Author: Amin H. Karim MD

Graduate of Dow Medical College Class of 1977.

Diabetes and Its Long-Term Complications.

A Clinical Case Report
Author: Nuha Emad Awada
Medical school: Jordan University of Science and Technology (JUST)

Introduction

Diabetes mellitus is a common chronic metabolic disorder characterized by persistent hyperglycemia resulting from inadequate insulin secretion, impaired insulin action, or both. Long-standing hyperglycemia can damage multiple organ systems and lead to microvascular and macrovascular complications.

According to the Centers for Disease Control and Prevention (CDC), an estimated 40.1 million people in the United States had diagnosed or undiagnosed diabetes in 2023. Diabetes is associated with an increased risk of cardiovascular disease, kidney disease, neuropathy, retinopathy, foot ulceration, and lower-extremity amputation.

This case illustrates the potential consequences of prolonged untreated or poorly monitored type 2 diabetes in a patient who had gone approximately five years without routine medical follow-up or recommended screening.

How Chronic Hyperglycemia Causes Complications

Chronic hyperglycemia produces cellular and vascular injury through several interrelated biochemical pathways. Excess intracellular glucose increases activity of the polyol pathway, contributing to sorbitol accumulation, NADPH depletion, oxidative stress, and cellular injury. Hyperglycemia also increases diacylglycerol (DAG) and protein kinase C (PKC) activity, contributing to endothelial dysfunction, altered vascular permeability, and inflammation. Increased flux through the hexosamine pathway can alter protein and gene regulation and contribute to abnormal extracellular matrix deposition. Together, these mechanisms contribute to progressive neurological, vascular, retinal, and renal injury.

Clinical Case Presentation

A 57-year-old Hispanic man with a more than 20-year history of type 2 diabetes mellitus presented to a clinic for a disability evaluation. He reported that he had not attended routine medical follow-up or undergone recommended screening for approximately five years. He attributed his lack of medical care primarily to financial and insurance-related difficulties and hoped that obtaining disability status would provide access to medications, screening, and other medical services.

At presentation, he reported excessive thirst, increased hunger, polyuria, severe fatigue, and blurred vision. He also described longstanding tingling, numbness, and swelling involving both the upper and lower extremities. These sensory symptoms had not previously been formally evaluated or treated.

The patient reported that his last ophthalmologic evaluation had been approximately five years earlier. He also reported a family history of diabetic retinopathy and currently experienced blurred vision.

His diabetic history was complicated by significant lower-extremity disease. In 2024, he developed an ulcer of the great toe that became severely infected and ultimately required amputation of the affected great toe. Subsequently, he developed another ulcer on the plantar surface of the foot. At the time of presentation, he reported that the ulcer was extremely painful and appeared infected. The condition had impaired his mobility, and he walked with a limp.

The patient reported diabetes mellitus in both his maternal and paternal family histories. He acknowledged awareness of the potential complications of diabetes but had continued to defer medical evaluation and treatment.

He described his diet as generally balanced, consisting primarily of protein, vegetables, and fruit, with occasional fast-food consumption. He reported occasional alcohol use, typically one beer. He was a former smoker and reported that he had stopped smoking approximately 17 years earlier. He also reported daily physical activity, including push-ups, sit-ups, and jumping jacks.

The patient worked as a chef at BJ’s and reported prolonged periods of standing. He stated that his feet frequently became wet during work, particularly during cleaning activities at the end of his shift, and that he did not always dry his feet thoroughly afterward. This occupational exposure is clinically relevant in the setting of an active chronic foot ulcer.

He denied known hypertension, hyperlipidemia, sleep apnea, and paroxysmal nocturnal dyspnea. However, his blood pressure was markedly elevated at 184/99 mmHg on presentation and remained elevated at 168/100 mmHg approximately 30 minutes later, raising concern for previously unrecognized or untreated hypertension.

He also reported approximately one year of acid reflux. He stated that his last electrocardiogram had been approximately 20 years earlier and that he had not undergone recent cardiovascular evaluation. His only reported prior surgery was the great-toe amputation in 2024.

Major Diabetes-Related Complications Illustrated by the Case

Peripheral Neuropathy

The patient’s longstanding tingling and numbness of the extremities are concerning for diabetic peripheral neuropathy. Loss of protective sensation can allow minor injuries to go unnoticed and can increase the risk of foot ulceration and infection. Current American Diabetes Association (ADA) guidance recommends assessment for diabetic peripheral neuropathy beginning at the diagnosis of type 2 diabetes and at least annually thereafter.

Diabetic Foot Ulceration and Prior Amputation

The history of a severely infected great-toe ulcer requiring amputation, followed by another plantar foot ulcer, places this patient in a high-risk category for recurrent ulceration and further limb complications. Neuropathy, peripheral arterial disease, foot deformity, prior ulceration, prior amputation, smoking history, and kidney disease can all contribute to diabetic foot risk. The presence of an open ulcer or suspected infection warrants prompt clinical assessment.

Possible Diabetic Retinopathy

Blurred vision after approximately five years without ophthalmologic screening raises concern for diabetic retinopathy or another ocular disorder. Importantly, the case does not establish a diagnosis of diabetic retinopathy because no recent ophthalmologic examination or retinal findings are provided. For people with type 2 diabetes, the ADA recommends a comprehensive dilated eye examination at the time of diagnosis, with subsequent screening intervals determined by retinal findings and individual risk.

Cardiovascular and Vascular Risk

Diabetes substantially increases cardiovascular risk and is associated with peripheral arterial disease and other vascular complications. The patient’s markedly elevated blood pressure on two measurements also raises concern for previously unrecognized or untreated hypertension. The available case information does not establish coronary artery disease or peripheral arterial disease, so these should be considered clinical concerns requiring evaluation rather than confirmed diagnoses.

Possible Kidney Involvement

The case discusses the renal consequences of diabetes in general, but it does not provide laboratory data establishing chronic kidney disease in this patient. Assessment of kidney function and urine albumin excretion would be appropriate when evaluating a person with long-standing type 2 diabetes, particularly when other end-organ complications are present.

Discussion

This case demonstrates how prolonged gaps in diabetes care can allow multiple complications to develop without timely detection or intervention. The patient’s neuropathic symptoms, history of an infected foot ulcer requiring amputation, recurrent plantar ulceration, and visual symptoms are clinically significant. His markedly elevated blood pressure adds another potentially modifiable cardiovascular risk factor.

The case also highlights the importance of access to care. Although the patient reported that he had deferred care partly because of financial and insurance-related difficulties, the clinical consequences illustrate the potential cost of delayed screening and treatment. Early identification and management of hyperglycemia, hypertension, lipid abnormalities, neuropathy, retinopathy, kidney disease, and foot complications can reduce the risk of severe morbidity.

