From the phenotype to precision medicine: an update on the cardiomyopathies diagnostic workflow

Abstract

 

Cardiomyopathies are disease of the cardiac muscle largely due to genetic alterations of proteins with ‘structural’ or ‘functional’ roles within the cardiomyocyte, going from the regulation of contraction-relaxation, metabolic and energetic processes to ionic fluxes. Modifications occurring to these proteins are responsible, in the vast majority of cases, for the phenotypic manifestations of the disease, including hypertrophic, dilated, arrhythmogenic and restrictive cardiomyopathies. Secondary nonhereditary causes to be excluded include infections, toxicity from drugs or alcohol or medications, hormonal imbalance and so on. Obtaining a phenotypic definition and an etiological diagnosis is becoming increasingly relevant and feasible, thanks to the availability of new tailored treatments and the diagnostic advancements made particularly in the field of genetics. This is, for example, the case for transthyretin cardiac amyloidosis, Fabry disease or dilated cardiomyopathies due to laminopathies. For these diseases, specific medications have been developed, and a more tailored arrhythmic risk stratification guides the implantation of a defibrillator. In addition, new medications directly targeting the altered protein responsible for the phenotype are becoming available (including the myosin inhibitors mavacantem and aficamten, monoclonal antibodies against Ras-MAPK, genetic therapies for sarcoglycanopathies), thus making a precision medicine approach less unrealistic even in the field of cardiomyopathies. For these reasons, a contemporary approach to cardiomyopathies must consider diagnostic algorithms founded on the clinical suspicion of the disease and developed towards a more precise phenotypic definition and etiological diagnosis, based on a multidisciplinary methodology putting together specialists from different disciplines, facilities for advanced imaging testing and genetic and anatomopathological competencies.

Diagnostic approach to cardiomyopathies in the era of precision medicine

The classification of inherited heart muscle diseases remains a relevant and unsolved issue: from the initial statement of the European Society of Cardiology (ESC)¹ mainly based on the phenotypic characteristics of left ventricular morphology and function (i.e. hypertrophic, dilated, restrictive and arrhythmogenic cardiomyopathies), efforts are now underway to combine both phenotypic and genotypic information into a ‘precision medicine’ model with the aim of identifying unique signatures. According to the original ESC classification, many cardiomyopathies cannot be clearly assigned to a specific category due to overlapping phenotypic expression and variable penetrance. In the modern era, the concept of ‘precision medicine’ in inherited cardiomyopathies has emerged as a more comprehensive approach, aimed at both the achievement of a specific diagnosis and the development of an individualized management plan including targeted disease-modifying interventions when available. This review aims at summarizing the current most appropriate diagnostic workflows for/to major cardiomyopathies and at offering an update of the advancements in knowledge made in the intricate matter of genotype-phenotype correlations.

The clinical suspicion of a cardiomyopathy remains the cornerstone in the management of the disease, through a cardiomyopathy-oriented approach, based on the interpretation of clinical and instrumental findings to ultimately generate a detailed etiological diagnosis.² In this view, the phenotype recognition is just the starting point and the specific diagnosis the main goal, yet it is crucial to settle specific therapeutic interventions either to modify disease progression (i.e. chaperone therapy or enzyme replacement therapies for Fabry disease, protein transthyretin stabilizers for both familial and wild-type transthyretin-related cardiomyopathy) and/or to prevent fatal events [i.e. internal cardioverter defibrillator (ICD) implantation in cardio-laminopathies]. Patients with suspected cardiomyopathy may present through different ways, such as unexpected finding during sports medicine/work-related screening or during clinical evaluation for noncardiac surgery; because of the appearance of cardiac symptoms or events; during family screening in relatives of CMP patients; as a sudden death victim; or during workup of a multiorgan disease associated with cardiac involvement.

