(P170) MYOSIN HEAVY CHAIN SEVEN VARIANT ASSOCIATED CARDIOVASCULAR DISEASE: AN UNUSUAL CASE OF HEART FAILURE IN A YOUNG MALE

Case background: A 37-year-old male with a past medical history of type two diabetes and asthma presented to his local hospital with a two-week history of worsening dyspnea. He endorsed orthopnea and paroxysmal nocturnal dyspnea. On examination, his oxygen saturation was 95% on 2 L via nasal cannula, and he was afebrile. He was tachycardic at 108 beats per minute, hypertensive at 159/117 mmHg, and tachypneic at 24 breaths per minute. Auscultation revealed a right upper sternal border systolic ejection murmur and bilateral basilar crackles with a diffuse wheeze. Significant lower extremity bilateral pitting edema was present with an elevated jugular venous pressure.

The patient had no significant family history related to cardiac disease or otherwise. He had no known allergies. His routine outpatient medications were non-contributory. He is a life-long non-smoker of tobacco cigarettes.

Blood tests (Table 1) were significant for a troponin elevation of 53 ng/L and creatinine elevation of 298 µmol/L. His troponin and creatinine peaked at 59 ng/L and 416 µmol/L, respectively. His electrocardiogram revealed sinus tachycardia without evidence of left ventricular (LV) hypertrophy. A coronary angiogram revealed normal coronaries. His initial transthoracic echocardiogram (TTE) revealed an LV ejection fraction (LVEF) of 7.9%, low-flow low-gradient severe aortic stenosis (AS), bicuspid aortic valve (BAV), severe LV dilatation, and severely increased ventricular mass and wall thickness.

A computed tomography scan of his chest was negative for a pulmonary embolism but revealed hilar lymphadenopathy. This prompted an initial concern for sarcoidosis and a temporary course of steroids, but a subsequent sarcoidosis positron emission tomography nuclear scan and bronchial biopsy were unremarkable. Lastly, a renal biopsy showed glomerulosclerosis without granulomatous changes.

The patient was diagnosed with non-ischemic cardiomyopathy, an exacerbation of new-onset heart failure with reduced ejection fraction (HFrEF), and a cardiorenal acute kidney injury. He was treated with intravenous furosemide for diuresis for two weeks and started on isosorbide dinitrate, hydralazine, and spironolactone. The patient’s renal function limited the advancement of guideline-directed medical therapy (GDMT) for HFrEF.

Two weeks into his admission, a repeat TTE revealed an improved LVEF of 35%. Cardiovascular magnetic resonance imaging (CMR) revealed prominent LV trabeculations and a small area of subepicardial late gadolinium enhancement (LGE) in the mid-inferolateral segment with an adjacent pericardial effusion. His LGE findings with concurrent elevated signal intensity on T2-weighted short tau inversion recovery images suggested mild myocarditis with active inflammation (Figure 1). Cardiology specialty consensus determined that the mild degree of myocardial involvement on LGE would not explain the severity of his LV dysfunction or other structural abnormalities. His extensive work-up was unremarkable for ischemic, metabolic, infiltrate, infectious, toxic, oncologic, connective tissue, and autoimmune etiologies. The patient was then discharged in stable condition.

At the one-year follow-up, the patient’s LVEF recovered to 54% with optimized GDMT on bisoprolol, dapagliflozin, hydralazine, and isosorbide dinitrate. Further GDMT at that time was limited by the development of chronic kidney disease secondary to diabetic nephropathy.

Outpatient genetic testing was positive for an MYH7 variant (c.1956+1G>A), and cardiogenetics consultation suggested this as a contributor to his non-ischemic cardiomyopathy. Further cardiology assessments concluded that urgent aortic valve replacement for his severe AS was not indicated, given symptom improvement. Given the absence of other clear causes, the unifying etiology of his cardiomyopathy and other structural cardiac abnormalities were deemed to be likely related to his MYH7 variant.

Management Challenges: Pathological chromosome 14 mutations of the MYH7 gene can have deleterious effects on the β-cardiac myosin heavy chain structure, leading to dilated and hypertrophic cardiomyopathies and impairment of cardiac inotropy. This case contributes to the growing body of evidence linking MYH7 mutations not only to cardiomyopathies but also to a broader spectrum of cardiac pathologies, including myocarditis and structural heart diseases, such as BAV and excessive trabeculation.

The diagnosis of excessive trabeculation is increasingly being recognized through the use of CMR. While this patient’s case does not meet the complete criteria for excessive trabeculation, he does show significant features on CMR, such as prominent LV trabeculations and LV hypertrophy. MYH7 is the most common mutated gene in patients with excessive trabeculation and can be simultaneously associated with Ebstein anomaly or other congenital heart diseases, such as BAV. Furthermore, literature has described a definitive association between MYH7 gene mutations and excessive trabeculation. BAV is present in approximately one to two percent of the population and can lead to valvular abnormalities such as AS and aortic regurgitation.

Mutations in MYH7 have been associated with myocarditis and are among the most represented in biopsy-proven myocarditis. Genetic sequencing of adults with acute myocarditis also revealed an association with MYH7 gene mutations. On imaging, acute myocarditis can present with myocardial edema, chamber dilatation, pericardial effusions, and ventricular dysfunction. Weeks after disease onset, myocardial edema declines, but lateral wall myocardial involvement can persist in post-inflammatory myocarditis. In this case report, the patient’s CMR findings of non-ischemic subepicardial LGE in the inferolateral walls with concurrent elevated T2 signal intensity suggested mild myocarditis with active inflammation of an unclear etiology. However, expert cardiology consensus concluded that his mild myocardial involvement would not explain his severely reduced LVEF or his other structural changes.

This patient’s dilated cardiomyopathy with LV hypertrophy, BAV, and features of myocarditis and excessive trabeculation are all conditions associated with pathogenic MYH7 variants. As per the clinical molecular geneticist analyzing this patient’s MYH7 variant (c.1956+1G>A), “this occurred in the invariant region of the splice consensus region and it is predicted to abolish or destroy the donor splice site of intron 16, which is expected to disrupt messenger ribonucleic acid splicing and likely result in an absent or disrupted protein (cardiomyocyte β-myosin)”. Given this genetic analysis and the absence of evidence for other etiologies after an extensive work-up, his MYH7 variant is likely a unifying underlying contributor to his presentation. His practitioners in the cardiology and heart function clinics further suspected this as a predisposing condition. This patient’s MYH7 pathological variant as an underlying explanation for his presenting heart failure emphasizes the importance of considering genetic causes in atypical cardiac presentations.