Crucial Role of Early Detection in Managing Heart Failure in Kearns-Sayre Syndrome: A Case Report

Introduction

Kearns-Sayre syndrome (KSS) is a rare mitochondrial disorder, which in most cases is caused by single, large deletions of mitochondrial DNA (mtDNA). The most frequent form is the deletion of 4.977bp, but multiple mutations in both mtDNA and nuclear genes can also cause KSS [1]. The disease is characterized by the triad of chronic progressive external ophthalmoplegia (CPEO), pigmentary retina degeneration, and cardiac conduction disorders, with onset before the age of 20 years. KSS, due to its multi-system, progressive character can also manifest as muscle weakness, hearing loss, pharyngeal and esophageal dysfunction, impaired cognitive function, cerebellar ataxia, and endocrinopathies. Furthermore, patients can have CV complications, which consist of progressive degeneration of the cardiac conduction system, syncopal attacks, heart failure (HF), and sudden cardiac death, and these are the most important prognostic factor in KSS patients. In KSS patients, the 20% mortality rate is attributed to sudden cardiac death; therefore, treatment of CV complications is of great clinical importance [1–6]. Early permanent pacemaker implantation should be considered in all KSS patients with PR prolongation or any degree of atrioventricular (AV) block [7].

This report presents the broad spectrum of complications and challenges encountered in the clinical care of patients with KSS. Additionally, we discuss the lack of clear guidelines or recommendations for management of HF in this patient group.

Case Report

A 46-year-old man was admitted to the Clinic of Cardiac Transplantation and Mechanical Circulatory Support to qualify for heart transplantation (Htx). The first manifestations were noticed in 2003 when at age 25 years he was diagnosed with third-degree AV block and Morgagni-Stokes-Adams syndrome, which led to implantation of a dual-chamber pacemaker. Due to the deterioration of left ventricle (LV) function with low ejection fraction (EF), an upgrade from pacemaker (PM) to cardiac resynchronization therapy with defibrillator (CRT-D) was performed in April 2013. In January 2023 he was admitted to a local hospital due to symptomatic decompensation of HF. Coronary computed tomography angiography revealed no stenosis in coronary arteries. In April 2023, a follow-up examination found another decompensation of HF. The patient admitted to not taking the recommended HF medication.

Upon admission, the patient had dyspnea New York Class Association class III. Physical examination revealed a diminished breath sounds murmur, edema of lower limbs and scrotum, and admission blood pressure was 99/64 mmHg. Laboratory tests revealed: N-terminal prohormone of brain natriuretic peptide 10 594 pg/ml (normal range, 0–125 pg/ml), lactate 1.3 mmol/l (normal range, 0.5–1.5mmol/l), creatine kinase 262 U/l (normal range, 0–171 U/l), with estimated glomerular filtration rate 74 ml/min/1.73m2, uric acid 8.7 mg/dl (normal range, 3.5–7.2 mg/dl), bilirubin 5.5 mg/dl (normal range, 0.2–1.2 mg/dl), and C-reactive protein 13.97 mg/l (normal range, 0–5 mg/l).

Regarding endocrinological complications of KSS, our patient presented impaired function of the thyroid gland, as laboratory tests revealed an increase in thyroid-stimulating hormone level and a decrease in free triiodothyronine level. Parathyroid status was normal and he was not diagnosed with diabetes mellitus (DM); however, the situation required frequent follow-up. Apart from endocrine disorders, he developed advanced retinitis pigmentosa, left ptosis, and mild weakness of the neck and upper- and lower-limb muscles.

Transthoracic echocardiogram demonstrated persistent global LV hypokinesia with EF=15%, as well as right ventricle (RV) dysfunction with reduced fractional area change <35%, and reduced tricuspid annular plane systolic excursion (TAPSE of 1.2 cm), (see Videos 1 and 2). Mild mitral and severe tricuspid valve regurgitation were noticed. There was fluid in the peritoneal and pleural cavities, and an indirect high probability of pulmonary hypertension was revealed. Peak tricuspid regurgitation velocity 2.15 m/s was correct, but we noticed incorrect RV outflow Doppler acceleration time 95 ms and right atrial area at end-systole 35 cm2.

The ergospirometry test was performed with a low ramp protocol. The test was stopped after 6 min 17 s due to patient fatigue. The results were 7.0 ml/kg/min maximal oxygen consumption (18% of the norm), 3.9 metabolic equivalent, 1.07 respiratory exchange ratio, and 39.9 carbon dioxide production. However, ergospirometry in patients with muscular disorders such as KSS presents unique challenges, as it is not a standardized test in this population. Its results must be carefully interpreted in the context of the patient’s overall clinical condition, which in this case indicated advanced heart failure.