The basic assessment includes the collection of a detailed medical history, an accurate physical examination, first-line laboratory testing, 12-lead resting ECG and a transthoracic echocardiography, with the goal of recognizing and capturing specific features named ‘red flags’ that may guide the subsequent diagnostic workup. Depending on the suspected disease, subsequent investigations may include cardiac magnetic resonance (CMR), long-term ECG recording, and occasionally the execution of an endomyocardial biopsy (EMB). Genetic testing plays an important role in the characterization of specific cardiomyopathies, and sometimes, it has significant consequences in the management of the patient and his/her relatives. In this regard, clinicians should be aware of the paradigm shifts that have occurred in recent years: from ‘one gene – one disease’ to ‘one gene – several diseases’ to ‘several genes – one disease’. The development and progression of a cardiomyopathic phenotype depend on a complex interaction between initiated cellular signalling pathways, environmental stressors and individual genotype (including sex).³ In addition to standard genetic analysis, a multiomics approach has recently emerged as an integrated perspective, combining genomic data with transcriptomics, epigenetics and proteomics, to measure gene expression, gene activation and protein levels. Multiomics holds great promise in determining the biological pathways of cardiomyopathies that may have an impact on both diagnostic and therapeutic strategies.⁴ The combination of advanced imaging techniques with novel insights from genetics and molecular biology will likely help to overcome a purely phenotype-based classification, although at the price of introducing a considerable complexity of categorization. The use of artificial intelligence and computational analysis probably will help clinicians dealing with the challenge of moving from universal classifications to the single patient (precision medicine).⁵

Role of genetic testing in the diagnosis of cardiomyopathies

Since the development of genetic screening through the Sanger sequencing in 1977,⁶ genetic testing has rapidly improved and increased our knowledge of inherited cardiac disorders. Sanger sequencing is a DNA sequencing method able to accurately identify genetic variants. It has been the most used technique for about 40 years, until the next-generation sequencing (NGS) was developed and commercialized. The NGS is a high-throughput approach that allows the rapid screening of multiple genes at a low cost, and it has become the most used technology in clinical practice. The Sanger method is still used for smaller-scale genetic testing and validation of other sequencing results, thanks to its precision and accuracy. The more comprehensive whole-genome sequencing and whole-exome sequencing techniques permit nearly the entire DNA sequence to be processed at a single time.^7,8 These techniques have exponentially increased our ability to detect multiple genetic variants and to identify novel gene mutations associated with different aggressive phenotypes. Our genetic understanding has also been expanded by the development of genome-wide association studies– nongene-specific driven approach studies investigating single-nucleotide polymorphisms and other common variants as possible modulators of the disease expression.⁹

This greater genetic knowledge has cast doubts on the inheritance patterns of several cardiac diseases. Cardiomyopathies have always been thought to be monogenetic cardiac disorders, often with a Mendelian inheritance pattern. However, in recent decades, the genetic background of numerous cardiomyopathies has widened, and the concepts of multispectrum polygenic diseases and overlapping phenotypes have experienced a quick increase in relevance. These concepts may explain the incomplete penetrance and the variable expression of several inherited cardiac disorders. The current most accepted hypothesis is that there is a genetic spectrum ranging from (few) Mendelian disorders caused by a single genetic mutation causing a very specific disease to (several) polygenic disorders with the coexistence of different inheritance patterns within the same disease. This expanding genetic spectrum has raised the question of which gene should be tested in each specific phenotype. The increasing number of genes simultaneously screened has also exponentially increased the possibility of identifying variants of unknown significance (VUS), which should be carefully interpreted to avoid diagnostics errors.^10,11

When considering genetic testing for diagnostic purposes, it is therefore crucial to select the proper technique and panel of genes to be analysed and to account for the impact that the results of genetic testing may have on a patient's management and lifestyle.^12,13 The probability of detecting a disease-causing mutation ranges from 30% up to 70% depending on the disease and the phenotype.¹³ The principal benefit of performing genetic testing is earlier disease diagnosis in family members through clinical and genetic screening using a cascade approach starting from first-grade relatives.¹³ Those carrying the mutation without a phenotype (i.e. gene positive-phenotype negative) should be offered adequate follow-up investigations within a dedicated surveillance programme, whilst family members who have tested negative might be exempt from clinical surveillance.

