Cause Of Dilated Cardiomyopathy Research Articles

Truncated titin is incorporated into the sarcomere in human cardiac samples with dilated cardiomyopathy

The most common genetic cause of dilated cardiomyopathy (DCM) is mutations in titin gene, TTN, with truncating variants (TTNtv). TTN encodes the giant protein titin, a large (3-4 MDa) and abundant protein that forms the third myofilament type of striated muscle. Titin spans half the sarcomere, from the Z-disk to the M-line. The underlying mechanisms by which titin mutations induce DCM are poorly understood.

Deletion of the Lmna gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype

Introduction:Mutations in the LMNA gene, encoding Lamin A/C (LMNA), are established causes of dilated cardiomyopathy (DCM). The phenotype is typically characterized by progressive cardiac conduction defects, arrhythmias, heart failure, and premature death. DCM is primarily considered a disease of cardiac myocytes. However, LMNA is also expressed in other cardiac cell types, including fibroblasts.Aim:The purpose of the study was to determine the contribution of the fibroblasts to DCM caused by LMNA deficiency.Methods and Results:The Lmna gene was deleted by crossing the platelet-derived growth factor receptor α-Cre recombinase (Pdgfra-Cre) and floxed Lmna (LmnaF/F) mice. The LMNA protein was nearly absent in ~80% of the cardiac fibroblasts and ~25% of cardiac myocytes in the Pdgfra-Cre:LmnaF/F mice. The Pdgfra-Cre:LmnaF/F mice showed an early phenotype characterized by cardiac conduction defects, arrhythmias, cardiac dysfunction, myocardial fibrosis, apoptosis, and premature death within the first six weeks of life. The Pdgfra-Cre:Lmnawild type/F (LmnaW/F) mice also showed a similar but slowly evolving phenotype that was expressed within one year of age. RNA sequencing of LMNA-deficient and wild-type cardiac fibroblasts identified differential expression of ~410 genes, which predicted activation of the TP53 and TNFA/NFκB and suppression of the cell cycle pathways. In agreement with these findings, levels of phospho-H2AFX, ATM, phospho-TP53, and CDKN1A, markers of the DNA damage response (DDR) pathway, were increased in the Pdgfra-Cre:LmnaF/F mouse hearts. Moreover, expression of senescence-associated beta-galactosidase was induced and levels of the senescence-associated secretory phenotype (SASP) proteins TGFβ1, CTGF (CCN2), and LGLAS3 were increased as well as the transcript levels of additional genes encoding SASP proteins in the Pdgfra-Cre:LmnaF/F mouse hearts. Finally, expression of pH2AFX, a bonafide marker of the double-stranded DNA breaks, was increased in cardiac fibroblasts isolated from the Pdgfra-Cre:LmnaF/F mouse hearts.Conclusion:Deletion of the Lmna gene in fibroblasts partially recapitulates the phenotype of the LMNA-associated DCM, likely through induction of double-stranded DNA breaks, activation of the DDR pathway, and induction of expression of the SASP proteins. The findings indicate that the phenotype in the LMNA-associated DCM is the aggregate consequence of the LMNA deficiency in multiple cardiac cells, including cardiac fibroblasts.

Generation of a human induced pluripotent stem cell line YCMi004-A from a patient with dilated cardiomyopathy carrying a protein-truncating mutation of the Titin gene and its differentiation towards cardiomyocytes

Dilated cardiomyopathy (DCM) is a heart muscle disease that causes heart failure and is the leading cause for heart transplantation. It is a heart muscle disease resulted from a variety of genetics, toxic, metabolic, and infectious causes. One of the most prevalent genetic causes of DCM is a protein-truncating variant in the Titin gene (TTNtv). We have generated a human-induced pluripotent stem cell (hiPSC) line from patients who underwent heart transplantation due to DCM carrying a TTNtv mutation (c.70051C > T, p.Arg23351Ter) at the age of 20. The generated hiPSCs showed normal karyotype (46, XY) and expression of pluripotency markers, and were differentiated towards cardiomyocytes successfully.