The patient also developed neurological and ophthalmological complications of the KSS, which intensified during the last year. He had dysphagia, left ptosis, and stiffness and weakness of neck muscles, as well as reduced strength of 4 limbs with generalized slimming but correct mobility. During the neurological examination, he did not display signs of cognitive impairment. Ophthalmological consultation revealed advanced retinitis pigmentosa without pupils’ response to light.

During hospitalization, his body weight decreased from 67 kg to 60 kg following loop diuretics administration and reduction of fluid overload. The Transplantology Team qualified the patient for conservative treatment due to the poor functional condition related to neurological complications, which had significantly worsened over the past year, the inability to undergo rehabilitation, limited benefits from advanced HF therapies due to significant mobility restrictions, lack of social support, high surgical risk, and high Clinical Frailty Scale score. He was also not eligible for LVAD implantation due to the above contraindications, as well as right ventricular failure with severe tricuspid regurgitation. Additionally, the patient’s visual impairments would have created difficulties in managing driveline dressing changes and battery replacement. After the decision was made, the patient was discharged from the hospital in stable condition on guideline-directed medical therapy.

After a few months, he was admitted again to the hospital ward due to acute decompensations of HF (Figure 1), which ended with the patient’s death. During the hospitalization, multiple adequate interventions from CRT-D due to ventricular arrhythmias were observed. The settings of CRT-D and medical therapy were optimized with LV/RV pacing percentage of 95%. The fact that it was not 100% was attributed to the presence of ventricular ectopic beats, which occasionally interrupted biventricular pacing. Unfortunately, the therapeutic process was complicated by COVID-19 infection. In the next few days, he developed hypotension and low cardiac output syndrome that had to be treated with vasopressors. Despite escalation of therapy, his clinical state worsened, urine output decreased, and laboratory testing revealed markers of kidney impairment such as elevated creatinine and urea levels. Given the extremely poor prognosis and the patient’s disqualification from Htx, a decision was made to refrain from invasive interventions, including hemodialysis, as they were deemed futile.

Discussion

This case report presents a 46-year-old man with KSS and advanced HF who was disqualified from Htx and mechanical circulatory support due to significant non-cardiac complications. He had progressive conduction disease, left ventricular systolic dysfunction, and recurrent HF decompensations, despite guideline-directed medical therapy and CRT-D therapy. Unfortunately, late referral for advanced HF therapies contributed to the missed opportunity for Htx or LVAD implantation. The Kearns-Sayre syndrome is a rare, genetically-determined mitochondrial condition that reveals itself in the form of varied symptoms, the most threatening of which are CV complications. These involve progressive degeneration of the cardiac conduction system, syncopal attacks, HF, and sudden cardiac death, which are the most important prognostic factors in KSS patients [8]. Apart from cardiac problems present in nearly 60% of patients, the most characteristic manifestations of the syndrome are CPEO, pigmentary retinopathy, mild weakness of skeletal muscles, deficiencies in hearing, and cerebellar signs, as well as endocrine disorders involving DM, hypothyroidism, and hypoparathyroidism [1,9]. A study of 32 patients with primary mitochondrial respiratory chain disorders found cardiomyopathy in 25%, showing the higher risk in this population [10]. However, due to the disease’s low prevalence, data on HF in KSS are scarce.

ECG abnormalities in KSS include complete and incomplete right bundle branch block, left bundle branch block, fascicular block, and nonspecific intraventricular conduction delays [4]. Ventricular conduction defects can progress to complete AV block. According to the ESC guidelines, in case of high-degree AV block at any anatomic level in association with neuromuscular diseases, cardiac pacing is indicated [7,11]. Our patient was diagnosed in the late stage of KSS with a third-degree AV block; therefore, the PM was implanted. The first PM was replaced with CRT-D. According to studies, in more than one-third of patients after successful CRT-D device implantation, cardiac resynchronization therapy is interrupted. In our patient, deterioration of LV function and symptomatic decompensation of HF were observed during therapy [12,13]. Nonetheless, the fact that our patient has been admitted with advanced CV complication remains the most important problem in this case. Ten years passed from the diagnosis of symptomatic HF to the moment of referral to the transplantation center, so the optimal time for transplantation was probably lost. The patient was already referred with excessively developed complications, so he could not benefit from Htx or mechanical circulatory support. There are reports of successful transplantation in KSS, but in a better functional condition [14,15]. The timing of referral for advanced HF therapies is critical in patients with mitochondrial cardiomyopathies. Key indicators for early referral include progressive decline in EF despite optimized guideline-directed medical therapy (GDMT), frequent hospitalizations for HF decompensation, evidence of right ventricular failure, high BNP levels and worsening renal function, and recurrent ventricular arrhythmias. Patients with mitochondrial disease often face additional challenges in transplant candidacy, including frailty, neuromuscular dysfunction, and systemic involvement [16,17]. In cases like ours, these factors may ultimately preclude transplantation or LVAD implantation. However, earlier intervention and referral may increase the likelihood of achieving a window of eligibility before complications become prohibitive [17]. Nevertheless, if the patient had been carefully monitored before the occurrence of third-degree AV block, it could have been possible to delay the development of the disease or even prevent the progression of the most life-threatening complications, and it could have at least been possible to qualify the patient for Htx. For this reason, it is of great importance to diagnose the KSS as early as possible and initiate continuous medical supervision to detect any arising CV symptoms, even asymptomatic deterioration of LV function with an early upgrade from PM to CRT. As it can be seen while analyzing our patients’ medical path, the management of KSS patients presents several clinical challenges. Delayed diagnosis is common due to the rarity and variable presentation of the disease, often leading to late recognition of cardiac complications. Additionally, multi-system involvement complicates management and necessitates a multidisciplinary approach to address neuromuscular, endocrine, and cardiovascular manifestations. Progressive conduction disease is a hallmark of KSS, requiring early pacemaker implantation and close monitoring for timely CRT upgrade to prevent further deterioration [1–6]. However, a significant challenge is the lack of established guidelines for HF management in mitochondrial disorders, making treatment decisions less standardized. Furthermore, ethical and practical considerations arise when determining transplant eligibility, as systemic complications such as neuromuscular dysfunction and endocrine disorders may limit the feasibility of advanced HF therapies. These factors underscore the need for proactive monitoring, structured follow-up, and early referral for HF therapies to optimize outcomes in KSS patients.