In recent years, the results of genetic testing have emerged as useful tools also for patients’ management and risk stratification. There are mutations in specific genes known to be associated with worse phenotypes. In addition, it is becoming evident that not only the gene itself but also the type of genetic defect may affect the phenotype, with larger variants or variants located in specific portions of the gene being responsible for worse phenotypes.^14–18 Incorporation of genetic modifiers into the genetic testing may further expand our risk stratification capacity, although the amount of information being generated and the high costs of these procedures make this a field of abiding interest not only for clinicians and researchers, but also for computer scientists, tech companies and healthcare administrators.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a disease characterized by inappropriate hypertrophy, myocardial fibrosis and diffuse disarray with diverse phenotypic expression, clinical course and prognosis.^19,20 In the general population, HCM has prevalence of 1 : 500 persons and a higher prevalence (1 : 200) is described when both clinical and genetic diagnosis are considered.^19–22 HCM is caused by mutation in sarcomeric genes (12 identified), and it is inherited as a Mendelian autosomal dominant trait with incomplete penetrance.²³ HCM patients have different clinical presentations, natural history and prognosis, although some major clinical phenotypes can be identified: with a stable course (around 60%); with left ventricular outflow obstruction; with severe systolic or diastolic dysfunction (end-stage); with apical aneurysm; with atrial fibrillation and risk of thromboembolism and stroke; at a high risk of sudden cardiac death (SCD) with no symptoms of heart failure; and at risk of developing overt HCM (genotype-positive/phenotype-negative).²³ The diagnostic workflow is aimed at identifying the individual phenotype and the clinical progression within one of these pathways to select the proper therapeutic interventions and to improve prognosis.

Echocardiogram must assess the magnitude and distribution of left ventricular hypertrophy, presence and severity left ventricular outflow obstruction, mitral regurgitation and left atrial dimension. The distinction between obstructive and nonobstructive HCM represents a key point in the evaluation of patients with HCM. The demonstration of a reduced left ventricular ejection fraction and a restrictive left ventricular filling pattern may allow the identification of patients with end-stage phase of HCM.²² The 12-lead ECG usually shows QRS and/or S-T segment abnormalities.^19–21 The absence of ECG abnormalities does not exclude HCM, with mild and localized ventricular hypertrophy generally experiencing a benign course of the disease.²⁴

The patient interview must investigate a family history of cardiac disease and SCD in young relatives that may have important implications in clinical profiling and risk stratification.^19–21,23 It is also important to record the modality of the initial diagnosis of HCM and age at the time of diagnosis.²⁵ Presence of dyspnoea and fatigue related to the disease should be accurately investigated, as important management decisions and prognostic considerations are based on the severity of symptoms.^19–21,23 Syncope and presyncope are relatively infrequent in patients with HCM but may have important prognostic implications with regard to the risk of SCD.²⁶

CMR allows the detection of unusual patterns of left ventricular hypertrophy, such as lateral and apical distribution, the identification of apical aneurysm, right ventricular as well as papillary muscles hypertrophy, and mitral valve anomalies. Areas of myocardial late gadolinium enhancement (LGE) representing replacement fibrosis are a common finding expressed in up to 80% of the HCM population^27,28 so that only quantitative analysis (i.e. LGE >10–15% of left ventricular mass) is a robust marker of progressive systolic dysfunction and malignant arrhythmias.^21,29 CMR has also emerged as a valuable instrument to predict a positive genotype in family members without left ventricular hypertrophy and can contribute to the differential diagnosis between sarcomeric HCM and phenocopies or secondary hypertrophy.^19,21,23

Genetic testing has an essential role in identification of phenocopies (non-sarcomeric forms of left ventricular hypertrophy) and for family screening.^19,21,23 At present, genetic information cannot by itself predict prognosis and guide patient management.²³ Once a genetic variant is demonstrated in the proband, cascade genetic testing should be offered to the family. The extension of the genetic analysis to the family may identify individuals who are carriers of the sarcomeric mutation, but without left ventricular hypertrophy (gene positive/phenotype negative). The natural history of these individuals is not completely known, with some developing the complete form of the disease, whilst others remain stationary/unchanged during their lifetime.^23,30

The set of data obtained with the abovementioned diagnostic workflow allows the specific definition of the clinical phenotype of cardiac hypertrophy. However, the development of more advanced technologies is leading to the identification of more articulated pathobiological features within the main phenotypes and of ‘intermediate’ features between these phenotypes. The scientific path to these goals primarily involves genetics and imaging data. The classical paradigm of HCM as a monogenic disease has been questioned on the basis of the observation that different clinical phenotypes express different pathobiological substrates (endophenotype) that cannot be explained by the consequences of a single mutation in a sarcomeric gene.³¹ In addition, we have evidence of genetic negative forms of HCM in which two individuals from the same family show the classic disease phenotype; individuals with known pathogenic sarcomere mutation who do not have the disease phenotype even at an advanced age (up to 70 years); discordant cardiac morphology of monozygotic twins³²; population genetic studies in which 0.5% of nonsynonymous sarcomere variants are unassociated with clinical/imaging evidence of HCM³³; and a strong polygenic influence and diastolic blood pressure as a modifiable risk factor for sarcomere-negative HCM, in a large genome-wide association study.³⁴ These observations can be explained by a more complex pathogenesis of HCM with an interaction between genetic and nongenetic phenomena (epigenetics and environmental/acquired).^21,31,34

