Synopsis

Keywords: Cardiovascular: Cardiovascular, Cardiovascular: Cardiac, Cardiovascular: Myocardium

Non-ischemic cardiomyopathies constitute a heterogeneous group of conditions characterized by morphological and functional ventricular abnormalities not due to coronary disease or its sequelae. Pragmatic classification of these disorders is based on observable morphofunctional traits (ventricular size, function, wall thickness, tissue characteristics, electrical abnormalities) and is combined with clinical, genetic, and laboratory/histopathologic data to arrive at a precise diagnosis. Inflammatory cardiomyopathies are defined as myocardial inflammation (myocarditis) associated with cardiac remodeling or dysfunction. Etiology has been crudely classified as “inherited” or “acquired”, however, it is increasingly recognized that conditions hitherto regarded as acquired can also have a genetic contribution or basis.

Syllabus

Non-ischemic cardiomyopathies constitute a heterogeneous group of conditions characterized by morphological and functional ventricular abnormalities not due to coronary disease or its sequelae. The definition usually also excludes abnormal loading conditions on the ventricles such as due to significant primary valvular heart disease, hypertension, or persistent tachycardia/tachy-arrhythmia. Diagnosis often involves combining clinical, imaging, genetic, and laboratory/histopathologic findings.

Cardiomyopathies can be classified according to their cause (etiology) or by the appearances of the heart (phenotype). The labels used to describe cardiomyopathies are often phenotypes of general features rather than a precise diagnosis. Cardiovascular magnetic resonance allows a more refined description of cardiomyopathies adding tissue characterization to morphologic and functional findings provided by other imaging modalities. It can be used to refine the differential diagnosis and, in some cases, to arrive at a precise diagnosis.

The main cardiomyopathy phenotypes include:
Hypertrophic cardiomyopathy (HCM) – left ventricular hypertrophy (>15 mm) in any ventricular segment (or >12 mm if there is a family history or genetic predisposition) not explained by loading conditions on the ventricle (e.g., hypertension, severe aortic stenosis).

Dilated Cardiomyopathy (DCM) – left ventricular dilatation with systolic dysfunction not explained by abnormal loading conditions on the ventricle (e.g., hypertension, significant valvular heart disease).

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) – a genetic disorder characterised by progressive fibrofatty replacement of the RV myocardium and arrhythmia.

Restrictive Cardiomyopathy (RCM) – a group of disorders resulting primarily in ventricular diastolic dysfunction (e.g., amyloid, sarcoid, iron-overload cardiomyopathy, genetic).

Inflammatory cardiomyopathies are defined as myocardial inflammation (myocarditis) associated with cardiac remodeling or dysfunction.

The 2023 European Society of Cardiology Cardiomyopathy guidelines have also defined a new phenotype of “non-dilated LV cardiomyopathy” which is characterized by a non-dilated LV with LV fibrosis or fibrofatty change regardless of LV function, or isolated LV dysfunction without fibrosis or LV dilatation. This phenotype may subsume conditions which will evolve into a dilated cardiomyopathy or into an arrhythmogenic cardiomyopathy with biventricular involvement and reflects the limitations of a purely phenotype-based approach.

CMR can play an important role in the deep phenotyping of cardiomyopathy as it is the gold-standard for quantifying cardiac chamber volumes and function. It also allows multiparametric tissue characterization (T1, T2, T2*, ECV, LGE).

Late gadolinium enhancement imaging remains at the cornerstone of cardiomyopathy evaluation. Gadolinium chelates are large macromolecules and as such cannot penetrate the intact cell membrane. Areas of fibrosis or scar tissue have less cellular content and are largely made up of extracellular space. Gadolinium accumulates in higher concentrations in areas of scar while rapidly washing out of normal myocardium which has a higher cellular content and better capillary supply. T1 relaxation is shortened by gadolinium chelates in proportion to the contrast concentration. An inversion recovery prepared T1-weighted sequence can therefore be used to depict differences in gadolinium concentration between areas of scar tissue and surrounding healthy myocardium after a period to allow differential washout to occur (typically 10-15 minutes).
Three main patterns of late gadolinium enhancement are seen:
Ischaemic: regional sub-endocardial which can become transmural – signifying myocardial infarction of ischaemic injury.
Non-ischemic: epicardial or mid-wall or global subendocardial (amyloid, endomyocardial fibrosis, transplant rejection).
Mixed: this can occur due to dual pathology, i.e., two different diseases being present at the same time, or to disorder such as sarcoid and giant cell myocarditis which can cause myocardial injury in multiple cardiac layers including the sub-endocardium.