A heterozygous TTN (c. 79,684C>T) mutant human induced pluripotent stem cell line (ZZUNEUi023-A) generated from a Kazakh patient with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a nonischaemic heart muscle disease with structural and functional myocardial abnormalities. TTN truncating mutations are a common cause of DCM, occurring in ∼25% of familial cases of DCM and in 18% of sporadic cases. In this study, we generated a human induced pluripotent stem cell line ZZUNEUi023-A from peripheral blood mononuclear cells of a Kazakh DCM patient with the p. Arg26562Ter (c. 79684C>T) mutation in TTN using non-integrative Sendai virus. This cell line expressed pluripotency markers, showed normal male karyotype and could differentiate into all three germ layers in vitro.

Poorly controlled hypertension as a cause of dilated cardiomyopathy and cardiac decompensation - case report

Poorly controlled hypertension as a cause of dilated cardiomyopathy and cardiac decompensation - case report

Role of Cardiac Magnetic Resonance Imaging in Hypocalcemia-Induced Dilated Cardiomyopathy in Pediatric Population.

Background Hypocalcemia is a rare reversible cause of dilated cardiomyopathy in pediatric population. Myocarditis is another more frequent cause of cardiomyopathy with overlapping presenting features. Cardiac magnetic resonance imaging (CMRI) is a vital modality capable of tissue characterization for the evaluation of cardiomyopathy. The present study is the first attempt to determine if any specific characteristics on CMR exist in patients with hypocalcemic dilated cardiomyopathy. Methods A retrospective analysis of 10 cases of hypocalcemic dilated cardiomyopathy (August 2012–August 2019), among which CMRI of nine patients were analyzed. Patients were categorized in to three categories; category 1 defined as absence of edema and late gadolinium enhancement (LGE), category 2 having edema only, and category 3 with presence of both edema and LGE. A diagnosis of myocarditis was considered if both edema and LGE were present. Results The mean age of the cohort was 5.5 ± 3.3 months. The mean ejection fraction of the cohort was 20.5 ± 6.85% that improved significantly to 35.22 ± 9.3% at the time of discharge. Five of nine patients had no edema or LGE (category 1), whereas two patients each were categorized into category 2 and 3. All cases in category 1 had normalized ventricular function on follow-up. One patient in category 2 had normal ejection fraction and one was lost to follow-up. Out of the two patients in category 3, there was one mortality and another was lost to follow-up. Of the six patients at follow-up (19 ± 11.0 months), the mean left ventricle ejection fraction improved to 56.5 ± 6.1%. Conclusion Hypocalcemic dilated cardiomyopathy has a favorable outcome on rapid initiation of treatment. CMR can be utilized for further prognostication of these patients. Absence of edema and LGE predicts a good outcome, whereas presence of LGE and/or edema either indicates a worse prognosis or an underlying coexistent myocarditis warranting an early myocardial biopsy.

Immune Mechanism, Gene Module, and Molecular Subtype Identification of Astragalus Membranaceus in the Treatment of Dilated Cardiomyopathy: An Integrated Bioinformatics Study.

Astragalus membranaceus has complex components as a natural drug and has multilevel, multitarget, and multichannel effects on dilated cardiomyopathy (DCM). However, the immune mechanism, gene module, and molecular subtype of astragalus membranaceus in the treatment of DCM are still not revealed. Microarray information of GSE84796 was downloaded from the GEO database, including RNA sequencing data of seven normal cardiac tissues and ten DCM cardiac tissues. A total of 4029 DCM differentially expressed genes were obtained, including 1855 upregulated genes and 2174 downregulated genes. GO/KEGG/GSEA analysis suggested that the activation of T cells and B cells was the primary cause of DCM. WGCNA was used to obtain blue module genes. The blue module genes are primarily ADCY7, BANK1, CD1E, CD19, CD38, CD300LF, CLEC4E, FLT3, GPR18, HCAR3, IRF4, LAMP3, MRC1, SYK, and TLR8, which successfully divided DCM into three molecular subtypes. Based on the CIBERSORT algorithm, the immune infiltration profile of DCM was analyzed. Many immune cell subtypes, including the abovementioned immune cells, showed different levels of increased infiltration in the myocardial tissue of DCM. However, this infiltration pattern was not obviously correlated with clinical characteristics, such as age, EF, and sex. Based on network pharmacology and ClueGO, 20 active components of Astragalus membranaceus and 40 components of DMCTGS were obtained from TCMSP. Through analysis of the immune regulatory network, we found that Astragalus membranaceus effectively regulates the activation of immune cells, such as B cells and T cells, cytokine secretion, and other processes and can intervene in DCM at multiple components, targets, and levels. The above mechanisms were verified by molecular docking results, which confirmed that AKT1, VEGFA, MMP9, and RELA are promising potential targets of DCM.