With regard to imaging, a deep learning model applied to echocardiography has been tested to quantify ventricular hypertrophy and predict the cause of increased left ventricular wall thickness (i.e. HCM versus cardiac amyloidosis).³⁵ Similarly, HCM studies have investigated the potential contribution of tissue characterization by CMR in patients’ risk stratification.³⁸

Dilated cardiomyopathy

Nonischemic dilated cardiomyopathy (DCM) is actually an ‘umbrella’ term that describes the final common pathway of different pathogenic processes and gene-environment interactions.^1,36 The clinical spectrum and presentation of DCM are extensive, ranging from heart failure to life-threatening arrhythmias, but systolic dysfunction is the most representative sign of this degenerative process.^1,37–39 In 2016, Pinto et al.⁴⁰ revised the phenotypic definition of DCM encompassing the broad clinical features and the changes of the disease over time, and introduced an intermediate phenotype named hypokinetic nondilated cardiomyopathy, in which decreased left ventricular ejection fraction is mandatory, but a combination with dilation is not fundamental. When facing a newly discovered nonischemic DCM patient, a red-flag-based cardiomyopathy-oriented approach should be systematically pursued. Collection of an accurate patient's history is the first pivotal step, which helps in raising the suspicion of specific DCM causes, guiding all subsequent evaluations. In particular, familial history (mostly focused on arrhythmic events or SCD) and a history of unexplained syncope should not be underestimated, because they might suggest a mainly arrhythmic expression of DCM. Furthermore, a specific underlying cause should be accurately searched by investigating syndromic pictures, history of supraventricular high-rate arrhythmias, alcohol or drug abuse, previous chemotherapy treatments, thyroid abnormalities or specific findings of inflammatory disease (Fig. 1). A thorough collection of the patient's medical history is extremely relevant not only in potentially reaching a final etiological diagnosis, but also for its therapeutic and prognostic implications.⁴¹

Fig. 1: The paradigm shift of clinical diagnostic approach to a cardiomyopathy patient: from a phenotype-based approach to a personalized approach, by using all the available tools, guided by the clinical suspicion.

Other fundamental tools in identifying specific forms of DCM are ECG and echocardiography, which are easily available and should be deeply analysed.⁴² Low QRS voltages or Q waves or fragmented QRS complexes could be induced by extensive myocardial fibrosis⁴³; inverted antero-lateral T waves could suggest the presence of malignant arrhythmic genotypes (i.e. DSP or FLNC); atrio-ventricular blocks could suggest mutations in LMNA other than specific inflammatory cardiomyopathies such as cardiac sarcoidosis. In most cases, enlarged QRS complexes have been identified as a predictive sign of negative prognosis.^43,44 In specific cases, left-bundle branch block can represent the cause of left ventricular dysfunction induced by ventricular dyssinchrony.⁴⁵ Echocardiography is the first imaging approach for DCM patients; left ventricular dimensions, regional contractility and left ventricular ejection fraction measurements are essential in disease identification and should be repeated at follow-up in order to monitor the progression of the disease.^43,46 Several echocardiographic findings have proven important for prognostic stratification, including right ventricle (RV) function and pulmonary pressure evaluation,^47,48 restrictive filling pattern⁴⁹ or left atrial volume.⁵⁰ From this perspective, follow-up and periodical evaluations should always be pursued in DCM, in order to monitor therapeutic response and to offer the right therapeutic option at the right time.

