From Cardiac Stress to Organ Distress: Acute Hepatorenal Dysfunction after Dipyridamole Myocardial Perfusion Imaging

Abbreviations

AKI, Acute kidney injury

ASCO, American Society of Clinical Oncology

CAD, Coronary artery disease

HCC, Hepatocellular carcinoma

ICI, Immune checkpoint inhibitor

irAE, Immune-related adverse event

MPI, Myocardial perfusion imaging

^99mTc, Technetium-99m

INTRODUCTION

Myocardial perfusion imaging (MPI) is a widely used non-invasive diagnostic modality for coronary artery disease (CAD). In Taiwan, the utilization of MPI has significantly increased over the years, with an average of 155,724 procedures performed annually.¹ Pharmacologic stress agents are commonly used in MPI, particularly dipyridamole. While generally considered safe with a low incidence of serious adverse events, certain factors may predispose patients to uncommon complications. We present a rare case of acute hepatorenal dysfunction following dipyridamole-induced stress testing in a patient with a complex oncologic history, including hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitor (ICI) therapy. This case highlights important considerations for risk stratification and management of patients with liver disease and prior exposure to immunotherapy undergoing cardiac imaging procedures.

CASE

A 68-year-old man presented with chest pain and was scheduled for dipyridamole nuclear perfusion cardiac imaging. He had a major past medical history of HCC, which was initially managed with a laparoscopic hepatectomy on July 8, 2020, followed by multiple recurrences treated with repeat hepatectomies (August 2021, June 2023, and September 2024), transarterial chemoembolization (September 2021), and atezolizumab-bevacizumab immunotherapy (Cycle 1 Day 1 on October 1, 2021). His last atezolizumab-bevacizumab dose (Cycle 34) was on December 13, 2024, 6 days before the MPI examination. He also had a history of chronic comorbidities including type II diabetes mellitus, hyperlipidemia, and viral hepatitis (hepatitis B and C).

He underwent a rest-stress technetium-99m (^99mTc) sestamibi scan. His baseline blood pressure was 115/68 mmHg and heart rate was 69 beats per minute (bpm). Dipyridamole was infused for 4 minutes and ^99mTc sestamibi was injected 2 minutes later. After 10 minutes, his blood pressure was recorded at 104/60 mmHg and an electrocardiogram showed sinus rhythm with a heart rate of 73 bpm. A routine dose of 75 mg of aminophylline was given at that time to mitigate the potential adverse effects of dipyridamole. However, while waiting for the scan he vomited profusely, followed by malaise and bilateral leg soreness. The symptoms gradually resolved spontaneously, and the dipyridamole MPI showed suspected mild ischemia only (Figure 1). However, yellowish skin discoloration, decreased urine output, and tea-colored urine were observed within 12 hours after the examination. He visited the oncology outpatient department the next day, and was admitted for further management.

Figure 1.

The dipyridamole – rest myocardial perfusion image showed mild stress-induced ischemia in the midto basal anterior, mid to basal inferolateral walls with transient left ventricular cavity dilatation after stress (end-diastole volume, stress/rest = 78 ml/68 ml).

Upon admission, he had a mildly icteric appearance, and laboratory tests revealed elevated liver enzymes (ASpartate aminoTransferase/ALanine aminoTransferase: 223/432 U/L), hyperbilirubinemia (direct/total bilirubin: 5.45/7.9 mg/dL), and acute kidney injury (AKI) (blood urea nitrogen/creatinine: 37/2.38 mg/dL). Empirical piperacillin/tazobactam, silymarin, and tenofovir disoproxil were initiated for possible infection and hepatitis B reactivation, with a subsequent examination showing undetected hepatitis B and C viral load. Methylprednisolone 40 mg every 12 hours was administered for 2 days, then tapered to 40 mg daily for another 2 days, targeting a suspected immune-related adverse event. Hepatoprotective agents, silymarin and Stronger Neo-Minophagen C, were used as supportive treatment. An abdominal ultrasound revealed liver cirrhosis, mild right pleural effusion, and post-surgical hyperechoic change with posterior acoustic shadowing. His urine output improved and tea-colored urine resolved during the hospital course. Side effects from the steroids including mild moon face and bilateral leg edema were managed with diuretics and albumin supplementation. His condition gradually stabilized with better appetite and disposition, and he was discharged 4 days later.

DISCUSSION

This case describes a 68-year-old man with a history of HCC and prior exposure to immunotherapy who developed unexpected adverse events within one day following dipyridamole MPI. His subsequent clinical course, marked by gastrointestinal upset, acute hepatic dysfunction and AKI, and the causal relationship between dipyridamole MPI are discussed below.

