Improvement of propionic acidemia-associated dilated cardiomyopathy through nutritional adjustment and heart failure medication: A case report

Abstract

Propionic acidemia (PA) is a known cause of secondary dilated cardiomyopathy (DCM). However, little is known about how diet and heart failure treatment impact long-term cardiac outcomes in adult PA patients. We report the successful treatment of metabolic disease and secondary DCM-associated heart failure in a 20-year-old male patient with neonatal-onset PA and intellectual disability. At age 19 years, echocardiography had revealed DCM without impaired cardiac contractility. At age 20 years, he developed heart failure, presumably from a common cold infection, and was hospitalized. Acute heart failure treatment improved his symptoms, leading to discharge, but they worsened again, necessitating re-admission. He then was discharged only after successfully adding carvedilol and pimobendan to his medication. Six weeks later, however, he developed hyperammonemia with elevated serum propionyl carnitine and decreased free carnitine levels. He received acute phase treatment for this metabolic crisis and his diet therapy was readjusted, including by reducing natural protein. In the following 5 years, while continuing and slightly adapting heart failure medication and dietary regimens, the patient's cardiac function stably improved and his diuretic dose could be reduced. Our findings support that careful diet therapy and modulation of heart failure medication can improve cardiac function in PA patients with DCM.

Learning objective

Neonatal-onset propionic acidemia (PA) tends to be the most severe form of PA and life-threatening metabolic disease. Even if the impact of the disease can be ameliorated by adapting the diet, later in life these patients often develop symptoms such as intellectual disability, metabolic crises, and dilated cardiomyopathy (DCM), as observed in this case. This case demonstrates that heart failure medication and dietary therapy can help protect against metabolic disease and DCM-associated heart failure in an adult patient with neonatal-onset PA.

Introduction

Propionic acidemia (PA) is an autosomal recessive inherited disorder of organic acid metabolism, caused by a decreased activity of propionyl-CoA carboxylase (PCC) [1]. This deficiency leads to the accumulation of organic acids, such as propionic acid, with hallmark PA symptoms including metabolic acidosis and hyperammonemia. During acute exacerbations, PA can cause central nervous system disorders, with disturbances of consciousness and convulsions, and in the long-term PA can lead to intellectual disabilities and cardiac disorders, including cardiomyopathy and arrhythmia [1]. In PA-associated cardiomyopathy—which tends to be chronic and progressive—both dilated and hypertrophic types have been reported, with a higher prevalence of dilated cardiomyopathy (DCM) [2].

The clinical presentation of PA can vary extensively. However, acute onset PA shortly after birth is typically severe, and—despite chronic phase management by diet therapy and drug treatment following early detection—tends to result in intellectual disability and cardiomyopathy as the main complications [1,2]. Herein, we report the case of a patient with neonatal-onset PA who developed heart failure due to DCM in adulthood and whose cardiac symptoms improved through the adjustment of heart failure medication and diet therapy.

Case report

The patient was a 20-year-old man, height 160 cm, weight 61 kg, body mass index 23.8, with confirmed intellectual disability (intelligence of a 5-year-old). In his neonatal period, he developed hyperammonemia and metabolic acidosis and was diagnosed with PA owing to PCCB alleles p. Arg410Trp and p. Arg512Cys. Since then, he followed a protein-restricted diet supplemented with precursor amino acid-free milk, levocarnitine administration, and metronidazole for combating propionic acid-producing intestinal bacteria. However, he was repeatedly hospitalized because of hyperammonemia during his infancy. The levocarnitine dose was adjusted to 180–200 mg/kg/day, and free carnitine (C0) was maintained at >50 μmol/L, according to his blood test results. The patient underwent regular monitoring via blood tests, chest X-rays (CXR), electrocardiograms (ECG), and ultrasound echocardiography (UCG). At age 19 years, UCG revealed DCM morphology with preserved left ventricular contractility; concurrently, serum propionyl carnitine (C3) levels were elevated.