Prevention and Routine Monitoring

  • Regular monitoring of glycemic control and individualized glucose-lowering therapy.
  • Blood-pressure assessment and treatment when hypertension is confirmed.
  • Regular assessment for diabetic kidney disease, including appropriate laboratory testing.
  • Routine comprehensive eye examinations and prompt ophthalmologic evaluation when visual symptoms occur.
  • At least annual assessment for diabetic peripheral neuropathy and loss of protective sensation, with more frequent evaluation in high-risk patients.
  • At least annual comprehensive foot evaluation, with inspection at every visit for patients with prior ulceration or amputation.
  • Prompt evaluation of any new foot ulcer, redness, swelling, drainage, pain, or suspected infection.
  • Lifestyle measures including a balanced diet, physical activity appropriate to the patient’s medical condition, smoking cessation, and maintenance of a healthy body weight.

Conclusion

Long-standing type 2 diabetes can affect the nervous system, eyes, kidneys, cardiovascular system, and lower extremities. This case illustrates the consequences that may occur when routine follow-up and recommended screening are interrupted for several years. The patient’s sensory symptoms, recurrent foot ulceration and prior amputation, visual complaints, and markedly elevated blood pressure demonstrate the importance of comprehensive diabetes care and early recognition of complications.

Important Clinical Note

This article is intended for educational and informational purposes. It is not a substitute for individualized medical evaluation, diagnosis, or treatment. A patient with an active or suspected infected diabetic foot ulcer, new visual changes, markedly elevated blood pressure, or other concerning symptoms should receive timely professional medical assessment.

References

  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report. Updated 2026. https://www.cdc.gov/diabetes/php/data-research/index.html
  2. American Diabetes Association Professional Practice Committee for Diabetes. 12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes—2026. Diabetes Care. 2026;49(Suppl 1):S261–S276. https://doi.org/10.2337/dc26-S012
  3. American Diabetes Association Professional Practice Committee for Diabetes. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026. Diabetes Care. 2026;49(Suppl 1):S216–S260. https://doi.org/10.2337/dc26-S010
  4. Alila Medical Media. Diabetes Type 1 and Type 2, Animation. YouTube. 2014. https://www.youtube.com/watch?v=XfyGv-xwjlI
  5. Alila Medical Media. Diabetic neuropathy, animation. YouTube. 2021. https://www.youtube.com/watch?v=CyOdY5L-YeE
  6. Cleveland Clinic. 10 Early Signs of Diabetes. 2024. https://www.youtube.com/watch?v=wcQCmX8fHW0
  7. MedlinePlus. Diabetes complications. U.S. National Library of Medicine. https://medlineplus.gov/diabetescomplications.html
  8. Zhao L, Yuan J, Yang Q, et al. Diabetes and its complications: molecular mechanisms, prevention and treatment. Signal Transduction and Targeted Therapy. 2026;11:22. https://doi.org/10.1038/s41392-025-02401-w

Wernicke Encephalopathy: A Diagnostic Challenge

MRI-Negative Neuropathy-Predominant Wernicke Encephalopathy: A Diagnostic Challenge — Case Report and Literature Review

Diana Fernanda Aguayo (MD student),
Universidad de Monterrey.

José David Santiago Luna (MD student).
Universidad Anáhuac Oaxaca

Amin H. Karim MD
Baylor College of Medicine, Houston, Texas

Abstract

Wernicke encephalopathy (WE) is an acute neurological emergency caused by thiamine (vitamin B1) deficiency. Although classically characterized by confusion, ophthalmoplegia, and gait ataxia, the complete clinical triad is present in a minority of patients. Normal neuroimaging findings and atypical manifestations, such as severe peripheral neuropathy or optic atrophy, present significant diagnostic challenges. We report the case of a 48-year-old male with alcohol use disorder who presented with MRI-negative, neuropathy-predominant WE complicated by persistent lower extremity polyneuropathy, gait dysfunction, and bilateral optic atrophy despite thiamine supplementation. Initial diagnostic complexity was heightened by elevated cerebrospinal fluid protein levels, leading to suspicion of autoimmune encephalitis. This paper highlights the clinical spectrum of thiamine deficiency, discusses key differential diagnoses, and emphasizes the necessity of prompt empiric treatment regardless of neuroimaging findings.

Introduction

Wernicke–Korsakoff syndrome (WKS) is a neurologic disorder resulting from thiamine (vitamin B1) deficiency. It encompasses two distinct clinical entities representing different stages of disease progression. Wernicke encephalopathy (WE) is the acute, life-threatening manifestation characterized by confusion, ophthalmoplegia, nystagmus, and gait ataxia. In contrast, Korsakoff syndrome (KS) is a chronic neuropsychiatric condition resulting from uncorrected or recurrent thiamine deficiency, defined by severe anterograde and retrograde amnesia, executive dysfunction, and confabulation [1].

While WKS is most frequently encountered in individuals with alcohol use disorder, non-alcoholic etiologies are increasingly recognized. These include bariatric surgery, hyperemesis gravidarum, severe anorexia nervosa, chronic parenteral nutrition, and inflammatory bowel disease [2].

WE remains primarily a clinical diagnosis. The classic triad occurs in only 16% of confirmed cases. Consequently, the European Federation of Neurological Societies (EFNS) guidelines recommend diagnosing WE if at least two of the following criteria are met: (1) dietary deficiency state, (2) oculomotor abnormalities, (3) cerebellar dysfunction, and (4) altered mental status or mild memory impairment [2,3].

Diagnostic imaging, particularly magnetic resonance imaging (MRI) of the brain, serves as a supportive tool. Characteristic MRI findings include symmetric hyperintensities in the mammillary bodies, medial thalami, tectal plate, and periaqueductal gray. However, brain MRI sensitivity remains suboptimal, and normal neuroimaging does not rule out the condition [3]. Because delay in therapy risks permanent neurocognitive injury or mortality, empiric intravenous thiamine must be initiated immediately upon clinical suspicion.

Here, we present the case of a 48-year-old male with alcohol use disorder who developed neuropathy-predominant WE with persistent polyneuropathy, gait instability, and severe bilateral visual loss despite thiamine therapy. Normal acute brain MRI findings and elevated cerebrospinal fluid (CSF) protein initially complicated the diagnostic workup. A comprehensive literature review accompanies the case to outline key differential considerations and rare manifestations of thiamine depletion.

Case Description

Patient History & Initial Hospitalization

A 48-year-old male with a history of chronic pain presented for continuous neurological evaluation following a diagnosis of Wernicke–Korsakoff syndrome.

The acute illness began in 2024 following a 1-week episode of heavy alcohol intake. The patient sustained a fall down a flight of stairs and was found immobilized on the floor by his family and local police. Shortly thereafter, he experienced progressive confusion, short-term memory impairment, visual hallucinations, severe lower back pain, and bilateral lower extremity neuropathic pain.

During his initial emergency hospitalization, his clinical course was complicated by sepsis, delirium, and convulsive seizures. Suspecting WE, clinicians ordered a brain MRI, which revealed no classic signal abnormalities in the mammillary bodies or periventricular structures. Given the presence of seizures, altered mental status, and negative neuroimaging, an autoimmune etiology was investigated. Cerebrospinal fluid (CSF) analysis demonstrated albumino-cytological dissociation with an elevated protein level of 172 mg/dL without pleocytosis. Empiric therapy with intravenous immunoglobulin (IVIG) produced no measurable clinical improvement. Subsequently, high-dose (HD) intravenous (IV) thiamine was administered for 5 days, followed by oral thiamine (100 mg daily).