Some cardiomyopathies can occur as a result of infiltration of the myocardium with abnormal proteins (amyloid) or immune cells (e.g., sarcoid).

Amyloid
This is a disorder due to the extracellular deposition of fibrils abnormally folded proteins. Amyloid fibrils form from multimers/polymers of low molecular weight soluble proteins which have undergone conformational changes to adopt an antiparallel beta-pleated sheet secondary structure (mis-fold and aggregate). Disease is mainly due to effects of fibril deposition (mechanical and toxic). At least 30 different types (based on precursor proteins) are known. The main types involving the heart include:

Primary Amyloid (AL-amyloidosis): monoclonal immunoglobulin light chain (from plasma cell dyscrasia) – affect the heart in 50% of patients.

Secondary: AA (serum amyloid A protein) amyloid – associated with chronic inflammatory conditions; involves heart in 5%.

ATTR (transthyretin/prealbumin) amyloid:
– wild-type (senile amyloid);
– mutant (inherited – principal cause of familial amyloid cardiomyopathies)

Atrial amyloid – ANP-associated (age-related))

Cardiac amyloid can present as a restrictive cardiomyopathy. It can be complicated by heart failure, orthostatic hypotension, arrhythmias (conduction disease, atrial fibrillation, malignant ventricular arrhythmias), sudden death, angina (due to coronary artery amyloid or microvascular dysfunction), and stroke (LV thrombus, atrial fibrillation).
CMR in amyloid is characterized by circumferential subendocardial to mid-wall late gadolinium enhancement in up to two-thirds of patients. The septum has endocardium on both sides so enhancement of both sides can result in a zebra stripe pattern of enhancement. Sub-endocardial late enhancement is in a non-coronary in distribution. The blood pool appears dark due to avid uptake of gadolinium by amyloid and consequent rapid blood pool washout. Early gadolinium enhancement imaging is useful for identifying intracardiac thrombus. Difficulties in nulling the myocardium can be clues to the presence of amyloid. Amyloid infiltration causes increases in native T1 and ECV. The amyloid burden can be quantified using ECV – something that is likely to assume greater importance for monitoring response to nascent treatments for cardiac amyloid.

Myocarditis
Acute myocarditis is defined as acute inflammatory injury of the myocardium. This can extend to involve the pericardium (peri-myocarditis). Inflammatory cardiomyopathy is the term used to describe myocarditis accompanied by ventricular dysfunction. Limited inflammation of the myocardium in the context of acute pericarditis is referred to as myo-pericarditis. Chronic myocarditis is defined as myocarditis evolving over or persisting longer than 3 months. The term fulminant is used to describe myocarditis which is both very sudden in onset and significant in severity often associated with malignant arrhythmias (ventricular tachyarrhythmias, or significant bradyarrhythmias/conduction disease) and/or cardiogenic shock.
Myocarditis is not a single disease but a group of different diseases with inflammation as a feature. The etiology can be infectious (viral, bacterial, protozoal/parasitic) or non-infectious. Non-infectious causes include autoimmune disease (e.g., connective tissue diseases, vasculitides, giant cell, sarcoidosis) as well as hereditary/genetic causes (e.g., desmosomal disease). Toxins (e.g., chemotherapy, cocaine, venoms) can also induce myocarditis.
Inflammation can cause or be the response to myocardial injury and is characterized by hyperaemia/tissue oedema, myocyte injury/necrosis, replacement fibrosis, and contractile dysfunction. CMR is an important tool for detecting myocarditis and can be used to arrive at a diagnosis or differential diagnosis. The diagnosis of acute myocarditis is made according to the modified Lake Louise Criteria which require:
– Increased regional or global myocardial T2 on T2W imaging sequences or myocardial T2 times (on T2 mapping) [T2-based criterion - oedema]
– Increased myocardial native T1, typical late gadolinium enhancement (LGE) pattern, or increased extracellular volume (ECV) [T1-based criterion – oedema/fibrosis/necrosis]
CMR may identify associated pericardial inflammation which may support the diagnosis or extracardiac features that may point towards the etiology, e.g., significant mediastinal lymphadenopathy in sarcoidosis.