At age 20 years, the patient developed symptoms of a presumed common cold, including nighttime coughing, orthopnea, malaise, and edema, and was admitted to our hospital (Fig. 1). These included the following elevated levels: serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), 4994 pg/mL; and C3, 98 mmol/L. However, venous blood gas analysis revealed: pH, 7.475; pCO₂, 33.7 mmHg; HCO₃⁻, 24.3 mmol/L; Base Excess, 1.2 mmol/L; and Lactate, 1.3 mmol/L (Table 1). The patient was negative for metabolic acidosis, hyperammonemia, and hypoglycemia. CXR revealed cardiomegaly [cardiothoracic ratio (CTR): 60.7 %] and pulmonary congestion, whereas ECG suggested left ventricular hypertrophy and myocardial disorder. Unlike when the patient was 19 years old, the UCG now showed significant left ventricular dilatation, decreased contractility, and moderate regurgitation of both the tricuspid and mitral valves. The diagnosis at the first admission (week 0) was DCM associated with PA, and Fig. 1 summarizes the treatment course and patient data over the subsequent 300 weeks.

Fig. 1.

Treatment course. Treatment regimens with heart failure medication (carperitide, furosemide, azosemide, spironolactone, tolvaptan, trichlormethiazide, enalapril, losartan, carvedilol, pimobendan, and dobutamine) managed to control the patient's heart failures at first and second admission as indicated by his NT-proBNP levels. When the patient's C3 levels and NH3 levels increased to levels representing metabolic disease, it was attempted to control this by changing his diet [energy, natural protein (protein in normal food), total protein, precursor amino acid-free milk, essential amino acid] based on the observed levels of C3, C0, and NH3.

C0, free carnitine; C3, acylcarnitine; HF, heart failure; NH3, ammonia; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Table 1.

Blood test findings at the first admission.

Cell blood count			Biochemical
WBC	7600	/μL	TP	5.6	g/dL
RBC	489	×104/μL	Alb	3.5	g/dL
Hb	13.4	g/dL	AST	17	U/L
Hct	40.3	%	ALT	15	U/L
PLT	29	×104/μL	LDH	186	U/L
Neu	73	%	CK	58	U/L
Lymp	22	%	BUN	7.4	mg/dL
			CRE	0.93	mg/dL
Venous blood gas assay			CRP	0.87	mg/dL
pH	7.48		GLU	104	mg/dL
pCO2	33.7	mmHg	NH3	64	μg/dL
pO2	74	mmHg	Na	142	mmol/L
HCO3−	24.3	mmol/L	K	4.3	mmol/L
BE	1.2	mmol/L	Cl	106	mmol/L
Lac	1.3	mmol/L	HANP	262	pg/mL
			NT-proBNP	4994	pg/mL
Serum acylcarnitine analysis
C0	45.3	μmol/L	(Reference value: 20–70)
C3	98	μmol/L	(Reference value: <2.0)

WBC, white blood cell; RBC, red blood cell; Hb, hemoglobin; Hct, hematocrit; PLT, platelet; Neu, neutrophil; Lymp, lymphocyte; BE, base excess; Lac, lactate; TP, total protein; Alb, albumin; AST, Aspartate Aminotransferase; ALT, Alanine Aminotransferase; LDH, Lactate Dehydrogenase; CK, Creatine Kinase; BUN, Blood Urea Nitrogen; CRE, Creatinine; CRP, C-Reactive Protein; GLU, Glucose; NH3, Ammonia; Na, Sodium; K, Potassium; Cl, Chloride; HANP, Human Atrial Natriuretic Peptide; NT-proBNP, N-terminal pro B-type Natriuretic Peptide; C0, free carnitine; C3, propionyl carnitine.