Based on the age, sex and presenting symptoms of the patient, the pretest probability of obstructive CAD was high, warranting further diagnostic testing for risk stratification. Table 1 outlines the common non-invasive diagnostic methods for CAD based on the guidelines from the Taiwan Society of Cardiology (2023), American College of Cardiology/American Heart Association (2023), and European Society of Cardiology (2024).^2-4 While these guidelines suggest considering coronary computed tomography angiography in some high-risk patients, the complex medical history of our patient with malignancies and multiple treatments meant that nuclear MPI was an appropriate choice, since the functional assessment would be particularly valuable given the possible cardiac implications of his cancer treatment.

Table 1. Comparison of non-invasive diagnostic modalities for coronary artery disease.

Diagnostic modality	Sensitivity/specificity2	Advantages	Disadvantages	Risk of serious adverse events	Mortality
Exercise ECG	58%/62%	• Low cost	• Limited accuracy	• MI:4 0.02-0.1%	• Deaths or cardiac arrests:4 0-0.06%
		• No radiation & pharmacologic stressors exposure	• Requires ability to exercise
		• Assesses functional capacity
Stress echocardiography	85%/82%	• Widely available	• Not applicable for coronary stenosis severity analysis	• Serious complications:3	• Deaths:3
		• No radiation	• Lacks the automated quantification of perfusion studies	– exercise: 0.015%	– exercise: 0%
		• Provides real-time functional imaging		– dobutamine: 0.18%	– dobutamine: 0.014%
				– dipyridamole: 0.08%	– dipyridamole: 0.004%
SPECT MPI	87%/70%	• Provides functional information; quantify ischemic burden	• Higher radiation exposure (10-20 mSv)	• Serious complications:10	• Deaths:10
		• Flow reserve assessment using dedicated scanners	• Potential for artifacts and false-negative results due to balanced ischemia	– dobutamine: 0%	– dobutamine: 0%
				– adenosine: 0.097%	– adenosine: case reports
				– dipyridamole: 0.07-0.26%	– dipyridamole: 0.05%
				– regadenoson: case reports	– regadenoson: case reports
PET MPI	83%/91%	• Higher resolution than SPECT	• Limited availability and higher cost compared to SPECT
		• Lower radiation (0.9-2.0 mSv)
		• Viability imaging & quantitative blood flow measurement
Stress CMR	89%/80%	• High spatial resolution	• Limited availability	• Serious complications:*	• Deaths:*
		• No radiation	• High cost and longer scan times	– dobutamine: 0-0.36%	– dobutamine: 0%
		• Multiparametric (function, perfusion, viability)	• Contraindicated in claustrophobic patients	– adenosine: 0.04-0.11%	– adenosine: 0%
				– dipyridamole: 0.06%	– dipyridamole: 0%
				– regadenoson: 0%	– regadenoson: 0%
				• Gadolinium contrast related nephrogenic systemic fibrosis:10 0-18%
CCTA	97%/78%	• Excellent negative predictive value	• Moderate radiation exposure (3-5 mSv)	• Severe allergic reactions:4 0.04% (nonionic)	• Deaths:2 0%
		• Definitive anatomical evaluation	• Risks of contrast agent	• AKI:4 0-6.4%, dialysis: 0.3%
			• Requires heart rate control

* Reference: Uhlig J, et al. Eur Radiol 2019;29(7):3686-95; Kaolawanich Y, et al. PLoS One 2023;18(10):e0292950; Monmeneu Menadas JV, et al. Eur Heart J Cardiovasc Imaging 2016;17(3):308-15.

AKI, acute kidney injury; CCTA, coronary computed tomographic angiography; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram; MI, myocardial infarction; MPI, myocardial perfusion imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography.

MPI is generally safe and serious adverse events are rare. Dipyridamole is a common vasodilator used in stress testing that functions primarily by inhibiting adenosine reuptake, and it typically causes mild side effects such as headache, dizziness, gastrointestinal discomfort, and hypotension. In a large study of 3,911 patients undergoing dipyridamole-MPI,⁵ major adverse events occurred in only 0.26% of cases, including fatal (0.05%) and nonfatal myocardial infarction (0.05%) and bronchospasm (0.15%); however, AKI or acute hepatorenal syndrome was not reported. The acute presentation of our patient including projectile vomiting followed by hepatic dysfunction and AKI raises the possibility that dipyridamole may have precipitated a more pronounced systemic response through multiple mechanisms. While adenosine/dipyridamole causes vasodilation in most arterial beds, it predominantly induces vasoconstriction in renal afferent arterioles, which can then temporarily lower the glomerular filtration rate before resolving within 48 hours.⁶ In our case, dipyridamole likely contributed to the initial renal stress, but the severity and persistence of the AKI suggest that other factors were involved. Volume depletion from vomiting, impaired dipyridamole metabolism due to reduced hepatic reserve, and rare but potential nephritis related to prior ICI therapy⁷ likely amplified and prolonged what may otherwise have been a transient effect. Moreover, the splanchnic vasodilation that occurs in advanced liver disease combined with the systemic vasodilatory effects of dipyridamole could theoretically have worsened the effective circulatory volume and arterial underfilling, thereby contributing to hepatorenal syndrome.