Discharge documentation from October 2024 noted recurrent urinary tract infections and persistent confabulation. Following medical stabilization, he was transferred to an inpatient rehabilitation facility. Despite physical and occupational therapy, his recovery was complicated by recurrent falls and severe spatial disorientation. Neuropsychological evaluation confirmed profound cognitive deficits, leading to formal diagnoses of Wernicke encephalopathy and Korsakoff syndrome.

Follow-up testing in November 2024 demonstrated significant ongoing cognitive dysfunction affecting attention, memory encoding, abstract reasoning, and problem-solving. A Saint Louis University Mental Status (SLUMS) evaluation yielded a score of 18/30, indicating severe cognitive impairment with prominent anosognosia.

Follow-Up Physical & Neurological Evaluation

By early 2026, the patient continued to report progressive bilateral visual impairment, severe neuropathic pain in both lower extremities, and progressive immobility requiring a cane for ambulation. He remained dependent on family support for activities of daily living.

  • Past Medical History: Chronic pain syndrome, severe visual impairment, Wernicke encephalopathy, Korsakoff syndrome.
  • Family History: Essential hypertension (father), premature myocardial infarction (paternal line), age-related macular degeneration.
  • Social History: Former finance professional; 10-pack-year tobacco history (quit ~10 years prior); past heavy alcohol use, currently reporting minimal social intake.

Physical & Diagnostic Examination Findings

  • Ophthalmologic Assessment (March 2026): Visual acuity measured 20/150 in both eyes (Snellen equivalent 20/200 bilaterally during uncorrected screening). Slit-lamp exam demonstrated bilateral temporal optic disc pallor. Optical coherence tomography (OCT) confirmed bilateral temporal retinal nerve fiber layer (RNFL) thinning and asymmetric optic nerve head cupping, consistent with optic atrophy. Pupillary light reflexes, extraocular movements, and intraocular pressures were normal.
  • Neurological Examination: The patient was alert and oriented to self but exhibited subtle ongoing memory retrieval deficits. Cranial nerves II–XII were grossly intact except for visual field constriction. Motor examination revealed preserved muscle tone and bulk (5/5 strength throughout). Sensory testing revealed marked hypesthesia to light touch and pinprick in a stocking distribution over the lower extremities, left greater than right. Deep tendon reflexes were intact and symmetric. No appendicular dysmetria or dysdiadochokinesia was noted.
  • Gait & Stance: Wide-based, ataxic gait. Tandem gait was severely impaired. The patient required a single-point cane and assistance for turn stability.

Literature Review & Pathophysiology

Pathophysiology of Thiamine Deficiency

Thiamine (vitamin B1) is a water-soluble coenzyme critical for cellular energy metabolism. Its biologically active form, thiamine pyrophosphate (TPP), serves as an essential cofactor for key enzymes in the tricarboxylic acid (TCA) cycle and pentose phosphate pathway, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase [4].

Because human tissue thiamine storage capacity is limited (approximately 30 mg), biological depletion can occur within 2 to 3 weeks of inadequate intake. Thiamine is actively absorbed in the proximal small intestine via $Na^+$-dependent active transport mechanisms. Depletion disrupts neuronal oxidative oxidative phosphorylation, leading to cell membrane depolarization, intracellular glutamate accumulation, focal lactic acidosis, oxidative stress, and eventual microvascular disruption [4].

Acute histopathological lesions demonstrate severe vascular congestion, endothelial swelling, microglial activation, and petechial hemorrhages. Chronic lesions progress to demyelination, dense gliosis, and parenchymal tissue loss. The most specific pathological hallmark of WKS is bilateral atrophy of the mammillary bodies, dorsomedial thalami, tectal plate, and periaqueductal gray [5].

Clinical Manifestations & Atypical Features

The classic triad (encephalopathy, oculomotor dysfunction, and gait ataxia) is present in less than twenty percent of acute cases. Encephalopathy typically manifests as profound spatial disorientation, inattentiveness, and apathy. Oculomotor abnormalities include horizontal nystagmus, lateral rectus palsies, and conjugate gaze palsies [3,6]. Gait ataxia stems from combined cerebellar damage and severe sensory peripheral neuropathy [6].

Atypical manifestations reported in the literature include:

  • Neuro-Ophthalmic: Progressive vision loss, optic disc edema, retinal hemorrhages, and permanent optic atrophy [7].
  • Neuromuscular & Peripheral: Severe flaccid quadriparesis, prominent distal sensory polyneuropathy, dysarthria, and dysphagia [7].
  • Autonomic & Systemic: Hypothermia, severe hypotension, hypovolemic shock, and refractory hyponatremia [7].

Diagnostic Workup

WE remains a clinical diagnosis supported by laboratory and imaging studies:

  1. Biochemical Testing: Serum thiamine levels or red blood cell transketolase activity assays can confirm deficiency. However, because processing often requires days, normal or pending values must never delay treatment [6].
  2. Neuroimaging: Brain MRI sensitivity is estimated between 53% and 70%, though specificity approaches 93%. Characteristic changes include $T_2$/FLAIR hyperintensities surrounding the third ventricle, mammillary bodies, and medial thalami [3]. A completely normal MRI does not rule out acute or subacute WE.

Differential Diagnosis

When patients present with acute delirium, ataxia, or unexplained encephalopathy—particularly alongside heavy alcohol use—several differential diagnoses must be systematically evaluated:

ConditionOverlapping FeaturesDistinguishing Clinical / Diagnostic Features
Autoimmune EncephalitisAltered mental status, memory loss, seizures, elevated CSF protein.Absence of clinical response to IVIG/plasmapheresis; positive neuronal cell-surface or intracellular autoantibodies [10].
Delirium Tremens (DT)Confusion, hallucinations, psychomotor agitation, autonomic instability.Resolves typically within 3 to 7 days post-cessation; lacks classic ocular palsies; responds to benzodiazepine protocols [11].
Hepatic EncephalopathyDelirium, asterixis, fluctuating consciousness, sleep-wake inversion.Elevated serum ammonia, presence of stigmata of chronic liver disease (ascites, jaundice, spider angiomas); clear response to lactulose/rifaximin [12].
Vitamin B12 DeficiencySensory ataxia, subacute combined degeneration, optic neuropathy, cognitive decline.Low serum cobalamin, elevated methylmalonic acid (MMA) and homocysteine; characteristic megaloblastic anemia on CBC [13].
HyponatremiaAcute confusion, unsteady gait, muscular lethargy, convulsive seizures.Serum sodium level $<135\text{ mEq/L}$; clinical response following controlled sodium correction [14].

Management Guidelines

WE is a neuro-medical emergency. Parenteral thiamine administration must be initiated immediately upon suspicion.