Because cardiological problems constitute an important part of KSS, proper pharmacological management is important. The current standard of care includes early pacemaker implantation for conduction defects, CRT for ventricular dysfunction, and GDMT for HF. In patients with KSS, frequent monitoring for worsening cardiac function is necessary, and early consideration for Htx may be beneficial. Emerging therapeutic strategies such as mitochondrial-targeted therapies, gene therapy, and coenzyme Q10 supplementation have been explored; however, their role remains investigational, and further research is needed to determine their efficacy in modifying disease progression and improving cardiovascular outcomes. In severe cases, early Htx may provide the best long-term prognosis, provided the patient does not present with severe systemic comorbidities [10,18]. Described 4 pillars of the therapy of heart failure with reduced ejection fraction were prescribed to our patient according to currently applicable guidelines [19]. However, this treatment was initiated relatively late. Given the patient’s condition and progressive disease, early diagnosis of HF and application of the full spectrum of the therapy could have benefitted him. For this reason, close surveillance and full compliance are the cornerstones of effective management of KSS patients.

Considering the genetic nature of the disease, screening of family members is essential, especially since recent research on mtDNA transmission shows that biparental inheritance of mtDNA is possible [20], which in our patient created a chance for mitochondrial mutation being transmitted to his children. Our patient’s family history was noncontributory, but every patient with KSS who is a parent should have their children screened. The most commonly used diagnostic tests include long-range PCR, which is a first-line test for detecting large mtDNA deletions; Southern blot analysis, used to confirm deletions and assess heteroplasmy levels; next-generation sequencing (NGS) and whole-exome sequencing (WES), which can identify smaller mutations contributing to the clinical phenotype; and quantitative PCR (qPCR), which estimates mtDNA copy number variations and helps evaluate disease severity [21,22]. A key challenge in mtDNA testing is heteroplasmy variation, where the proportion of mutated mtDNA differs among various tissues. As a result, blood-based testing sometimes yields false-negative results, necessitating muscle biopsy for a more accurate diagnosis. The interpretation of mtDNA abnormalities is also complex, as the severity of clinical manifestations does not always correlate with the mutation burden [22]. Despite these challenges, early genetic testing is crucial in identifying KSS and guiding appropriate cardiac and neuromuscular management.

Conclusions

KSS is a rare mitochondrial disorder with significant CV complications, which critically impact prognosis. Our case emphasizes the importance of early diagnosis and continuous monitoring, as delayed management led to advanced HF and missed transplantation opportunities. While the patient ultimately did not qualify for mechanical circulatory support or transplantation due to non-cardiac factors, earlier intervention in HF management – such as closer monitoring and timely CRT-D upgrade – could have contributed to stabilizing cardiac function before reaching an irreversible stage. Our patient’s progressive deterioration of LV function over a decade highlights the need for proactive surveillance to optimize medical and device therapy before transplant candidacy expires. This case emphasizes the importance of early diagnosis, structured follow-up, and comprehensive HF treatment in patients with KSS to maximize therapeutic opportunities before systemic complications become limiting factors. Comprehensive HF therapy, initiated early, is essential in improving outcomes. Given the genetic background of KSS, family screening is advised due to potential mtDNA inheritance. Early detection and intervention are crucial for optimal management of KSS.