A Very Rare Cause of Dilated Cardiomyopathy after Bariatric Surgery: Selenium Deficiency

Background: Sleeve gastrectomy for weight loss has increased significantly nowadays. Various complications may develop after this surgery that requires long-term follow-up of these patients. Nutrition is the most important aspect of the follow-up. The deficiency of trace elements, fat-soluble and water-soluble vitamins following bariatric surgeries have been well-described complications. Although nutritional supplementations are often initiated after bariatric surgery, the clinical outcomes related to the deficiency of trace elements have not been well known yet. Case Presentation: A 27-year-old woman who underwent a laparoscopic sleeve gastrectomy for surgical treatment of obesity 9 months ago presented to the emergency department with a signs of heart failure. Transthoracic echocardiography revealed dilated, poorly functioning left ventricle with reduced ejection fraction (28.9%) consistent with dilated cardiomyopathy. We assumed nutritional deficiencies secondary to sleeve gastrectomy as a cause of dilated cardiomyopathy, as the patient had inappropriate nutritional supplements after surgery. Laboratory tests revealed selenium and zinc deficiency that supported our hypothesis. Our patient completely recovered with adequate supplementation of selenium, zinc and thiamine. Conclusion: We highlighted that the early diagnosis of dilated cardiomyopathy due to selenium deficiency following bariatric surgery is of great importance since selenium deficiency is a cause of reversible cardiomyopathy.

A Case Report on Ischemic Dilated Cardiomyopathy with Compensated Alcoholic Liver Disease with Acute Pancreatitis and Right Sided Pleural Effusion

Introduction: Ischemic heart disease is the most common cause of dilated cardiomyopathy. In ischemic heart disease, the capability of the coronary heart to pump blood is reduced due to the fact that the principle pumping chamber of the heart, the left ventricle, is enlarged and dilated. This is due to a loss of blood supply to the heart muscles due to coronary artery disorder. This condition is sometimes referred to as dilated cardiomyopathy.
 Clinical Finding: shortness of breath since 3 months, dry cough, loss of appetite, loss of weight (Weight 50 Kg), lower limb swelling, increased frequency of stools since 3 months.
 Diagnostic Evaluation: chest x-ray right hydropneumothorax, ECG QS complexes in V1, V2, V3, 2 D Echo ejection fraction 15%, all chambers dilated, poor biventricular systolic function, mild mitral regurgitation, tricuspid regurgitation.
 USG for liver mild hepatomegaly, USG for thorax gross pleural effusion on right side,
 CECT Abdomen bulky tail of pancreas, right side pleural effusion with collapse of underlying lung.
 Therapeutic Intervention: Patient was treated with diuretics, alpha and beta-blocker, angiotensin receptor, Antibiotic, protein powder and supportive treatment and intercostals chest drainage was done.
 Outcome: pleural tapping was done. Patient general condition was poor with breathlessness.
 Conclusion: This situation indicates the subsequent mental impact at the affected person, as well as on career and family. After getting appropriate treatment patients symptoms relived and the progression of heart failure slowed down.

B-PO05-213 REVERSAL OF HYPOCALCEMIA-INDUCED DILATED CARDIOMYOPATHY TREATED WITH CRT-D

Hypocalcemia is a rare cause of dilated cardiomyopathy (DCM). Pathophysiology involves decreased myocyte contractility and prolongation of QTc interval. CRT-D is a proven therapy in patients with DCM. We present a novel case of hypocalcemic DCM and syncope that was refractory to GDM, including calcium replacement, that responded to CRT. N/A A 52-year-old woman with DCM and chronic hypocalcemia secondary to hypoparathyroidism presented for biventricular ICD placement. Hypocalcemia began after hemithyroidectomy. She was first diagnosed with heart failure after 10 years of hypocalcemia (mean 6.6 +/- .92 mg/dL). ECG was sinus rhythm with left bundle branch block (QRS 146 ms). TTE showed LVEF of 20% and 4-chamber enlargement. Cardiac catheterization did not show coronary artery disease. After 3 months of GDM and correction of calcium, she continued to have NYHA class III symptoms without change in EF. She was hospitalized for syncope concerning for malignant arrhythmia. QTc was 524 ms (JTc = 378 ms). Cardiac MR did not show evidence of fibrosis or scar. She had class 1b indication for CRT due to LVEF <35% and LBBB and underwent successful placement of Biotronik BiV ICD with LV lead placed into posterolateral branch. At 3-month follow-up she had 100% biventricular pacing. Her LVEF increased from 20% to 35%, LVIDd and LVIDs decreased by 15% (6.76 to 5.73 cc) and 24% (6.10 to 4.64 cc). After prolonged correction of calcium, QTc normalized (474 ms). CRT-D therapy has multiple indications in hypocalcemia-induced DCM, including improvement of LV size and function and prevention of fatal arrhythmias related to QTc prolongation.