Therapeutic Regimens

  • United States Standard Guidelines: Parenteral thiamine 100 mg IV/IM daily for 3 to 7 days, followed by maintenance oral therapy (100 mg daily) [3,6].
  • EFNS / Royal College Guidelines: High-dose protocols are strongly favored to cross an impaired blood-brain barrier:
    • EFNS Criteria: Thiamine 200 mg IV every 8 hours until clinical improvement plateaus [3].
    • Royal College Criteria: Thiamine 500 mg IV every 8 hours for 3 consecutive days, followed by 250 mg IV daily for an additional 3 to 5 days, transitioning thereafter to oral maintenance (100–300 mg daily) [3,6,7].

Discussion

This case highlights critical challenges in identifying and managing atypical presentations of Wernicke encephalopathy. Despite presenting with acute delirium, ataxia, and memory failure, the patient’s diagnostic trajectory was prolonged by a negative brain MRI and elevated CSF protein levels.

The absence of classic periventricular MRI signal alterations occurs in up to 47% of WE patients [3,17]. Relying solely on neuroimaging for diagnostic confirmation risks delaying definitive treatment. In this patient, albumino-cytological dissociation in the CSF initially directed therapeutic efforts toward autoimmune encephalitis. However, elevated CSF protein without cellular reaction can occasionally reflect concurrent severe peripheral nerve demyelination or non-specific central tissue disruption [10,18]. The complete lack of response to IVIG alongside rapid stabilization post-thiamine confirmed nutritional deficiency as the underlying etiology.

Furthermore, this patient’s long-term disease course demonstrates the rare and severe sequelae of thiamine deficiency. While ocular motor palsies often improve quickly post-treatment, optic neuropathy with permanent optic atrophy is a devastating, irreversible manifestation [7]. Additionally, while gait disturbances in WE are frequently attributed to central cerebellar loss, severe peripheral axonal polyneuropathy can dominate the presentation and lead to persistent, long-term disability [15,18].

Early empiric administration of high-dose parenteral thiamine remains the single most critical factor in preventing permanent neurocognitive transition to Korsakoff syndrome or irreversible sensory-motor deficits.

References

  1. So Y. Wernicke encephalopathy. UpToDate. Updated 2024. Accessed August 2026.
  2. Wijnia JW. A clinician’s view of Wernicke-Korsakoff syndrome. J Clin Med. 2022;11(22):6755. doi:10.3390/jcm11226755
  3. Habas E, Farfar K, Errayes N, Rayani A, Elzouki AN. Wernicke encephalopathy: An updated narrative review. Saudi J Med Med Sci. 2023;11(3):193-200. doi:10.4103/sjmms.sjmms_416_22
  4. Pazirandeh S, Burns D. Overview of water-soluble vitamins. UpToDate. Updated 2024. Accessed August 2026.
  5. Akhouri S, Kuhn J, Newton EJ. Wernicke-Korsakoff syndrome. In: StatPearls. StatPearls Publishing; 2023.
  6. Singh J, Regina A. Wernicke Encephalopathy. In: StatPearls. StatPearls Publishing; 2026.
  7. Li S, Xing C. Wernicke encephalopathy: a mini review of the clinical spectrum, atypical manifestations, and diagnostic challenges. Front Neurol. 2025;16:1566366. doi:10.3389/fneur.2025.1566366
  8. Covell T, Siddiqui W. Korsakoff syndrome. In: StatPearls. StatPearls Publishing; 2023.
  9. Eva L, Brehar FM, Florian IA, et al. Neuropsychiatric and neuropsychological aspects of alcohol-related cognitive disorders: An in-depth review of Wernicke’s Encephalopathy and Korsakoff’s Syndrome. J Clin Med. 2023;12(18):6101. doi:10.3390/jcm12186101
  10. Dalmau J, Rosenfeld M. Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis. UpToDate. Updated 2026. Accessed August 2026.
  11. Pace C. Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis. UpToDate. Updated 2025. Accessed August 2026.
  12. Ridola L, Riggio O. Hepatic encephalopathy in adults: Clinical features and diagnosis. UpToDate. Updated 2026. Accessed August 2026.
  13. Mukhtar AN, Koch CA. Vitamin B12 deficiency. ClinicalKey. Updated 2025. Accessed August 2026.
  14. Sterns R. Diagnostic evaluation of adults with hyponatremia. UpToDate. Updated 2025. Accessed August 2026.
  15. Sechi G, Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol. 2007;6(5):442-455. doi:10.1016/S1474-4422(07)70104-7
  16. Isenberg-Grzeda E, Kutner HE, Nicolson SE. Wernicke-Korsakoff syndrome: Under-recognized and under-treated. Psychosomatics. 2012;53(6):507-516. doi:10.1016/j.psym.2012.04.008
  17. Oudman E, Wijnia JW, Oey M, van Dam M, Painter RC, Postma A. Wernicke’s encephalopathy in hyperemesis gravidarum: A systematic review. Eur J Obstet Gynecol Reprod Biol. 2019;236:84-93. doi:10.1016/j.ejogrb.2019.03.006
  18. Scalzo SJ, Bowden SC, Ambrose ML, Whelan G, Cook MJ. Wernicke-Korsakoff syndrome not related to alcohol use: a systematic review. J Neurol Neurosurg Psychiatry. 2015;86(12):1362-1368. doi:10.1136/jnnp-2014-309598

Cardiac Function and Renal Transplant.

Jessica Kameni Muna Simeu
University of Edinburgh, UK


Amin H. Karim MD
Baylor College of Medicine, Houston, Texas
and Houston Methodist Hospital.

Case report
Title: Optimisation of Cardiac Function in patients with Advanced
Kidney Disease in order to Improve Perioperative Risk and Prognosis
of Renal Transplant: A case Report and Review of Literature


Case Summary:
A 63-year-old African American woman with type II diabetes mellitus, diabetic nephropathy, and retinopathy presented with multiple cardiovascular risk factors, including hypertension, hyperlipidaemia, obesity, and advanced chronic kidney disease requiring thrice-weekly dialysis. Echocardiography demonstrated concentric left ventricular hypertrophy, left atrial dilation, and a preserved ejection fraction of 60–65%, consistent with heart failure with preserved ejection fraction (HFpEF). Cardiac catheterisation revealed significant three-vessel coronary artery disease involving the RCA, LAD, and ostial ramus artery. She subsequently underwent coronary artery bypass grafting (CABG), with marked improvement in left ventricular function on follow-up echocardiography. This case highlights the importance of comprehensive cardiovascular assessment prior to renal transplantation, particularly in patients with multiple cardiovascular risk factors and advanced kidney disease. Identification and optimisation of significant cardiovascular disease prior to transplantation improves perioperative risk stratification and long-term patient and allograft outcomes.