Regarding hepatitis, although dipyridamole has been associated with a moderate elevation in liver enzymes, it has not been linked to instances of clinically apparent acute liver injury.⁸ Rather, as a frequent complication of immunotherapy⁷ and response to methylprednisolone treatment, ICI hepatotoxicity is a more likely explanation. Although a liver biopsy was not performed, the 2021 American Society of Clinical Oncology (ASCO) guideline recommends biopsy primarily for cases with diagnostic uncertainty or steroid-refractory disease.⁷ In this case, the temporal proximity to ICI exposure, a hepatocellular injury pattern with conjugated hyperbilirubinemia, exclusion of other causes (e.g., viral reactivation, biliary obstruction), and favorable steroid response supported the diagnosis of immune-mediated hepatitis. Additionally, liver tri-phase computed tomography scans performed one month prior to admission and one month after discharge revealed no recurrence of HCC. Given the risks of biopsy in a cirrhotic liver with post-surgical changes, the impression of immune-related hepatic toxicity was established based on clinical, laboratory, and imaging findings, and histological confirmation was deemed unnecessary.

The 2021 ASCO guideline and other major reviews recommend that while many immune-related adverse events (irAEs) occur within the first few weeks or months, late-onset events can emerge long after ICI therapy has been discontinued.⁷ This supports the possibility that patients may remain in a subclinical, immunologically dysregulated state, vulnerable to subsequent triggers. Dipyridamole used in stress MPI could induce systemic vasodilation, resulting in transient hypoperfusion and possibly cellular stress — both potent stimuli for immune activation. In patients with prior ICI exposure, such stress may serve as a "second hit", unmasking or amplifying a subclinical irAE.

Aminophylline is widely used to reverse dipyridamole-related adverse effects, and it was administered to our patient during the MPI study. Although gastrointestinal discomfort such as nausea and vomiting are possible adverse reactions to aminophylline, evidence from Lin et al. (2014)⁹ supports that a single low dose (typically 25 mg) can effectively reverse dipyridamole-induced minor adverse effects without causing severe hepatic or renal injury. Therefore, aminophylline is unlikely to be the major cause of the severe adverse events observed in our patient, and its use would more likely help to mitigate the progression of the initial dipyridamole-related symptoms.

Given the adverse events following dipyridamole MPI in our patient, alternative stress modalities should be considered for such cases. Exercise stress testing is physiologically natural and avoids pharmacologic adverse effects; thus, it would be an ideal first-line choice if the patient is physically capable. If exercise testing is not feasible, regadenoson stress MPI has emerged as a suitable second-line alternative. It offers the advantages of selective A2A receptor agonism, rapid onset, and short initial half-life, significantly reducing the risk of prolonged systemic side effects compared to dipyridamole, and the use of a reversal agent such as aminophylline is not needed. However, the cost is substantially higher, and regadenoson has not been approved by the Taiwan Food and Drug Administration. Dobutamine is a cost-effective synthetic catecholamine that increases heart rate and contractility, and it would have also been an option in our patient. However, its association with significant hemodynamic effects and arrhythmias would have increased the risk in our patient given his complex medical history. Adenosine stress MPI is well-tolerated,¹⁰ but despite the short half-life of adenosine (< 10 seconds) and rapid resolution of effects, the broader receptor activation and similar vasodilatory mechanisms as dipyridamole meant that it may be an unsuitable choice for our patient who had already demonstrated sensitivity to vasodilatory stress agents. Key characteristics of the four agents mentioned above are compared in Table 2.¹⁰

Table 2. Key characteristics of common stress agents for myocardial perfusion imaging (modified from Henzlova MJ, et al.¹⁰).