Substrate Characterization and Outcomes of Ventricular Tachycardia Ablation in TTN (Titin) Cardiomyopathy: A Multicenter Study.

[Figure: see text].

Electrocardiogram Changes in the Spectrum of TTNtv Dilated Cardiomyopathy: Accuracy and Predictive Value of a New Index for LV-Changes Identification

Truncating TTN variants (TTNtv) are the main cause of dilated cardiomyopathy (DCM). The dynamic nature of this entity has previously been described. Based on own empirical observations and previous evidences, this study assessed repolarisation patterns and the possible association with morphological and functional status of TTNtv-DCM patients. Electrocardiograms (ECGs) of index patients with TTNtv-DCM and their relatives were included and matched in time with an echocardiogram. All individuals were classified into five phenotype groups: 1) Reduced left ventricular ejection fraction (LVEF <50%); 2) Recovered LVEF: at least 10% increase and LVEF >30% after optimal medical treatment; 3) Borderline phenotype (mildly enlarged ventricle and/or hyper-trabeculation); 4) Genotype positive, phenotype negative; and 5) Non-carriers. All electrocardiograms were evaluated by two blinded observers in qualitative and quantitative terms [T index (mm)=Σ T-wave amplitude (V5, V6, II, aVF)] and these data were compared with demographic and clinical information. The Δ T-index was calculated in those individuals with more than one electrocardiogram. Seventy-eight (78) electrocardiograms were included (46% female, mean age 50 years). T-index and prevalence of an abnormal T-wave had significantly different results among the groups (p<0.0001). Age and haemodynamic factors were shown to be ECG-modifiers, especially in phenotype-negative patients. T-index enabled individuals with reduced LVEF (<2.5) to be identified and to differentiate patients with favourable and unfavourable responses to treatment (Δ T index >3.5 and ≤2, respectively). Repolarisation changes enabled characterisation of the spectrum of TTNtv-DCM. The T-index identified potential carriers and patients with the worst profiles of the spectrum of the disease.

The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy.

Our insight into the diverse and complex nature of dilated cardiomyopathy (DCM) genetic architecture continues to evolve rapidly. The foundations of DCM genetics rest on marked locus and allelic heterogeneity. While DCM exhibits a Mendelian, monogenic architecture in some families, preliminary data from our studies and others suggests that at least 20% to 30% of DCM may have an oligogenic basis, meaning that multiple rare variants from different, unlinked loci, determine the DCM phenotype. It is also likely that low-frequency and common genetic variation contribute to DCM complexity, but neither has been examined within a rare variant context. Other types of genetic variation are also likely relevant for DCM, along with gene-by-environment interaction, now established for alcohol- and chemotherapy-related DCM. Collectively, this suggests that the genetic architecture of DCM is broader in scope and more complex than previously understood. All of this elevates the impact of DCM genetics research, as greater insight into the causes of DCM can lead to interventions to mitigate or even prevent it and thus avoid the morbid and mortal scourge of human heart failure.

Diet associated canine dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a common cause of heart failure in the dog. Primary DCM is often a disease of exclusion, but inherited genetic breed dispositions have been reported. Secondary causes of DCM include toxins, nutritional deficiency, systemic and infectious disease. The number of dogs diagnosed with DCM has increased significantly in the last 20 years, and has been linked to the rise in popularity of boutique, exotic and grain-free, legume-rich diets. Veterinary cardiologists raised concerns as DCM was being reported in atypical breeds. Subsequently, the United States Food and Drug Agency released a statement in 2018 warning pet owners of the risks of grain-free and novel protein diets. It is assumed that the problem also occurs in the UK because these diets are popular here also. Contrary to primary causes of DCM, dogs have improved clinically and on echocardiograph when their diet has been changed and/or supplemented. No clear cause has yet been identified between these diets and DCM, but the potential reasons seem to be multifactorial and limited by a lack of understanding of the bioavailability, digestibility and metabolism of the novel proteins and legume-rich diets.