The first admission (week 0 to 3)

To control his acute heart failure, treatment was started with furosemide, spironolactone, carperitide, and enalapril, while tolvaptan was added later in accordance with the Japan Circulation Society/Japanese Heart Failure Society (JCS/JHFS) 2017 Guideline on Diagnosis and Treatment of Heart Failure in Japan (Fig. 1). His body weight and NT-proBNP level dropped from 61 to 57 kg, and 4994 to 2856 pg/mL respectively. Hyperammonemia was not observed at admission, and metabolic dynamics remained stable. His energy consumption decreased, possibly due to his recovery from acute heart failure, and his diet was adjusted to maintain total protein (amino-acid) intake by decreasing natural protein and essential amino acid supplementation while increasing precursor amino acid-free milk (Fig. 1, lower table). Around week 2, the blood ammonia level was stable and the patient was discharged. However, after discharge, a mildly elevated ammonia level (64 → 157 μg/dL) was observed from week 9.

The second admission (week 14 to 20)

Heart failure seemed to improve temporarily, but NT-proBNP increased again from 2584 pg/mL to 6858 pg/mL, and the patient was re-admitted to the hospital at week 14. After first relying on dobutamine and carperitide, pimobendan (0.02 mg/kg/day) and carvedilol (0.05 mg/kg/day) were introduced. Also, furosemide and enalapril were replaced by azosemide and losartan, respectively. The patient was discharged after the carvedilol dose was increased to 0.1 mg/kg/day successfully. After the second admission, symptoms of heart failure did not worsen, and his body weight was maintained around 58 kg.

The third admission (week 28 to 31)

Sixteen weeks after the second discharge, the patient was readmitted because he experienced a metabolic crisis characterized by fatigue, ketone-positive urine, elevated blood ammonia (230 μg/dL), elevated serum C3 (158 μmol/L), and decreased serum C0 (19.3 μmol/L). His diet was readjusted regarding natural and total protein content, and his ammonia level decreased to <100 μg/dL, leading to his discharge. Even afterwards, his diet kept being fine-adjusted based on blood ammonia, serum C3, and serum C0 levels (Fig. 1, lower table). His cardiac function was stable at this admission.

Development until 5 years later: cardiac function and metabolism

Over the following 5 years, the patient was admitted several times for infections (Fig. 1). However, his cardiac function remained stable during this entire period, and his diuretic (azosemide) dose could be tapered and discontinued. While the discontinuation of pimobendan is being considered, it has thus far been continued, as there is no evidence suggesting a negative impact on prognosis, and it appears to be effective in maintaining the current stable condition. Comparing cardiac function at first admission and 5 years later revealed major improvements: NT-proBNP, 6858 → 51 pg/mL; chest CTR, 60.7 → 50.3 % (Fig. 2A); normalized ECG patterns (Fig. 2B); left ventricular end-diastolic/end-systolic diameter (LVDd/Ds), 67/60 → 48/36 mm; left ventricular ejection fraction (LVEF), 27 → 47 %; and improvement in valve regurgitation as indicated by UCG (Fig. 2C). His daily diets showed the following differences: total calorie intake, 2300 → 1800 kcal; natural protein intake, 32 g (0.52 g/kg) → 22 g (0.38 g/kg); precursor amino acid-free milk (containing 459 kcal and 12.0 g amino acids per 100 g), 80 g → 120 g; and total protein intake, 47.9 g (0.77 g/kg) → 37 g (0.63 g/kg).

Fig. 2.

Cardiac function five years after treatment compared to at first admission.

A) CTR decreased from 60.7 % to 51.5 % in five years, as indicated by chest X-ray images.

B) 12-lead ECG analysis indicated an improvement of T waves on I, II, aVR, aVF, V5, and V6.

C) LVDd and LVDs decreased, and EF was improved according to trans-thoracic echocardiography. CTR, cardio-thoracic ratio; ECG, electrocardiogram; EF, ejection fraction; LVDd/Ds, left ventricular end-diastolic/end-systolic dimension; UCG, ultrasound echocardiography.

