(P171) NON-ISCHEMIC CARDIOMYOPATHY AND MITOCHONDRIAL DISEASE: A CASE REPORT OF TWO PPA2 VARIANTS IN A PATIENT WITH TWO HEART TRANSPLANTS

Case background: A 28-year-old woman presented to the emergency department with shortness of breath on exertion. Echocardiography showed a dilated hypokinetic left ventricle (LV) with severe LV impairment (LV ejection fraction of 20%) and moderate to severe mitral regurgitation. There was no family history of cardiomyopathy or sudden unexplained cardiac death. There was no history of excessive alcohol or substance use. The patient was discharged on optimal guideline-directed medical therapy for heart failure with reduced ejection fraction. In follow-up 2 months later, she continued to exhibit NYHA class II symptoms, and laboratory investigations showed NT-proBNP was above normal range ( < 180 pg/mL) at 708 pg/mL without any other significant abnormalities.

Six months following initial presentation, an endomyocardial biopsy was conducted (Figure 1). This revealed nonspecific features suggestive of cardiomyopathy consisting of fibrosis and focal perivascular fibrosis on trichome stain with no convincing histological evidence of acute myocarditis, granulomatous inflammation, vasculitis, ischemia or thrombosis, glycogen storage disease, amyloid, or microorganisms/viral inclusions. A rare collection of mature adipocytes was identified; however, the extent of “marbling” was considered insufficient for a diagnosis of arrhythmogenic right ventricular cardiomyopathy.

A cardiac MRI 9 months following initial presentation identified mild left ventricular dilation, and global hypokinesis of the left ventricle with normal and uniform LV thickness and no evidence of myocardial scarring from delayed enhancement images. Echocardiograms conducted at 6 months, 1 year and 2-years following initial presentation demonstrated stabilization with all reporting LV ejection fractions around 40%.

The longstanding diagnosis since initial work-up was idiopathic nonischemic cardiomyopathy (NICM) presumed to be secondary to remote viral myocarditis.

Management Challenges: Over the subsequent years, the patient suffered strokes at age 32 and 34 with a head CT scan showing a left cerebellar infarct, and LV thrombus demonstrated on repeat echocardiography. A repeat cardiac MRI demonstrated LV ejection fraction drop to 28%, soon after which our patient had a single-chamber implantable cardioverter-defibrillator implanted and transcatheter edge to edge repair of the mitral valve for severe functional mitral regurgitation. Despite these measures, she continued to decline, and a left ventricular assist device was implanted as bridge to transplant at 38 years of age, followed shortly thereafter by orthotopic heart transplantation. However, soon after this first transplant, she had severe allograft vasculopathy, resulting in multivessel vasospasm confirmed on ergonovine provocation, and a second transplant was received at 42 years of age.

In the 6 years since the second transplant, her allograft function has remained normal, with no signs of rejection, heart failure, or functional limitations. However, she developed hypertension, myalgias and premature cataracts in this period.

At age 47, referral for genetic testing was advised on the basis of idiopathic NICM presenting under the age of 40. Genetic testing (Blueprint Genetics’ Comprehensive Cardiology Panel Plus) identified two pathogenic missense variants in the inorganic pyrophosphatase 2 (PPA2, OMIM #617223) gene (c.476C>T, p.(Thr159Met) and c.683C>T, p.(Pro228Leu)), which cause a rare mitochondrial disease deemed responsible for her NICM. Based on these genetic findings, she was referred to a metabolic specialist for consultation on mitochondrial disease management. It was suspected that initially unrecognized mitochondrial disease had contributed to her symptoms of myalgia (longstanding, managed with pregabalin) and neuropathic-like pain (burning in her feet). Interestingly, since starting semaglutide (age 47), she noted significant improvements in both myalgias and fatigue. Further management recommendations were primarily supportive given the lack of targeted disease-modifying treatment: avoidance of mitochondrial toxins such as ethanol, aminoglycosides, and tobacco smoking; avoidance of physical stressors such as extreme heat and sleep deprivation; and a trial of supplements (eg., co-enzyme Q10, creatine, B vitamins, and antioxidants). Based on previous anecdotal PPA2 case reports of acetic acid worsening myalgias in this disease, a suggestion was made to avoid vinegars.

PPA2 encodes the mitochondrial enzyme inorganic phosphatase 2, responsible for hydrolyzing pyrophosphate (PPi) into orthophosphate (Pi), thus providing Pi for biomolecular processes (e.g., ATP production). Clinical phenotypes associated with PPA2 were first described in 2016: To date, 10 studies have been published summarizing 62 patients with biallelic PPA2 mutations causing partial loss of gene function, which suggest an autosomal recessive mechanism of disease. The most common phenotype is infantile ( < 2 years old) sudden cardiac death, described in 41/62 (66%) of the reported cases. However, neuromuscular phenotypes are also present in some patients (16/62, 26%). Across age groups, most cases had a suspected or confirmed viral trigger to cardiac presentation (33/62, 53%). Of patients over 13 years old at their first presentation (13/62, 21%), all had sensitivity to alcohol, and alcohol was a trigger of the cardiac event for most of these cases (8/13, 62%). Only 5/62 (8%) of reported cases have lived past 18 years, with the oldest prior to our patient reported at 40 years old at time of publication.

Table 1 summarizes cardiac, myopathic and neurological phenotype similarities between our patient and prior reported cases of PPA2 mitochondrial disease patients who also lived to over 18 years old. Interestingly, our patient is the only one who did not report a high sensitivity to alcohol, generally defined across the case reports as adverse cardiac and/or neurological symptoms and/or extreme pain following 2 or fewer standard alcoholic beverages. The rest of the phenotypic features are shared with other cases, but not the exact combinations, which may be related to the age at symptom onset and/or current age at publication.

In conclusion, genetic testing has important implications for both the patient and potential family members with regards to treatment planning and modification. The landscape of genetic testing is changing rapidly, with current international guidelines supporting broad panel-based genetic testing for all unexplained NICM. However, critical diagnoses are missed owing to poor availability and uptake of genetic testing. Standardizing testing criteria and access to genetic testing would balance an improved diagnostic process with judicious resource utilization.