TTN-related dilated cardiomyopathy in a patient with positive unknown familiarity for heart failure and bicuspid aortic valve

Non-ischaemic dilated cardiomyopathies (DCM) represent a diagnostic and therapeutic enigma, with different course of disease, long-term prognosis, risk of arrhythmias and pattern of response to heart failure medications according to the underlying specific aetiology. As demonstrated in the following clinical case report, comprehensive phenotype assessment, including an in-depth family history and genetic testing, are keys in the management of these patients.

A 49 years old male patient presented to the Emergency Department for the worsening of new onset dyspnoea since 1 month, which was rapidly progressing into NYHA class IV. He also had general fatigue and cough. He was tachycardic (heart rate 115 b.p.m.), tachypnoic (respiratory rate 24/min) and with low O₂-saturation (85%), afebrile and hypertensive (150/90 mmHg). At the clinical examination, he had bilateral pulmonary rales, jugular vein distension with hepato-jugular reflux and bilateral moderate lower limb oedema. The patient was known for a prior episode of severe acute anaemia due to an upper GI tract haemorrhage due to erosive esophagitis 2 years ago. He was obese (grade 1, BMI 31 kg/mq) and active smoker (20 pack years). He could present as well a positive family history for DCM; his brother had a severe left ventricular dysfunction (EF 20%), which was supposed to be linked to a bicuspid aortic valve disease with severe aortic insufficiency for which he underwent aortic valve replacement (Edwards 27 mm). The brother died 10 years later, after a re-do intervention with surgical replacement for the degeneration of the aortic valve bio-prothesis, complicated by fatal mixed cardiogenic, distributive and haemorrhagic shock despite extensive mechanical assistance with extra-corporeal membrane oxygenation (ECMO) and intra-aortic balloon pump (IABP).

In the ER, the baseline ECG showed a sinus tachycardia (115 bpm) without atrio-ventricular blocks, low-voltage in the peripherical leads, unspecific interventricular conduction delay and negative T waves in V5-V6 (Figure 1). The blood sample showed an increase in NT-proBNP (5144 ng/L, normal < 173 ng/L) and increased level of hs troponin-T without delta (90 ng/L, normal < 14 ng/L) while inflammatory, hepatic and renal markers were within normal limits. A chest X-ray was suggestive of acute decompensated heart failure and a transthoracic echocardiography (ETT) showed severe dilated left ventricular cavities (EDVi 101 mL/mq, normal < 75 mL/mq), diffuse hypokinesia causing severe systolic dysfunction with an EF 26% and an apical left ventricular thrombus (9 × 11 mm), mild-to-moderate functional mitral regurgitation, absence of aortic valve defects and a mild pericardial effusion (Figure 2). The patient was put on non-invasive ventilation, high-dose diuretics and vasodilators and oral anticoagulation (rivaroxaban 20 mg). Coronary artery disease was excluded by means of normal coronary angiography.

Extensive laboratory work-up showed no evidence for underlying rheumatic diseases (antinuclear IF, anti-cytoplasm, anti-ENA screen, ANCA-PR3, MPO and RF), viral or bacterial infections (HCV, HBV, HIV, CMV, EBV, parvovirus B19, HHV-6, B. burgdorferi, TBC, A/B influenza-virus and SARS-CoV-2), infiltrative pathologies (serum electrophoresis and urinal immunofixation) and metabolic alterations (glycaemic profile and thyroid function). Moreover, there was no history of cardio-toxic drugs, radiotherapy and drug abuse and alcohol abuse. The levels of transferrin saturation and ferritin were low (14% and 131.4 μg/L), and therefore, the patient received ferric carboxymaltose. A cardiac magnetic resonance (MRI) confirmed the severe biventricular systolic dysfunction with midwall fibrosis of interventricular septum, while the apical thrombus was not present anymore (Figure 3). The patient progressively recovered, and we could introduce guideline-directed medical therapy (GDMT) with SGLT2-inhibitors (dapaglifozin, 10 mg), MRA (spironolactone, 50 mg), beta-blocker (metoprolol tartrate, 150 mg) and ARNi (salcubitril/valsartan, 300 mg per day). During the hospitalization, the patient had a single episode of monomorphic non-sustained ventricular tachycardia (NSVT) (Figure 1), so we further up-titrated the beta-blocker therapy and we discharged the patient with a wearable defibrillator (Zoll Wearable Life-Vest).