Additional diagnostic and prognostic information is offered by tissue characterization obtained through CMR.⁵¹ LGE is the most relevant noninvasive tool in searching for fibrous and scar tissue in myocardial tissue; it has been demonstrated in up to 35–40% of DCM patients with three different patterns being described⁵² and midwall distribution being the most frequent and specific one.⁵³ LGE presence, patterns of distribution and extension have been related to a higher global risk, mostly related to arrhythmic events independently of the amount of left ventricular dysfunction.^54,55

The role of EMB, guided by clinical suspicion, remains essential in differential diagnosis of DCM with inflammatory cardiomyopathies (i.e. sarcoidosis or myocarditis). Histologic findings from EMB may guide clinicians in therapeutic management,^56,57 and have become fundamental in the characterization of the ‘hot phase’ of arrhythmogenic cardiomyopathy (ACM).^58,59

Genetic testing is finally an emerging tool for the accurate management of DCM, improving precise diagnosis, prognostic risk stratification and guiding therapeutic decisions in a growing number of cases. Genetic testing in the proband and in relatives is recommended by the most recent guidelines and position papers.^60–62 Familial patterns and genetic mutations have been identified as pathogenic in nearly 50% of previously defined ‘idiopathic’ DCM.^63,64 On the other hand, the genetic background of DCM is a complex and evolving issue. More than 50 genes encoding for sarcomeric proteins, cytoskeleton, sarcolemma, nuclear envelope, ion channels and intercellular junctions have been found to be involved in DCM, and the real extent of genes causing DCM is still unknown. Furthermore, the same gene mutation has been associated with different cardiomyopathies, and a precise correlation between clinical presentation and genetic mutation is lacking. A significant genetic overlap is emerging among DCM, HCM, ACM and channelopathies.^65–67 Notably, DCM and ACM present overlapping phenotypic and genotypic characteristics in the so-called ‘arrhythmogenic cardiomyopathy’^64,68; nonetheless, the knowledge of a specific genetic background (i.e. LMNA, FLNC, PLN and desmosomal gene mutations) remains useful in considering ICD implantation in primary prevention, even in absence of severe left ventricular dysfunction.^69,70

Arrhythmogenic cardiomyopathy

ACM is an inherited cardiac disease clinically characterized by ventricular morpho-functional abnormalities and presence of ventricular arrhythmias that can even lead to SCD.⁷¹ The disease prevalence is difficult to estimate due to frequent misdiagnoses, but it reasonably ranges from 1 : 1000 to 1 : 5000.⁷¹ The first diagnostic criteria were established in 1994, when an international task force (ITF) selected a series of clinical and instrumental parameters that had to be considered in the diagnostic workup.⁷² These criteria included family history of ACM, typical ECG features, presence of ventricular arrhythmias, histopathological findings, as well as structural and functional parameters of the RV.⁷² These ITF diagnostic criteria were grouped into six different categories and were classified as ‘major’ or ‘minor’ according to their specificity for detecting ACM. Diagnosis was reached in the presence of two major criteria or one major as well as two minor or four minor criteria from different categories. The 1994 criteria were a first attempt to bring order to a complex clinical context and were characterized by a good specificity for ACM; nonetheless, they lack sensitivity for certain phenotypes and early forms of the disease. For these reasons, a revised version of the ITF criteria was published in 2010.⁷³ In this latter classification, a multiparametric approach was retained, although revised. In detail, quantitative imaging references to define RV dimensions and function by means of echocardiography, ventricular angiography and CMR were included. Furthermore, a definition and quantitative assessment of fibro-fatty replacement at EMB of the myocardium was incorporated. Presence of T-wave inversion in V1–V3 as well as of ventricular tachycardia with a left-bundle branch block morphology with superior/indeterminate QRS axis, either sustained or nonsustained, became the major criteria. Among the novelties of the 2010 revised ITF criteria was the inclusion of genetic test results as a major criterion, due to the growing number of genetic studies demonstrating that several genes, mainly encoding for desmosomal proteins, were linked to ACM. In 2019, an international expert report emphasized some criticisms of the 2010 revised ITF criteria, considering new achievements obtained in detailing the wide phenotypic spectrum of the disease, mainly through CMR and genetic studies.⁷⁴ In 2020, a new consensus document including the so-called ‘Padua criteria’ was published, with the aim of overcoming limitations of previous diagnostic criteria, in particular with regard to diagnosis of left dominant forms of ACM.^75,76 Apart from revising certain parameters included in the diagnostic categories, the ‘Padua criteria’ provided a phenotypic classification of the disease into three forms: the ‘dominant-right’ variant [the classic arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) phenotype] characterized by the predominant RV involvement, with no or minor LV abnormalities; the ‘biventricular disease’ variant, characterized by the involvement of both RV and LV; and the ‘dominant-left’ variant (also referred to as ALVC) characterized by LV involvement, with no or minor RV abnormalities. The main innovation of the 2020 criteria was the introduction of tissue characterization findings by LGE for detection of fibro-fatty myocardial replacement of both ventricles. In addition, new criteria were added to increase the diagnostic sensitivity for ALVC, including peculiar ECG features (such as inferolateral T-wave inversion, low QRS voltages) and ventricular arrhythmias of left ventricular origin.⁷⁵