Most acute myocarditis is idiopathic (unknown cause) or presumed viral/post-viral. It typically involves the basal to mid-lateral walls with epicardial to mid-wall inflammation, usually sparing the sub-endocardium. Most patients make an uncomplicated recovery but 10-20% can develop a chronic inflammatory cardiomyopathy which can manifest as heart failure and arrhythmias (including sudden cardiac death). Typical findings on CMR include epicardial to mid-wall LGE and in the acute phase, elevated myocardial T2 signal/times.

Sarcoid
This can cause an infiltrative inflammatory cardiomyopathy. As inflammation can occur anywhere in the myocardium, it can mimic other disorders. Multisystem granulomatous disorder of unknown etiology characterised by non-caseating granulomata. The myocardium is focally or diffusely infiltrated by inflammatory cells. It likely represents an immune response to a yet unidentified antigen in genetically predisposed individuals. The typical age of onset is ~25-60 years (its rare <15 or >70 years). Cardiac involvement is seen in ~5% of patients clinically but in up to 60% of patients at post-mortem. It can present as conduction defects, arrhythmias, heart failure, and sudden death. Pericarditis is uncommon but described.

On CMR, it can present with multi-focal patterns of LGE with potential involvement of all three layers (endocardial, mid-wall, epicardial). RV extension/involvement of RV aspect of the septum/RV free wall can occur as can transmural fibrosis (infarct mimic). Acute inflammation may be characterized by increased myocardial T2 signal/times (myocarditis). Detecting and monitoring inflammation (which can respond to steroids/immunosuppression) are major challenges along with risk stratification for sudden cardiac death. CMR is often combined with FDG-PET-CT imaging to evaluate disease activity/inflammation.

Toxic Cardiomyopathy
A variety of drugs and toxins can induce a cardiomyopathy. The mechanisms involved are diverse and include:
- Direct myocyte injury (e.g., anthracycline chemotherapy, alcohol) esp in genetically susceptible individuals
- Aberrant activation of the immune system (e.g., immune checkpoint inhibitor associated myocarditis)
- Drug hypersensitivity (e.g., DRESS)
- Iron overload (iron poisoning, transfusion-related iron-overload, haemochromatosis)
Inflammation may play a role acutely in many of these cardiomyopathies either as the cause of tissue injury or as a response to it. Illustrating the limitations of classifying non-ischemic cardiomyopathies by etiology alone, many patients experience cardiotoxicity due to an underlying genetic vulnerability and experience inflammation as part of this. Genetic and inflammatory components therefore can play contributory roles in pathogenesis. In clinical practice, diagnosis cannot rely on imaging findings alone but must combine clinical information, imaging, laboratory data, and where relevant, genetic information to arrive at a precise diagnosis. The exact diagnosis is the starting point for offering tailored therapy and in the case of genetic cardiomyopathies, to identifying the need to screen at-risk relatives.

Summary
Non-ischemic cardiomyopathies constitute a heterogeneous group of conditions characterized by morphological and functional ventricular abnormalities not due to coronary disease or its sequelae. CMR can be used to refine the cardiomyopathy phenotype and diagnose the presence of myocardial inflammation. Infiltrative cardiomyopathies (e.g., amyloid, sarcoid) cause marked myocardial tissue abnormalities which can be readily detected by CMR. Myocardial injury can be incited by appropriate and aberrant activation of the immune system or by exogenous toxins. Myocardial infiltration, injury, and inflammation cause abnormalities of myocardial structure, function, and tissue characteristics which can readily be detected by multi-parametric CMR.

Acknowledgements

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