Parvovirus B19 DNA detectable in hearts of patients with dilated cardiomyopathy, but absent or inactive in blood.

AimsParvovirus B19 (B19V) is often assumed to be a cause of dilated cardiomyopathy (DCM), based on the quantification of B19V DNA in endomyocardial biopsies (EMB). Whether the presence of B19V DNA correlates with active infection is still debated. Application of the enzyme endonuclease to blood samples results in degradation of B19V DNA remnants but leaves viral particles intact, which enables differentiation between active and past infection. In this study, the susceptibility to degradation by endonuclease of B19V DNA in blood was compared between DCM patients and a control group of recent B19V infections.Methods and resultsTwenty blood samples from 20 adult patients with DCM, who previously tested positive for B19V DNA in EMB and/or blood, were tested with B19V PCR before and after application of endonuclease to the samples. Six blood samples tested positive for B19V DNA with a mean viral load of 2.3 × 104 IU/mL. In five samples, B19V DNA became undetectable after endonuclease (100% load reduction); in one sample DNA load showed a 23% log load reduction (viral load before endonuclease: 9.1 × 104 IU/mL; after: 6.5 × 103 IU/mL). Presence of cardiac inflammation did not differ between patients with B19V DNAemia (1/4) and patients without B19V DNAemia (6/14) ( P value = 1.0). In all 18 control samples of proven recent B19V infections, DNA remained detectable after application of endonuclease, showing only a mean log load reduction of 2.3% (mean viral load before endonuclease: 8.1 × 1011 IU/mL; after: 8.0 × 1011 IU/mL). Load reduction differed significantly between the DCM group and the control group; indicating the presence of intact viral particles in the control group with proven active infection and the presence of DNA remnants in the DCM group (P value = 0.000).ConclusionDuring recent B19V infection, viral DNA levels in blood were unaffected by endonuclease. In contrast, B19V DNA in blood in patients with DCM became undetectable or strongly reduced after application of endonuclease. Circulating viral DNA in this subset of patients with presumed parvovirus‐associated DCM does not consist of intact viral particles. Viral replicative activity cannot be assumed from demonstrating B19V DNA in cardiac tissue or in blood in DCM patients.

Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy.

Background: Mutations in the TTN gene are the most common causes of dilated cardiomyopathy (DCM). The clinical significance of TTN gene variants remains inadequately understood.Methods: Whole-exome sequencing and phenotypic characterisation were performed, and patients were followed up for a median of 44 months.Results: We analyzed the association of the TTN variants with the clinical outcomes in a prospective study of 1,041 patients with sporadic DCM. TTN truncating variants (tTTN) were detected in 120 (11.5%) patients as compared with 2.4/10,000 East Asian populations in the Genome Aggregation Database (GnomAD; p < 0.0001). Pathogenic TTN missense variants were also enriched in DCM as compared with the GnomAD populations (27.6 vs. 5.9%, p < 0.0001). DCM patients with tTTN had a lower left ventricular ejection fraction (28.89 ± 8.72 vs. 31.81 ± 9.97, p = 0.002) and a lower frequency of the left bundle branch block (3.3 vs. 11.3%, p = 0.011) than those without or with mutations in other known causal genes (OCG). However, tTTN were not associated with the composite primary endpoint of cardiac death and heart transplantation during the follow-up period [adjusted hazard ratio (HR): 0.912; 95% confidence interval: 0.464–1.793; p = 0.790]. There was also no sex-dependent effect. Concomitant tTTN and pathogenic variants in OCG were present in only eight DCM patients and did not affect the outcome.Conclusion: The phenotype of DCM caused by tTTN, major causes of sporadic DCM, is not distinctly different from those caused by other causal genes for DCM.