Discussion

Chronic kidney disease is an emerging major public health problem worldwide, [1] with cardiovascular disease (CVD) representing the primary cause of death in patients with advanced chronic kidney disease (CKD) or end-stage renal disease (ESRD). Compared to maintenance dialysis, kidney transplantation significantly improves survival and quality of life. [2] Among patients receiving renal replacement therapy (RRT), cardiac deaths account for 40–50% of total mortality, with 10–20% attributable to acute coronary events. [1] The risk of major adverse cardiac events (MACE) remains relatively constant while on the transplant waiting list, increases markedly in the early post-transplant period, and declines at a slower rate thereafter. These dynamics emphasize the necessity of managing coronary artery risk factors and mandate CVD screening during pre-transplant evaluations to stratify both perioperative risk and early post-transplant outcomes. [2]

Although this patient had multiple risk factors, she remained clinically asymptomatic—denying chest pain, syncope, palpitations, or dyspnea despite severe coronary artery disease (>70% stenosis across three major vessels). Initial echocardiography showed mild concentric LVH, mild left atrial dilation, and preserved LV systolic function (LVEF 60–65%). Subsequent cardiac catheterisation in September 2025 demonstrated severe multivessel CAD: 70–80% stenosis of the LAD, 60–70% of the RCA, and 70–80% of the ostial ramus. These findings underscore the necessity of diagnostic catheterisation in asymptomatic, high-risk candidates. Traditional CAD risk factors (hypertension, diabetes, dyslipidaemia, and smoking) substantially increase both CKD prevalence and CVD severity. [2]

Renal transplantation confers a major survival advantage over long-term dialysis. [3] Because cardiovascular disease remains the leading cause of post-transplant morbidity and mortality, pre-transplant evaluation aims to uncover occult disease, stratify risk, and optimize modifiable factors. Patients with ESRD face disproportionate risk due to concurrent diabetes, hypertension, dyslipidaemia, volume overload, and uraemia, necessitating pre-transplant revascularization when severe CAD is present.

The patient underwent CABG on February 10, 2026. Postoperative echocardiography revealed a hyperdynamic left ventricle with preserved right ventricular function. Recovery was complicated by a small provoked pulmonary embolism 10 days postoperatively, treated with six months of anticoagulation; follow-up ECG demonstrated normal sinus rhythm without ischaemia. This functional recovery aligns with data from Papestiev et al., [4] demonstrating that myocardial systolic and diastolic function can improve following CABG even in patients with preserved preoperative LVEF. Beyond surgical revascularisation, pre-transplant optimisation addressed blood pressure control (systolic BP consistently <140 mmHg), glycaemic management (HbA1c 5.3%), dyslipidaemia, weight management, and structured cardiac rehabilitation.

Conclusion

This case highlights the essential role of systematic cardiovascular screening in advanced CKD regardless of symptom status. ESRD remains an independent predictor of severe cardiovascular morbidity and mortality. Because kidney transplantation offers superior life expectancy, quality of life, and cost-effectiveness compared with dialysis, eligible candidates must be prioritized for pre-transplant cardiovascular optimisation. Early detection and revascularisation restore myocardial performance, improve perioperative safety, and support successful progression to renal transplantation.

References

Papestiev V, Jovev S, Risteski P, Popov AF, Sokarovski M, Andova V, et al. Myocardial function after coronary artery bypass grafting in patients with preoperative preserved left ventricular ejection fraction—the role of the left ventricular longitudinal strain. Medicina (Kaunas). 2023;59(5):932. MDPI

Yadav V, Jha SC, Gajurel RM, Poudel CM, Sahi R, Sharma M, Adhikari S. Spectrum of coronary angiographic findings in potential renal transplant recipients in a tertiary care center of Nepal. Transplant Res Risk Manag. 2020;12:15-22. ProQuest

Ewing EC, Edwards AR. Cardiovascular disease assessment prior to kidney transplantation. Methodist DeBakey Cardiovasc J. 2022;18(4):50-61. PubMed Central

Kanbay M, Abdel-Rahman SM, Brinza C, Ozbek L, Yayci E, Aktas O, et al. A meta-analysis of graft survival, patient survival and delayed graft function in first-time and repeat kidney transplants. Nephrol Dial Transplant. 2025;40(10):1906-1918. Oxford Academic

Links
1.
https://www.proquest.com/docview/2424514560?accountid=10673&parentSessionId=z35hJ

WJWqgbsyFNBkk%2BVxM3e5%2FFTzzZI5icjMBSS%2FE8%3D&pq-
origsite=primo&sourcetype=Scholarly%20Journals

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC9461695/
  2. https://academic.oup.com/ndt/article/40/10/1906/8113975
  3. https://mdpi-res.com/medicina/medicina-59-00932/article_deploy/medicina-59-
    00932.pdf?version=1683882935

Lipoproten (a) Management

Lipfendra and the Emerging Era of Lipoprotein(a) Management:
A Clinical Review

Authors:

Noe Rodrigo Martínez-Paredes, Medical Intern (Hospital de los Maestros SNTE Sección 50, Monterrey, Mexico).

  • Amin H. Karim, MD, Baylor College of Medicine, Houston, Texas and Institute for Academic Medicine, Houston, Texas.

ABSTRACT

Elevated Lipoprotein(a) [Lp(a)] is an independent, genetically driven, and highly prevalent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). While traditional statin therapies effectively lower low-density lipoprotein cholesterol (LDL-C) via hepatic receptor upregulation, they consistently fail to reduce Lp(a) levels and may paradoxically increase them. This review highlights the critical transition toward precision cardiovascular pharmacology, focusing on Lipfendra (enlicitide)—a breakthrough oral PCSK9 inhibitor—and the revolutionary development of RNA-targeted therapies designed to definitively silence hepatic Lp(a) production.

1. THE LIPOPROTEIN(a) CHALLENGE

Lp(a) is recognized as one of the most atherogenic and pro-thrombotic lipoproteins in human plasma, yet it remains significantly underdiagnosed in standard clinical practice.

  • Genetic Determinism: Unlike LDL-C, which is heavily influenced by diet, exercise, and metabolic syndrome, circulating Lp(a) levels are up to 90% genetically determined by the LPA gene locus on chromosome 6. Lifestyle modifications have virtually zero impact on its concentration.
  • Unique Pathophysiology: Lp(a) consists of a standard LDL-like particle covalently bound to a highly specific glycoprotein called apolipoprotein(a) [apo(a)].
  • Pro-Thrombotic Nature: The molecular structure of apo(a) is highly homologous to plasminogen. This structural mimicry allows Lp(a) to competitively inhibit plasminogen activation on the surface of fibrin clots, thereby impairing natural fibrinolysis and promoting a pro-thrombotic state.
  • Vascular Inflammation and Stenosis: Lp(a) serves as the primary carrier of oxidized phospholipids (OxPL) in the bloodstream. When deposited in the arterial intima, these OxPLs recruit monocytes, driving foam cell formation. In the aortic valve, they trigger an inflammatory cascade that leads to osteogenic differentiation, making Lp(a) a primary driver of CAVS.

2. THE STATIN PARADOX AND THERAPEUTIC LIMITS

Standard HMG-CoA reductase inhibitors (statins) are the undeniable foundation of ASCVD primary and secondary prevention. However, their mechanism reveals a critical vulnerability when managing elevated Lp(a).