Currently, his treatment with drugs for chronic heart failure has been continued, and monthly cardiological examinations have not found a worsening of DCM. His metabolic condition remains being carefully checked by blood tests once a month at the hospital and daily at home and has remained within the normal range. The patient visits a daycare facility and shows good appetite, while his weight remains stable.

Discussion

This case describes a patient with neonatal-onset PA who developed heart failure due to DCM in adulthood, which improved after adjustments to chronic heart failure treatment and dietary therapy. Cardiac complications occur in 9 %–23 % of PA cases, with cardiomyopathy being predominantly chronic progressive and often presenting as DCM, the leading cause of death [1,2]. Arrhythmias, characterized by prolonged QT intervals, have a high complication rate of 30 %–70 % [3]. Reports of treatments that improve PA-associated DCM are scarce.

Liver transplantation has been reported to improve DCM in PA, with significant improvements in LVDd (72 → 57 mm) and LVEF (17 % → 55 %), and favorable outcomes for over 10 years [4]. However, recurrence of DCM has also been reported, leading to death 8 years after transplantation [5]. Previous reports of PA-associated DCM managed without liver transplantation or newer pharmacologic agents have shown poor long-term outcomes [2]. Our case differs in that cardiac function improved over 5 years through conventional therapy and diet management, supporting a potentially non-transplant strategy in this patient.

Experimental studies have demonstrated that propionyl-CoA accumulation impairs mitochondrial energy metabolism by disrupting the TCA cycle and oxidative phosphorylation [6]. Excessive production of reactive oxygen species and morphological mitochondrial damage have been observed in both animal models and patient-derived cardiomyocytes [7,8]. These pathophysiological changes support the hypothesis that mitochondrial dysfunction is a central driver of cardiomyopathy in PA.

Carvedilol may be beneficial in PA-associated cardiomyopathy by reducing oxidative stress and suppressing myocardial energy consumption. Studies using PA model mice and induced pluripotent stem cell-derived cardiomyocytes have demonstrated that impaired mitochondrial metabolism and increased oxidative stress contribute to cardiac dysfunction [7,8]. Furthermore, carvedilol has been shown to improve mitochondrial respiratory chain complex function and regulate ATP production in failing hearts, which may enhance its cardioprotective effect in PA-associated mitochondrial dysfunction [9].

Even after improvement in cardiac function, continuous dietary adjustment remains essential in patients with severe PA. With decreased energy expenditure following heart failure recovery, the required intake of calories and natural protein also declines. If the dietary intake is not adjusted accordingly, the relative burden of propionate-precursor amino acids may increase, potentially triggering metabolic decompensation such as hyperammonemia.

Treatment for heart failure with improved ejection fraction has not been established in accordance with the JCS/JHFS 2025 Guideline on Diagnosis and Treatment of Heart Failure in Japan, but we are currently considering whether to add a sodium-glucose co-transporter 2 inhibitor.

The patient showed a favorable 5-year course. This provides evidence that controlling acute and chronic heart failure and balancing metabolic status through readjusting diet therapy with protein and energy intake can improve PA-associated DCM. The management of the cardio-metabolic linkage in PA patients warrants further studies.

Consent for publication

Written informed consent for the publication of medical information and images was obtained from the patient's parents reported in this publication.

Ethics approval and consent to participate

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2005 (5). The study protocol was approved by the Ethical Review Board for Human Genome Studies at Fujita Health University.

Funding

This study did not receive any specific grants from funding agencies in the public, commercial, or non-profit sectors.

Declaration of competing interest

The authors declare that they have no conflicts of interest.

Appendix A. Supplementary data

The following are the supplementary data related to this article.

Video 1

UCG at the first admission.

Video 2

UCG at 1 year later.

Video 3

UCG at 2 years later.

Video 4

UCG at 3 years later.

Video 5

UCG at 4 years later.

Video 6

UCG at 5 years later.