Left ventricular ejection fraction reduction due to atrial fibrillation: clinical and echocardiographic predictors

Abstract Funding Acknowledgements Type of funding sources: None. Background The diagnosis of atrial fibrillation (AF) induced cardiomyopathy can be challenging. It relies on ruling out other causes of dilated cardiomyopathy, upon recovery of left ventricular ejection fraction (LVEF) following return to sinus rhythm (SR). Aim The aim of this study was to identify clinical and echocardiographic predictors for developing new dilated cardiomyopathy in patients with AF or atrial flutter (AFL). Methods This is a retrospective study conducted in a large tertiary care center. Patients that suffered deterioration of LVEF under 50% during AF demonstrated by pre-cardioversion trans-esophageal echocardiography (TEE) were compared to those with preserved LV function during AF. All patients had documented preserved LVEF at baseline (EF &amp;gt;50%) while in SR. Patients with a previous history of reduced LVEF during SR were excluded. Results From a total of 482 patients included in the final analysis, 80 (17%) patients had reduced LV function and 402 (83%) had preserved LV function during the pre-cardioversion TEE. Patients with reduced LVEF were more likely to be male and with a more rapid ventricular response during AF/AFL. A history of prosthetic valves was also identified as a risk factor for reduced LVEF. Patients with reduced LVEF also had higher incidence of TR and RV dysfunction. Conclusion In "real world" experience, male patients with rapid ventricular response during AF or AFL are more prone to LVEF reduction. Patients with prosthetic valves are also at risk for LVEF reduction during AF/AFL. Lastly, TR and RV dysfunction may indicate relatively long-standing AF with an associated reduction in LVEF.

EP343 - Biallelic NRAP variants are a significant cause of dilated cardiomyopathy

eP343 - Biallelic NRAP variants are a significant cause of dilated cardiomyopathy

Genetics of dilated cardiomyopathy.

Dilated cardiomyopathy (DCM), which include genetic and nongenetic forms, is the most common form of cardiomyopathy. DCM is characterized by left ventricular or biventricular dilation with impaired contraction. In the United States, DCM is a burden to healthcare that accounts for approximately 10,000 deaths and 46,000 hospitalizations annually. In this review, we will focus on the genetic forms of DCM and on recent advances in the understanding of cytoskeletal, sarcomeric, desmosomal, nuclear membrane, and RNA binding genes that contribute to the complexity and genetic heterogeneity of DCM. Although mutations in TTN remain the most common identifiable cause of genetic DCM, there is a growing appreciation for arrhythmogenic-prone DCM due to mutations in LMNA, desmosomal genes, and the recently described FLNC gene encoding the structural filamin C protein. Mutations in RBM20 highlight the relevance of RNA splicing regulation in the pathogenesis of DCM. Although expanded genetic testing has improved access to genetic diagnostic studies for many patients, the molecular mechanisms in the pathogenesis of the disease remained largely unknown. : The identification of the molecular causes and subsequent insight into the molecular mechanisms of DCM is expanding our understanding of DCM pathogenesis and highlights the complexity of DCM and the need to develop multifaceted strategies to treat the various causes of DCM.

Crystallographic Structures of Titin Immunoglobulin-Like I21 Domains Involved in Dilated Cardiomyopathy

The protein titin is the main responsible for the passive elasticity of the sarcomere, determining the stiffness and contractile function of cardiomyocytes. Titin is also a key factor in the etiology of heart disease, given that truncating mutations in the titin gene are the most common cause of dilated cardiomyopathy (DCM). However, missense mutations have commonly been classified as variants of uncertain significance because of their high frequency in the general population and the absence of functional annotation. We have recently identified a missense mutation targeting a conserved cysteine in the I21 domain of titin as a cause of DCM in humans. Here, we present the structural characterization of the wild type domain, that follows a fold characteristic for the intermediate set (type I) of the immunoglobulin superfamily: 2 antiparallel 4-strand-β-sheets packed in a β-sandwich shape. Interestingly, we observed that the I21 titin domain contains a second cysteine located 5Å away from the cysteine position mutated in dilated cardiomyopathy patients. We also report the structural and biophysical characterization of the mutated domain. The mutated domain presents unaltered overall structure, although its thermal stability is severely compromised, showing a decrease of 17ºC in its melting temperature when compared to the wild type domain. Our results suggest that titin domain destabilization by missense variants can lead to DCM, even if the structure of the native state is preserved. Future research will investigate the origin of the thermal destabilization in the mutated domain, and the potential influence of intramolecular disulfide bonds.