Paroxysmal supraventricular arrhythmias occur during ambulatory electrocardiographic monitoring in up to 38% of patients. Ambulatory ECG monitoring is recommended at the initial clinical assessment to assess the risk of sudden cardiac death and stroke.

Electrocardiographic abnormalities suggesting specific diagnoses or morphological variants

Echo in HCM

• In most patients, hypertrophy preferentially involves the interventricular septum in the basal LV segments but often extends into the lateral wall, the posterior septum and LV apex. As increased ventricular wall thickness can be found at any location (including the right ventricle). Measurements of LV wall thickness should be performed at end-diastole, preferably in short-axis views. M-mode measurements in the parasternal long axis projection should be avoided if possible, to prevent over-estimation of septal thickness by oblique cuts. In patients with known or suspected HCM it is essential that all LV segments from base to apex be examined, ensuring that the wall thickness is recorded at mitral, mid-LV and apical levels.
• LVOTO is defined as an instantaneous peak Doppler LV outflow tract pressure gradient =30 mm Hg at rest or during physiological provocation such as Valsalva manoeuvre, standing and exercise. A gradient of =50 mm Hg is usually considered to be the threshold at which LVOTO becomes haemodynamically important.
• When a gradient is detected in the LV cavity, it is important to systematically exclude obstruction that is unrelated to SAM, including sub-aortic membranes, mitral valve leaflet abnormalities and mid-cavity obstruction, particularly when interventions to relieve LV outflow obstruction are contemplated.
• Although dynamic LVOTO is common in patients with HCM, it also occurs in other circumstances, such as calcification of the posterior mitral annulus, hypertension, hypovolaemia and hypercontractile states.

Echocardiographic features that suggest specific aetiologies

 

Compilation by Dr. Samad Ali Moradi, According to ESC guidelines.