Diagnostic work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases 

Abstract

In 2008, The ESC Working Group on Myocardial and Pericardial Diseases proposed an updated classification of cardiomyopathies based on morphological and functional phenotypes and subcategories of familial/genetic and non-familial/non-genetic disease. In this position statement, we propose a framework for the clinical approach to diagnosis in cardiomyopathies based on the recognition of diagnostic ‘red flags’ that can be used to guide rational selection of specialized tests including genetic analysis. The basic premise is that the adoption of a cardiomyopathy-specific mindset which combines conventional cardiological assessment with non-cardiac and molecular parameters increases diagnostic accuracy and thus improves advice and treatment for patients and families.

Introduction

In 2008, The ESC Working Group on Myocardial and Pericardial Diseases proposed an updated classification of cardiomyopathies that was designed to integrate current and future knowledge of the molecular basis of heart muscle diseases into everyday clinical practice.1 Being clinically oriented, this classification was based on morphological and functional phenotypes rather than putative pathophysiological mechanisms. Subcategories of familial/genetic and non-familial/non-genetic disease were proposed to highlight the importance of genetic mechanisms in cardiomyopathies.

In this position statement, we discuss the implications of this classification system for the diagnostic pathways that should be used in patients with a definite or suspected cardiomyopathy. The basic premise is that the adoption of a cardiomyopathy-specific mindset that combines conventional cardiological assessment with non-cardiac and molecular parameters increases diagnostic accuracy and improves advice and treatment for patients and families. A fundamental tenet of this approach is that the systematic search for diagnostic clues or ‘red flags’ can identify particular disorders and guide rational selection of diagnostic tests, including molecular genetic analysis. Importantly, each stage of the clinical pathway from history to molecular testing has value—in other words, the most technologically sophisticated (and expensive) examinations are not necessarily the most informative.

This statement is not meant to be an exhaustive compendium of all possible causes of heart muscle disease, but is designed instead to provide a conceptual template for diagnosing cardiomyopathies. The focus is predominantly on genetic forms of cardiomyopathy, but inflammatory diseases will be considered in a forthcoming position statement by the working group. The structure of the document follows the traditional stepwise approach of history, physical examination, electrocardiography, and cardiac imaging. Tests that should be performed routinely in all patients with suspected heart muscle disease are proposed, along with more specialized tests and their indications. This document does not consider diseases confined exclusively to neonates and infants, but does refer to conditions that affect adolescents and which can be diagnosed in adulthood. Whenever possible, each of the main phenotypes (i.e. dilated, hypertrophic, restrictive, and right ventricular cardiomyopathies) is considered separately.

Rationale for a cardiomyopathy-focused clinical approach

Cardiomyopathies are defined as myocardial disorders in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease sufficient to explain the observed myocardial abnormality.1 They are grouped into specific morphological and functional phenotypes, with each phenotype subclassified into genetic and non-genetic forms (genetic in this context referring to single gene mutations). Patients with cardiomyopathy can present for the first time with symptoms of heart failure, arrhythmia (including cardiac arrest), syncope, and chest pain, but many are diagnosed incidentally or during family screening. Once a morphological diagnosis has been made, further investigations are often protocol rather than hypothesis driven, but this approach can fail to identify an underlying disease mechanism. In this document, we propose a complementary diagnostic strategy built on an understanding of the complex aetiology and clinical presentation of heart muscle disorders. This approach does not necessarily involve the use of novel or particularly sophisticated tests, but it does require deliberate analysis of every aspect of the individual and their family as well as an integrated probabilistic interpretation of cardiac investigations. The details of this scheme differ to a greater or lesser extent between cardiomyopathies, but there are some common principles: We acknowledge from the outset that many recommendations and statements in this document are based on consensus opinion rather than a strong evidence base, but this is meant to be a flexible document that can be adapted to new knowledge as it emerges.

  • Elucidation of a specific cause for a cardiomyopathy can directly influence management of patients and their relatives.
  • Some cardiomyopathies are caused by single gene mutations, whereas others show familial aggregation as a result of a complex genetic background and an interaction with environmental triggers.
  • Diagnostic criteria in familial disorders can differ between probands and their relatives.
  • In the context of a familial disease, the information provided by the relatives can offer diagnostic clues because of the variable expression of the disease.
  • Reanalysis of clinical data is required throughout the diagnostic process as further information emerges.
  • The approach to patients with definite or suspected cardiomyopathy should be multidisciplinary in nature.

Clinical and family history

Although an unfocused dialogue with the patient may be necessary at the initial contact, this is not the optimal way of making a diagnosis. Deliberate exploration of diagnostic hypotheses is preferable; in other words, every question—however extemporary—needs to be hypothesis driven. The first step in achieving a diagnosis is to consider the personal and family history of the affected individual.

Age at diagnosis or first presentation is an important pointer to aetiology in all subtypes of cardiomyopathy. In neonates and infants, for example, inborn errors of metabolism and congenital dysmorphic syndromes are much more common than in older children or adults.2–4 In contrast, wild-type transthyretin (TTR)-related amyloidosis is a disease of older individuals.

Personal and family history

After exclusion of common causes of ventricular dysfunction such as hypertension, myocardial ischaemia, valve dysfunction, and prior exposure to toxins and environmental pathogens, the cardiologist should systematically consider the probability of a genetic origin of the cardiomyopathy.5,6 Cardiac and extra cardiac personal history should be recorded, especially when there is the possibility of a syndromic or metabolic cause of cardiomyopathy (see section dedicated to symptoms and physical examination). The next step is to take a detailed family history in order to identify other family members known or suspected to be affected by a myocardial disease or that have features suggestive of a genetic disorder; for example, a history of sudden cardiac death, heart failure, cardiac transplantation, pacemaker/defibrillator, stroke in a young individual, and skeletal muscle disease. This process is facilitated by the construction of a three- to four-generation family pedigree. This requires time and skill to create, but is essential as it helps to determine the probability of familial disease, the likely mode of inheritance, and identifies other clinical features that can provide aetiological clues. Importantly, a ‘negative’ family history does not exclude a genetic aetiology because the disease may be the result of a de novo genetic mutation or, more frequently, an unrecognized myocardial disease in the family. In addition, since a proportion of patients with suspected idiopathic dilated cardiomyopathy or suspected myocarditis may have an underlying immune-mediated inflammatory process, it is important to identify non-cardiac autoimmune diseases in the index case and in family members (e.g. type I diabetes mellitus, autoimmune thyroid disease, etc.), since familial aggregation is a feature of autoimmune disease.

A major objective of pedigree analysis is determination of the mode of genetic transmission. This not only allows identification of other clinically affected family members, but also helps refine the initial diagnosis of the proband. This aspect is especially relevant in families with mixed phenotypes. Table 1 summarizes the type of inheritance of the most common cardiomyopathies.

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