  • Mechanism Failure: Statins lower plasma cholesterol by inhibiting hepatic cholesterol synthesis, which subsequently upregulates LDL receptors (LDLR) on the hepatocyte surface. However, because the apo(a) moiety physically shields the binding domains of the Lp(a) particle, it has a extremely weak affinity for the LDLR. Consequently, statin-induced LDLR upregulation clears LDL-C but leaves Lp(a) circulating.
  • Paradoxical Elevation: Extensive clinical registry data and meta-analyses have demonstrated that statin therapy can actually increase Lp(a) serum levels by 10% to 20%. This is believed to occur due to a compensatory intracellular mechanism where the depletion of hepatic cholesterol triggers an increase in the transcription of both PCSK9 and the LPA gene.
  • The Residual Risk: Patients on high-intensity statins who achieve optimal LDL-C targets but have persistent Lp(a) elevations remain at a profoundly high risk for recurrent myocardial infarctions and ischemic strokes.

3. EMERGING THERAPIES: TARGETED MECHANISMS OF ACTION

To address this residual atherothrombotic risk, novel pharmacological pathways bypass the standard HMG-CoA reductase mechanisms entirely.

A. Oral PCSK9 Inhibition (Lipfendra / Enlicitide)

  • The Pharmacological Barrier: Historically, PCSK9 inhibitors required subcutaneous injections because peptides are rapidly degraded by gastrointestinal enzymes and possess poor epithelial permeability. Lipfendra utilizes a specialized macrocyclic peptide structure designed to overcome the gastric environment and achieve efficient systemic absorption.
  • Mechanism of Action: Once absorbed into the portal circulation, Lipfendra binds with exceptionally high affinity to circulating PCSK9 protein. By neutralizing PCSK9, it prevents the lysosomal degradation of LDLRs, dramatically extending their lifecycle on the hepatocyte surface.
  • Clinical Efficacy: It is the first once-daily oral PCSK9 inhibitor, dramatically improving patient adherence. While its primary role is achieving massive LDL-C reductions (up to 50%), it also provides a modest, yet clinically relevant, secondary reduction in Lp(a) of approximately 20% to 30%.
  • Advantages Over Injectables and Traditional Therapies: While monoclonal antibodies targeting PCSK9 (evolocumab, alirocumab) offer profound LDL-C reduction, they present significant logistical and psychological barriers, including the need for subcutaneous administration, cold-chain storage, injection-site reactions, and reduced long-term adherence due to needle fatigue. Lipfendra bridges this gap by delivering “biologic-level” efficacy in a convenient oral formulation. Furthermore, it overcomes the limitations of other traditional lipid-lowering classes. Unlike statins, which can paradoxically raise Lp(a) and cause debilitating myalgias, or ezetimibe and bempedoic acid, which provide only modest LDL-C reductions (15% to 25%), Lipfendra offers aggressive LDL-C lowering paired with a targeted reduction in Lp(a) without inducing muscle toxicity.
  • Safety Profile and Adverse Effects: Data from clinical trials indicate that enlicitide is highly tolerable. Because its mechanism of action is entirely extracellular and does not interfere with intracellular cholesterol synthesis like statins, it effectively eliminates the risk of statin-associated muscle symptoms (SAMS). The most commonly reported adverse effects are mild, transient, and primarily gastrointestinal—such as nausea, flatulence, or mild dyspepsia—which are often associated with the strict fasting conditions required for optimal absorption. Clinically significant hepatotoxicity or severe systemic immunogenic reactions have not been observed, making it an exceptionally favorable option for statin-intolerant patients.

B. RNA-Based Genetic Silencing (ASOs and siRNAs) 
These therapies represent the ultimate precision medicine approach, targeting the LPA mRNA directly in the hepatocyte to prevent the translation of the apo(a) protein. Without apo(a), the complete Lp(a) particle cannot be assembled.

  • Antisense Oligonucleotides (Pelacarsen): This ASO binds specifically to the transcribed LPA mRNA. Upon binding, it recruits RNase H1, an intracellular enzyme that degrades the target RNA strand. Administered via monthly subcutaneous injection, it achieves an ~80% reduction in circulating Lp(a).
  • Small Interfering RNAs (Olpasiran / Lepodisiran): Conjugated with GalNAc to specifically target hepatocyte receptors, siRNAs utilize the natural RNA-induced silencing complex (RISC) to continuously cleave LPA mRNA. Because the RISC complex is highly catalytic, a single subcutaneous injection can provide a sustained >95% reduction in Lp(a) for 3 to 6 months.

4. COMPARISON OF ADVANCED LIPID-LOWERING MODALITIES
The landscape of lipid management is rapidly evolving beyond standard statin therapy. Selecting the appropriate pharmacological agent now requires a nuanced understanding of a patient’s specific lipid profile, particularly when addressing residual risks associated with isolated Lp(a) elevations versus primary LDL-C management. The following table provides a comprehensive overview of the primary mechanisms, administration routes, and expected efficacies of both established and emerging lipid-lowering therapies, highlighting the distinct advantages of oral PCSK9 inhibitors and RNA-targeted silencing.

5. CLINICAL PRACTICE & FUTURE GUIDELINES

  • Universal Screening: Recognizing the hidden danger of genetic dyslipidemias, major cardiovascular societies (including the ACC/AHA and the ESC) now strongly recommend measuring Lp(a) at least once in an adult’s lifetime to identify individuals with inherited ASCVD risk.
  • Dosage and Administration of Lipfendra: Based on advanced clinical trials, the optimal therapeutic dosage for enlicitide ranges from 20 mg to 30 mg taken once daily. For optimal bioavailability, this once-daily dose must be administered on a strictly empty stomach, at least 30 minutes before the first meal or beverage of the day. This strict fasting is crucial, as the gastrointestinal absorption of these oral peptides is drastically reduced in the presence of food and active gastric secretions. Routine monitoring of liver function is standard practice, although hepatotoxicity rates remain minimal.
  • The Horizon of Cardiology: If ongoing Phase 3 cardiovascular outcomes trials (such as the HORIZON trial for Pelacarsen) demonstrate a definitive reduction in Major Adverse Cardiovascular Events (MACE), RNA-targeted therapies will swiftly transition to Class I guideline recommendations, establishing a new gold standard for isolated Lp(a) elevation.

6. KEY CLINICAL TAKEAWAYS

  • Lp(a) is statin-resistant and genetically driven: Routine lipid panels and standard statin prescriptions are fundamentally insufficient for patients harboring genetic Lp(a) elevations.
  • Lipfendra changes patient compliance: As a breakthrough oral PCSK9 inhibitor, it offers powerful LDLR upregulation without the psychological and physical burden of long-term injectable therapies.
  • RNA therapies are the definitive solution: By intercepting and silencing the LPA gene directly in the liver, ASOs and siRNAs can nearly eradicate circulating Lp(a), promising to close the gap on residual cardiovascular risk.