Patients usually receive medical attention due to detection of arrhythmic symptoms and/or ventricular arrhythmias, ECG abnormalities, imaging features suggesting ACM and/or a family history of ACM or SCD. The first diagnostic step consists of a careful personal and familial medical history collection with pedigree reconstruction, physical examination, 12-lead ECG and echocardiography. In addition, patients should undergo 24-h Holter ECG and stress test to ascertain the arrhythmic burden. CMR has become an essential component of the diagnostic workup, mostly because it allows an early identification of left ventricular involvement, which is often silent on the echocardiogram. In patients fulfilling ACM diagnostic criteria, a genetic test is indicated, considering that in 50–60% of cases pathogenic variants can be identified, potentially allowing presymptomatic diagnosis in family members. In the absence of a positive genetic test, clinical and instrumental evaluation with systematic follow-up in all first-degree relatives should be performed. In patients with possible ALVC forms, genetic testing and family screening are mandatory to achieve the diagnosis. Furthermore, in ALVC cases with negative genetic testing and absence of family history, it is necessary to rule out possible disease phenocopies, mainly DCM, cardiac sarcoidosis and myocarditis. In this context, EMB can have a pivotal role for differential diagnosis. Finally, in ACM patients, chest pain episodes accompanied by electrocardiographic changes and troponin release have been described and defined as ‘hot-phases’ of the diseases. These episodes are more common in ALVC phenotype and can in some cases be the initial presentation of the disease, entering into differential diagnosis with acute myocarditis.^58,77 A genetic background can be found in 12% of cases and desmoplakin seems to be the more common disease-gene, even if genetic variants of other desmosomal and non desmosomal genes have been reported. At present, the role of hot-phases episodes in disease progression and in arrhythmic risk evaluation still need further investigations in large cohorts of patients.^58,77

Rare diseases

Rare cardiomyopathies represent a broad group of disorders whose clinical phenotypes are similar to those of the four ‘classic’ morphologic subgroups of HCM, DCM, ACM and restrictive cardiomyopathies, but significantly differ in terms of cause, pathophysiology, risk stratification and treatment.⁷⁸ The identification of the etiological substrate of each specific cardiomyopathy has significant repercussions on the patient's management and prognosis, especially in those causes for which a targeted therapy is available.^78–82

Once the ‘phenotypic diagnosis’ of a cardiomyopathy has been made, it is mandatory to reach a definitive ‘etiological diagnosis’. A comprehensive assessment in the context of a dedicated multidisciplinary team of experts is required to improve the diagnostic workup and provide a tailored treatment.⁷⁸ Attention should be paid to the identification of potential diagnostic clues (‘red flags’), whose presence could orient the diagnostic suspicion towards a specific disease cause.^78,83,84 Examples of this ‘red flags’ approach for the diagnosis of rare cardiomyopathies are reported below.

Age and clinical presentation represent the first diagnostic clues in patients with cardiomyopathy. Presentation with HCM and biventricular obstruction in infants (often due to pulmonary valve or subvalvular stenosis) is a common clinical onset of RASopathies.^83,85,86 In contrast, heart failure with preserved ejection fraction presentation in an elderly patient with a hypertrophic-restrictive phenotype should raise the suspicion of cardiac amyloidosis.^80,87,88

