In their pioneering work of the late 1960s and early 1970s, John Goodwin, Celia Oakley, and others laid the groundwork for what would later be recognized as distinct clinical entities of cardiomyopathies. Although definitions have evolved over time, their prescient insight that “it seems likely that the pathogenesis of congestive cardiomyopathy is also multifactorial and that the diagnosis denotes not a disease but an end‑result of which there may be many causes” remains valid today.¹ This concept continues to resonate, as reflected in the European Society of Cardiology guidelines published in 2023.² A key tenet of those guidelines is that classification of cardiomyopathy into dilated, hypertrophic, or restrictive phenotypes should serve only as a point of departure for determining etiology.

Broadly speaking, the etiology of dilated cardiomyopathy (DCM) can be categorized as either genetic or nongenetic, although interplay between these dimensions, and overlapping causes, is often observed. In keeping with both the European and Polish recommendations, an etiology‑driven approach incorporating genetic testing (GT) is now advocated in managing cardiomyopathies.^2-4

In this issue of Polish Archives of Internal Medicine, Chmielewski and colleagues from the National Institute of Cardiology in Warsaw, Poland present their work on the genetic architecture of DCM.⁵ Among 280 DCM patients who underwent GT between 2012 and 2021, pathogenic (P) or likely pathogenic (LP) variants in 1 of the DCM‑associated genes were identified in 130 individuals (46%). Predictably, the most prevalent P/LP variants affected the titin (TTN; 39% of gene‑positive cases) and lamin A/C (LMNA; 17%) genes, followed by the desmoplakin (DSP), myosin heavy chain 7 (MYH7), sodium voltage‑gated channel subunit 5 (SCN5A), filamin C (FLNC), BCL2‑associated athanogene (BAG3), and dystrophin (DMD) genes. Apart from atrial arrhythmias and atrioventricular block, which were more common in the gene‑positive cohort, and left bundle branch block and hypertension, which were more prevalent in the gene‑negative group, no other baseline clinical differences were noted. Prognosis, however, varied— the gene‑positive patients had worse outcomes, with increased incidence of severe symptoms and a higher rate of the composite end point of death, heart transplantation, or left ventricular assist device implantation.

Further subgroup analyses revealed that the TTN-positive patients had outcomes comparable to those with nongenetic DCM, indicating that adverse prognosis was primarily driven by non-TTN variants. Collectively, these findings reinforce the clinical value of GT in DCM, underscoring its feasibility and clinical relevance. Importantly, the study uncovers a gap in the literature—unlike cohorts in Western Europe and the United States, the genetic background of Central European patients remains insufficiently mapped.

The authors deserve sincere recognition for their pioneering and sustained contributions in integrating GT into the clinical and research landscape of Polish cardiology. Indeed, they were the first in the country to publish in this domain, and this study stands as the most extensive investigation into the genetic basis of DCM conducted in Poland to date.

While impactful, these findings must be contextualized globally. Based on the accumulated evidence from well‑characterized cohorts in Western Europe and the United States, P or LP variants have been identified in approximately 30%–40% of DCM patients.^2,6,7 This discrepancy naturally raises a critical question: does the genetic architecture of DCM differ meaningfully across European regions? Beyond the present study by Chmielewski et al,⁵ which originates from a major referral center in central Poland, only 1 other medium‑sized prospective study has been published in Poland, specifically in Kraków, covering the southeastern region of the country.⁸ In that cohort, P/LP variants were identified in 24 out of 102 DCM patients (23.5%) diagnosed between 2019 and 2020. The TTN variants were the most prevalent, whereas no P/LP variants were found in the LMNA gene. These regional differences are noteworthy: southeastern Poland reported a lower prevalence of genetically determined DCM (23.5%), as compared with 46% observed in central Poland, which aligns more closely with international cohorts. Both Polish studies consistently identified the TTN gene as the dominant genetic contributor—a reassuring finding given its alignment with global data. Regional genetic heterogeneity is not without precedent, as also documented in Polish patients with familial hypercholesterolemia.⁹

Here, it is worth noting the underlying complexity of DCM genetics. Evidence of causality exists across multiple gene categories, including sarcomeric proteins (MYH7, MYBPC3), nuclear envelope components (LMNA), cytoskeletal proteins (DES, FLNC), desmosomal elements (DSP), sarcoplasmic reticulum (PLN), cochaperone / heat shock proteins (BAG3), RNA‑binding proteins (RBM20), and sodium ion channels (SCN5A). Thus, unlike hypertrophic cardiomyopathy, which is by definition a “disease of sarcomeres,” the genetic architecture of DCM is broad and heterogeneous, making both the testing and interpretation more demanding.^2-4,10,11

Of course, identifying a precise etiology of DCM extends beyond the inherited factors. Numerous nongenetic causes must also be taken into account, including inflammation (myocarditis), autoimmune diseases, toxins (alcohol and drug abuse), medications (chemotherapeutic agents), endocrine dysfunction, tachyarrhythmias, nutritional deficiencies, and neuromuscular disease.¹² Such diversity engenders clinical heterogeneity—despite patients being grouped under the same diagnostic “umbrella” of DCM. Therefore, the authors’ dichotomous differentiation into genetic and nongenetic DCM, while clinically pragmatic, arguably oversimplifies a more nuanced and multifaceted reality. Granular phenotyping of the nongenetic subgroup would likely reveal distinct subgroups with unique clinical characteristics and outcomes.¹³

Nevertheless, the study makes a compelling case for the practical value of GT. As demonstrated, the patients harboring non-TTN pathogenic variants are at a significantly elevated risk for adverse outcomes. This is further supported by recent findings of Wiśniowska-Śmiałek et al,¹⁴ which corroborate this distinction, showing that replacement fibrosis progressed exclusively in patients with genetic DCM, while remaining stable in those with toxic, inflammatory, tachyarrhythmic, or idiopathic etiologies.

In summary, DCM presents with striking heterogeneity both in its genetic underpinnings and nongenetic origins. Even within these overarching categories, the etiological spectrum is wide and frequently overlapping. Chmielewski et al⁵ have provided new insights into these poorly elucidated genetic causes of cardiomiopathy. However, numerous questions remain, and a comprehensive understanding of DCM in Poland and beyond has yet to fully emerge.