REFERENCES

  1. Reyes-Soffer G, Ginsberg HN, Berglund L, et al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42(1):e48-e60.
  2. Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69(6):692-711.
  3. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43(39):3925-3946.
  4. Zheng KH, Tsimikas S, Pawade T, et al. Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis. J Am Coll Cardiol. 2019;73(17):2150-2162.
  5. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2020;41(24):2275-2284. 
  6. Willeit P, Ridker PM, Nestel PJ, et al. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018;392(10155):1311-1320.
  7. Nissen SE, Wolski K, Prcela L, et al. Efficacy and Safety of an Oral PCSK9 Inhibitor in Statin-Treated Patients: A Phase 2 Randomized Clinical Trial. JAMA Cardiol. 2023;8(5):455-462. 
  8. Ballantyne CM, Banka P, Mendez G, et al. Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616. J Am Coll Cardiol. 2023;81(16):1553-1564. 
  9. Nurmohamed NS, Dullaart RPF, Stroes ESG. Oral PCSK9 inhibitors: A new era of accessible lipid-lowering therapy? Curr Opin Lipidol. 2024;35(1):15-21.
  10. O’Donoghue ML, Rosenson RS, Gencer B, et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease (Olpasiran). N Engl J Med. 2022;387(20):1855-1864. 
  11. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease (Pelacarsen). N Engl J Med. 2020;382(3):244-255. 
  12. Nissen SE, Wolski K, Balog C, et al. Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels (Lepodisiran). JAMA. 2023;330(21):2075-2083. 
  13. Katzmann JL, Laufs U. Pharmacological lowering of Lipoprotein(a). Curr Opin Lipidol. 2023;34(3):133-140.
  14. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation. 2019;139(25):e1082-e1143. 
  15. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-188.

Recent Clinical Observer Group 2026

Students are given opportunity to study a case and write up a talk for the other students:


Students from Nigeria, Pakistan, Mexico, India, Nepal. 2026.


Observers from Turkey, Mexico, USA, Indonesia. April 2026

Observers and medical students from Pakistan, Nigeria Mexico, Peru, Turkey.

Observers watching grand rounds.

Peri-operative Cardiovascular Medication Management for Non-cardiac Surgery.

By Jessica Eve (Java, Indonesia)

REFERENCES

  1. Winchester DE, Mehta JJ, Alexander JT. Perioperative cardiovascular medication
    management for noncardiac surgery. JAMA. Published online March 31, 2026.
    doi:10.1001/jama.2026.0067
  2. American Heart Association. 2024 AHA/ACC guideline for perioperative cardiovascular
    evaluation and management of patients undergoing noncardiac surgery. Circulation.
    2024;150:e351–e442. doi:10.1161/CIR.0000000000001285
  3. Devereaux PJ, Mrkobrada M, Sessler DI, Leslie K, Alonso-Coello P, Kurz A, et al;
    POISE-2 Investigators. Aspirin in patients undergoing noncardiac surgery. N Engl J Med.
    2014;370(16):1494–1503. doi:10.1056/NEJMoa1401105
  4. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, et al; POISE Study
    Group. Effects of extended-release metoprolol succinate in patients undergoing non-
    cardiac surgery (POISE trial): a randomised controlled trial. Lancet.
    2008;371(9627):1839–1847. doi:10.1016/S0140-6736(08)60601-7
  5. Neumann A, Maura G, Weill A, Alla F, Danchin N. Clinical events after discontinuation of
    β-blockers in patients without heart failure optimally treated after acute myocardial
    infarction: a cohort study on the French healthcare databases. Circ Cardiovasc Qual
    Outcomes. 2018;11(4):e004356. doi:10.1161/CIRCOUTCOMES.117.004356
  6. Lindenauer PK, Pekow P, Wang K, et al. Lipid-lowering therapy and in-hospital
    mortality following major noncardiac surgery. JAMA. 2004;291(17):2092-2099.
    doi:10.1001/jama.291.17.2092
  7. London MJ, Schwartz GG, Hur K, Henderson WG. Association of perioperative
    statin use with mortality and morbidity after major noncardiac surgery. JAMA Intern
    Med. 2017;177(2):231-242. doi:10.1001/jamainternmed.2016.8005
  8. Berwanger O, de Barros E Silva PG, Barbosa RR, et al. Atorvastatin for high-
    risk statin-naïve patients undergoing noncardiac surgery. Am Heart J. 2017;184:88-
  9. doi:10.1016/j.ahj.2016.11.001
  10. Graham MM, Sessler DI, Parlow JL, et al. Aspirin in patients with previous
    percutaneous coronary intervention undergoing noncardiac surgery. Ann Intern Med.
    2018;168(4):237-244. doi:10.7326/M17-2341
  11. Kobori T, Onishi Y, Yoshida Y, et al. Association of glucagon-like peptide-1
    receptor agonist treatment with gastric residue in an esophagogastroduodenoscopy.
    J Diabetes Investig. 2023;14(6):767-773. doi:10.1111/jdi.14005
  12. Joshi GP, LaMasters T, Kindel TL. Preprocedure care of patients on glucagon-
    like peptide-1 receptor agonists. Anesthesiology. 2024;141(6):1208-1209.
    doi:10.1097/ALN.0000000000005231

Heart Failure With Preserved Ejection Fraction and Atrial Fibrillation: Egg or the Chicken

Heart Failure with Preserved Ejection Fraction and Atrial
Fibrillation: What was first, the Egg or the Chicken?

Laiba Ejaz
Karachi Institute of Medical Sciences.

Samuel Sotelo Hernandez
Autonomous University of Durango-Cappus Zacatecas

Amin H. Karim MD
Methodist Academy of Medicine, Houston, Texas

Abstract
A 68-year-old African American man presented with recurrent lower extremity edema without dyspnea or chest pain. His history included hypertension, hyperlipidemia, and obesity. Evaluation revealed atrial fibrillation with a
controlled ventricular rate and echocardiographic findings consistent with heart failure with preserved ejection fraction (HFpEF). Secondary causes such as deep venous thrombosis were excluded. The patient was managed
with metoprolol and diuretics for rate and volume control, losartan and hydrochlorothiazide for hypertension, apixaban for anticoagulation, and amiodarone for rhythm stabilisation. After a year of persistent atrial
fibrillation, elective cardioversion successfully restored sinus rhythm following confirmation of the absence of atrial thrombus on transesophageal echocardiography. The patient remained clinically stable on subsequent
follow-up visits.

Introduction
Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) are common cardiovascular conditions that frequently coexist, particularly in older, hypertensive, and obese patients. AF can exacerbate
HFpEF by impairing atrial contribution to ventricular filling, while HFpEF may predispose to atrial remodelling and subsequent arrhythmia, creating a complex bidirectional relationship. Both conditions independently
increase morbidity and mortality and pose challenges in diagnosis and management, especially when symptoms such as edema or fatigue are subtle or overlapping. Understanding the temporal relationship between AF and
HFpEF is critical for optimizing therapy, including rate versus rhythm control, anticoagulation, and management of comorbidities. This case highlights a patient with recurrent lower extremity edema, AF, and HFpEF, raising
the clinical question of which condition preceded the other and illustrating the importance of individualized, comprehensive cardiovascular care.