The patient underwent an ambulatory rehabilitation programme and a strict clinical and echo follow-up. We up-titrate ARNi to sacubitril–valsartan 400 mg, and the patient showed a global improvement with reduction of dyspnoea (NYHA class I–II), normalization of NTproBNP levels and improvement in LV systolic function (EF recovered up to 45%) and in functional capacity (exercise bike, from 120 to 160 Watts).

In consideration of the young age of the patient, the suspected family history, the absence of a clear aetiology at the base of his dilated cardiomyopathy, and the potential implications also for the progeny, we performed genetic testing that revealed the Gene TTN Variant Exon 38–120 deletion, a likely-pathogenic (LP) mutation of Titin gene, whom mutation traditionally implies low arrhythmogenic potential with episodic non-sustained ventricular tachycardia in the absence of GDMT and a good recovery of ejection fraction.^1-3

After 6 months, we withdrew anticoagulation, and we decided to remove the ‘Life-Vest’ without implanting a definitive defibrillator, because EF recovered and MRI showed only mild fibrosis. The patient did not present significant arrhythmia in the tight rhythm follow-up monitoring through an implantable loop recorder (Biotronik Biomonitor IIIm). Meanwhile, we did screen the rest of the family with echocardiography and by genetic testing of the specific titin variant; fortunately, it is not present in other members.

This case is emblematic in showing the importance of deep phenotyping, in particular: thoughtful family history and appropriate genetic testing, in guiding the assessment and management of non-ischaemic DCM.

The brother of this patient presented several years ago a form of hypokinetic dilated cardiomyopathy, with already at the beginning a very severe LV systolic dysfunction, which was linked to bicuspid aortic valve disease with severe aortic insufficiency. Seen that the prevalence of inherited cardiomyopathy in patients with a bicuspid aortic valve disease is higher than in normal population,^{4, 5} with only a few genomic databases showing that TTN gene variant could be implied with bicuspid aortic valve disease,^{6, 7} it is possible to hypothesize retrospectively that also his brother was affected by titin-related dilated cardiomyopathy and most likely would have benefited from GDMT and could have faced the re-do surgery in better conditions.

Genetic testing has been of paramount importance in the definition of the specific aetiology of the presentation of the patient, with a very close genotype–phenotype correlation confirming the genetic causality. Gene TTN variant exon 38–120 deletion is a heterozygous large deletion variant comprising exons 38 to 120 of the TTN-gene, which is localized in the I-band of the TTN-protein. The variant has neither been described in the literature nor is listed in the clinical database ClinVar or in the Genome Aggregation Database (gnomAD). According to the ACMG criteria, the large TTN deletion variant comprising exons 38 to 120 is classified as likely pathogenic (presence of PVS1 null variant and PM2 variant).⁸ Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM), embodying a specific presentation of DCM. It responds very favourably to GDMT with prompt recovery in ejection fraction and presents a relatively low arrhythmogenic risk, especially at the beginning of the course of the illness, which has supported our choice to not directly implant a defibrillator. It may, however, pose a long-term risk of arrhythmia, which motivates our choice to continue heart rhythm monitoring through the implantation of a loop recorder and close follow-up using serial echocardiography and MRI at 2 years distance. Nonetheless, the utility of electrophysiology studies in this patient population remains limited for prognostic and therapeutic purposes, as clinical outcomes do not correlate with arrhythmia inducibility.⁹ Moreover, it has relevant prognostic information also on the progeny, with the possibility of detecting early signs and symptoms and start the correct therapy before development of heart failure.^{2, 3, 10, 11}

Intra-cavitary thrombi are frequent in dilated hypokinetic DCM, and it is debated whether to use DOAC or AVK and how long to maintain the medication. We put the patient on DOAC (rivaroxaban), and we decided to withdraw the anticoagulation after a 6-month period, considering the low thrombo-embolic risk profile (small thrombus, recovery of EF and rapid resolution at follow-up).^12-16

This case underscores the critical role of genetic testing and family history in dilated cardiomyopathy: the TTN mutation guided therapeutic decisions and an earlier recognition of this genetic condition could benefit either the patient or the patient's relatives, demonstrating the importance of precision medicine and familial screening in improving outcomes for inherited cardiomyopathies.