ECG is abnormal in most patients with cardiomyopathy and could present a specific pattern of abnormalities. For example, atrio-ventricular blocks are common in patients with hypokinetic/dilated phenotype with cardiac sarcoidosis.⁸⁹ At the same time, ventricular preexcitation could be observed in patients with storage (i.e. Danon disease, PRKAG2 syndrome, Pompe disease) or mitochondrial disorders.^78,82 Echocardiography is essential to define the cardiomyopathy phenotype and could offer diagnostic insights. The observation of biventricular hypertrophy, restrictive physiology, granular sparkling appearance of the myocardium and increased thicknesses of the cardiac valve is typical of cardiac amyloidosis.^80,87,88 A massive symmetric left ventricular hypertrophy in a child is consistent with metabolic or storage disorders, or the coexistence of concentric left ventricular hypertrophy and systolic dysfunction leads to the suspicion of storage or mitochondrial disorders.^78,82 CMR offers an incremental contribution to the diagnosis of cardiomyopathy, given its high spatial resolution and the possibility of defining the intrinsic magnetic properties of the myocardium and the distribution pattern of gadolinium-based contrast agents.^90,91 Abnormal findings may be related, among others, to myocardial fibrosis, amyloid infiltration, iron storage, fibro-fatty replacement or myocardial oedema.⁹² Routine laboratory assessment can be helpful in the detection of extra-cardiac conditions that could be interpreted in the context of a systemic cause of cardiomyopathy (i.e. creatine phosphokinase increases in glycogen storage disorders, proteinuria in Fabry disease or amyloidosis).^78,80,82,83

Next to these first-line diagnostic investigations and according to the clinical suspicion, additional investigation may be required (i.e. bone scintigraphy for transthyretin cardiac amyloidosis, muscle biopsy for some neuromuscular/mitochondrial disorders, PET for cardiac sarcoidosis).^78,80 Genetic testing and the introduction of NGS panels have significantly increased the diagnostic yield and are strongly recommended for diagnosis and family screening.^93–95 Recently, the application of artificial intelligence has been shown to improve diagnostic ability in the early phase of rare disease (i.e. cardiac amyloidosis).⁹⁶ Finally, the identification of the genetic cause is crucial for understanding prognosis and has the potential to result in personalized medical care^78–81,95 (Table 1). For instance, Noonan syndrome is among the leading causes of infantile HCM and carries a high risk for early mortality.⁸⁵ Pathophysiological-based treatment has been shown to reverse HCM phenotype and improve clinical status in patients with RASopathies, and could be available in the future.⁹⁷ Another example is represented by enzyme replacement therapy in patients with Fabry disease, whose use has been demonstrated to be associated with a better prognosis and quality of life.^81,91

Table 1 - Examples of future therapies for specific causes of rare cardiomyopathies

Disease	Future therapies
Noonan syndrome	MEK inhibitors	Case reports has shown the ability of trametinib to reverse LVH in patients with Noonan syndrome
Noonan syndrome with multiple lentigines	mTOR inhibitors	In mouse models, the administration of rapamycin induced regression of LVH
Pompe disease	Gene therapy	In mouse models, gene therapy has shown significant improvement in metabolic and physiologic function
Danon disease	Gene therapy	In mouse models, gene therapy has shown significant improvement in metabolic and physiologic function
Cori-Forbes disease	Gene therapy	In mouse models, gene therapy has shown significant improvement in muscle function
TTR amyloidosis	RNA-targeting therapy	Several clinical trials have been recently published or ongoing (APOLLO, 2018, Adams D et al. NEJM; ENDEAVOUR, 2020, Judge DP et al. Cardiovasc Drug Ther; HELIOS-B, 2022, ongoing; CARDIO-TTRansform, 2022, ongoing)
Fabry disease	Gene therapy	In a pilot trial, gene therapy was associated with a significant reduction in Gb3 and lyso-Gb3 levels.
DMD	Gene Therapy	In mouse models, gene therapy has shown significant improvement in muscle function
Lamin A/C	MAPK inhibitors	A phase 3 trial is currently ongoing (REALM-DCM, 2018, ongoing)

DMD, Duchenne muscular dystrophy; HCM, hypertrophic cardiomyopathy; TTR, transthyretin.

Conclusion

A cardiomyopathy-oriented mindset is key to a prompt etiological diagnosis and an optimal patient's management (Fig. 1). The collection of a detailed and wide medical history, a more educated interpretation of information derived from basic cardiologic evaluations and the increased availability of advanced diagnostic tools including genetics are determining a rapid increase in the current knowledge of several cardiomyopathies, and revealing unexpected genotype–phenotype correlations. Therapeutic options are quickly entering the market for specific subsets of patients with peculiar genetic mutations causing alterations of proteins with structural or functional roles within the cardiomyocyte. Cardiologists should be kept aware of the advancements that are continuously made in the field of cardiomyopathies, to offer the best diagnostic and therapeutic options to their patients, aiming towards a -- always more -- personalized approach.