Case Presentation
A 68-year-old African American man presented to the clinic with complaints of recurrent fluid buildup, mainly in his lower extremities, as noted by his primary care physician. He denied dyspnea, chest pain, orthopnea, or
paroxysmal nocturnal dyspnea. His medical history included hypertension, hyperlipidemia, and obesity. He reported occasional alcohol use and denied smoking. His family history was significant for coronary artery
disease, hypertension, hyperlipidemia, and diabetes mellitus. On examination, his weight was 280 lbs (127 kg) and height 73 inches, yielding a BMI of 37.7 kg/m2, consistent with Class I obesity. Blood pressure ranged
between 135–145/75–85 mmHg, and his pulse was irregular at 58–70 beats per minute.

Laboratory
investigations revealed a normal HbA1c and a lipid profile with total cholesterol 222 mg/dL, HDL 67 mg/dL, LDL 149 mg/dL, and triglycerides 60 mg/dL. An electrocardiogram (EKG) (figure 1) obtained during the initial
visit showed atrial fibrillation with a controlled ventricular rate of approximately 58 beats per minute. A subsequent 2D echocardiogram demonstrated a preserved left ventricular ejection fraction of 60–65% and mild
left atrial enlargement—findings consistent with heart failure with preserved ejection fraction (HFpEF). Chest X-ray showed chronic airway changes and mild atherosclerosis, while Doppler ultrasound ruled out deep
venous thrombosis. The patient was started on metoprolol and diuretics for rate and volume control, along with losartan and hydrochlorothiazide for blood pressure management. Anticoagulation with Eliquis (apixaban) and
rhythm control with amiodarone was initiated and continued for over a year without spontaneous conversion to sinus rhythm (figure 2). He subsequently underwent elective cardioversion, which successfully restored sinus
rhythm (figure 3) A transesophageal echocardiogram prior to the procedure confirmed the absence of thrombus in the left atrium or left atrial appendage. The patient continued regular follow-up and remained clinically stable
thereafter.

Discussion
This case highlights the complex interplay between atrial fibrillation (AF), hypertension, obesity, and heart failure with preserved ejection fraction (HFpEF) in an older African American male. The patient’s presentation
with peripheral edema, in the absence of dyspnea or orthopnea, emphasises that HFpEF can manifest subtly and that careful evaluation of cardiovascular risk factors and cardiac rhythm is essential for accurate diagnosis and
management (1,2). Atrial fibrillation is a common arrhythmia in elderly individuals, often associated with structural heart changes such as left atrial enlargement and diastolic dysfunction. In this patient, chronic
hypertension and obesity likely contributed to increased left ventricular stiffness and impaired relaxation, leading to diastolic dysfunction and, consequently, HFpEF (3,4). The echocardiographic findings of preserved left
ventricular ejection fraction (60–65%) with mild left atrial enlargement are consistent with this diagnosis. The irregularly irregular rhythm on electrocardiogram confirmed the presence of AF, while the controlled ventricular rate suggested adequate rate control with beta-blocker therapy (5).
HFpEF accounts for nearly half of all heart failure cases, and its prevalence continues to rise in parallel with obesity, hypertension, and metabolic syndrome (1,6). Pathophysiologically , the combination of increased
ventricular wall stress, endothelial dysfunction, and myocardial fibrosis results in elevated filling pressures despite normal systolic function (7). This leads to symptoms such as lower extremity edema, exercise intolerance, or mild dyspnea, which may fluctuate depending on volume status. Importantly, obesity is a key modifiable factor that exacerbates both HFpEF and AF by promoting systemic inflammation, left atrial remodelling, and neurohormonal activation (6,7). The management of this patient was appropriately focused on
controlling heart rate, optimizing blood pressure, managing volume status, and preventing thromboembolic events. Beta-blocker therapy (metoprolol) was effective for rate control, while diuretics addressed the peripheral
edema. Losartan and hydrochlorothiazide provided additional blood pressure control and diuresis. Given the patient’s CHA2DS2-VASc score—elevated due to age, hypertension, and heart failure—anticoagulation with
apixaban was warranted to reduce the risk of stroke, which is fivefold higher in individuals with AF (5,8). Despite more than a year of rate control and anticoagulation, the patient did not experience spontaneous
reversion to sinus rhythm. Therefore, elective cardioversion was pursued, preceded by transesophageal echocardiography to rule out intracardiac thrombus. The successful restoration of sinus rhythm improved cardiac
efficiency and potentially reduced the risk of HF progression (9). Ongoing rhythm surveillance is essential, as recurrence of AF is common, particularly in patients with underlying structural heart disease and obesity (10).
From a preventive perspective, aggressive risk factor modification remains a cornerstone of long -term management. Weight reduction, dietary sodium restriction, and increased physical activity can improve diastolic
function and reduce AF recurrence (1,2). Additionally, lipid lowering with statin therapy is indicated given the elevated LDL cholesterol level (149 mg/dL), further reducing cardiovascular risk (3,6).


In summary, this case underscores the importance of a multidisciplinary approach in managing AF and HFpEF , particularly in patients with multiple cardiovascular risk factors. Optimal control of hypertension, obesity, and
dyslipidemia, combined with rhythm management and anticoagulation, can lead to favorable clinical outcomes. The patient’s successful cardioversion and stable follow-up course demonstrate that with comprehensive care,
symptom control and maintenance of sinus rhythm are achievable in this complex patient population.

References:

  1. Kittleson MM, Panjrath GS, Amancherla K, et al. 2023 ACC Expert Consensus Decision
    Pathway on Management of Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol.
    2023;81(18):1835–78. doi:10.1016/j.jacc.2023.03.393
  2. American College of Cardiology. 2024 ACC Expert Consensus Decision Pathway on
    Clinical Assessment, Management, and Trajectory of Patients Hospitalized With Heart Failure. J Am Coll
    Cardiol. 2024. doi:10.1016/j.jacc.2024.06.002
  3. American College of Cardiology/American Heart Association. 2024 Update to the 2020
    ACC/AHA Clinical Performance and Quality Measures for Adults With Heart Failure. Circ Heart Fail/HCQ.
  4. doi:10.1161/HCQ.0000000000000132
  5. Riccardi M, et al. Current Treatment of Heart Failure with Preserved Ejection Fraction. J
    Clin Med. 2025;14(15):5406. doi:10.3390/jcm14155406
  6. European Society of Cardiology. 2024 ESC Guidelines for the Management of Atrial
    Fibrillation. Eur Heart J. 2024. Available from:
    https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Atrial-Fibrillation
  7. Shahid M, et al. A Contemporary Review on Heart Failure with Preserved Ejection
    Fraction. Front Cardiovasc Med. 2024. Available from:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060923/
  8. Romanò M, et al. Heart Failure Syndromes: Different Definitions of Ejection Fraction and
    Implications. J Clin Med. 2025;14(14):5090. doi:10.3390/jcm14145090
  9. Spotlight on the 2024 ESC/EACTS Management of Atrial Fibrillation. Eur Heart J
    Cardiovasc Pharmacother. 2025. doi:10.1093/ehjcvp/pvad014
  10. Drug Therapy for Acute and Chronic Heart Failure with Preserved Ejection Fraction.
    PubMed Central (PMC). 2025. Available from:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093799/
  11. Hoevelmann J. What’s New in Heart Failure? PubMed Central (PMC). 2025 Sep. Available

from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502451/