Agent	Mechanism of action	Dosing/administration	Half-life	Hemodynamic effects	Common side effects	Contraindications	Costs
Adenosine	Direct coronary vasodilation via A2a receptor activation; additional stimulation of A1, A2b, and A3 may contribute to side effects	140 mcg/kg/min continuous infusion over 4-6 minutes	10 seconds	HR: increase (14 ± 30 bpm)	Flushing (35-40%), chest pain (25-30%), dyspnea, dizziness, nausea, AV block (8%, complete block in < 1%)	Bronchospastic lung disease, high‐grade AV block, severe hypertension/hypotension, recent MI (< 2-4 days)	USA: approximately $65 per study (for a 75 kg patient)
				BP: decrease (systolic 10 ± 37 mmHg, diastolic 8 ± 19 mmHg)			Taiwan: approximately 1146 NTD per study (for a 65 kg patient)
Dipyridamole	Indirect vasodilator that increases endogenous adeno-sine levels by inhibiting its uptake and degradation	0.56 mg/kg IV over 4 minutes	30-45 minutes	HR: increase (17 ± 11 bpm)	Chest pain (20%), headache (12%), dizziness (12%), nausea, hypotension, AV block (2%)	Bronchospastic lung disease, severe hypertension/hypotension, recent MI (< 2-4 days)	USA: approximately $6.30 per study (for a 75 kg patient)
				BP: decrease (systolic 14 ± 15 mmHg)			Taiwan: approximately 72 NTD per study (for a 65 kg patient)
Regadenoson	Selective A2a receptor agonist with minimal activity at A1, A2b, and A3 receptors	Single IV bolus of 0.4 mg administered over 10 seconds	2-4 minutes in the phase with maximal plasma concentration	HR: increase (25 ± 11 bpm)	Headache (29%), dyspnea (25%), flushing (17%), chest discomfort (11%), 1st AV block (3%), 2nd AV block (0.1 %)	Bronchospastic lung disease, high‐grade AV block, severe hypertension/hypotension, recent MI (< 2-4 days)	USA: approximately $213.26 per dose
				BP: decrease (systolic 13 ± 14 mmHg, diastolic 10 ± 8 mmHg)
Dobutamine	Synthetic catecholamine that stimu-lates β1 (and β2) receptors, increasing HR, myocardial contractility, and BP	Titrated IV infusion starting at 5-10 mcg/kg/min with increases every 3 minutes up to 40 mcg/kg/min	2 minutes	HR: increase (45 ± 18 bpm)	Palpitations (29%), chest pain (31%), headache, flushing, dyspnea, arrhythmias (8-10%), ST-segment depression in about one-third of patients	Recent MI (< 2-4 days), significant LV outflow tract obstruction, aortic dissection, uncontrolled arrhythmias	USA: approximately $6.59 per 250 mg IV bag
				BP: increase (systolic 30 ± 21 mmHg)			Taiwan: approximately 108 NTD per 250 mg IV injection

A2a, adenosine 2a; AV, atrioventricular; BP, blood pressure; HR, heart rate; IV, intravenous; LV, left ventricular; MI, myocardial infarction; NTD, New Taiwan Dollar.

When MPI is indicated in individuals with known hepatic or renal compromise, several strategies may help reduce the likelihood of adverse events (Figure 2). A thorough pre-procedure evaluation beyond cardiovascular diseases is important, especially in those with complex medical conditions, multiple comorbidities, or in those receiving anti-cancer therapy for an active malignancy. It is also important to ensure adequate hydration to reduce the risk of hypotension, volume depletion, and renal hypoperfusion. Good hydration before the test, and continuous monitoring of vital signs during the stress test and immediately after stress imaging may allow for the early detection of hemodynamic changes, and extended observation can help to promptly treat any delayed severe complications. Considering our patient’s susceptibility to dipyridamole-related adverse effects, alternative stress methods such as dobutamine or exercise stress testing or other diagnostic modalities may have been considered. Finally, coordinated care among cardiologists, nuclear medicine physicians and other specialists is key to ensure patient safety.

Figure 2.

Key considerations for high-risk patients undergoing dipyridamole myocardial perfusion imaging (MPI) (Image generated by OpenAI 2025, GPT-4o). ECG, electrography; ICI, immune checkpoint inhibitor.

We acknowledge the lack of pathological confirmation for the acute hepatorenal dysfunction in this case. Although there is a sequential association with the dipyridamole stress test, the patient’s complex clinical presentation — including advanced liver disease and prior exposure to ICI — makes it difficult to confirm a causal relationship. The adverse events observed were likely multifactorial, and further studies are needed to clarify the mechanisms involved.

CONCLUSION

This case highlights the need for a thorough pre-stress MPI risk assessment in high-risk patients with complex clinical profiles. Ensuring proper hydration is fundamental to preventing dehydration or hypotension. Vigilant post-procedure monitoring is essential to detect and manage any delayed complications. Alternative stressors such as exercise, adenosine, regadenoson or dobutamine can be considered to minimize the risk of adverse events associated with dipyridamole. Lastly, effective interdisciplinary collaboration is important when treating high-risk patients with complex medical conditions or multiple comorbidities.

LEARNING POINTS

1. High-risk patients with complex medical conditions require careful pre-procedure assessment and multidisciplinary coordination before stress MPI.

2. Although typically safe, dipyridamole may precipitate unexpected acute liver and kidney dysfunction in individuals with complex medical conditions.

3. In patients in whom the use of dipyridamole may increase the risk of adverse events, short-acting vasodilators such as adenosine or regadenoson, or dobutamine can be safer alternatives. Exercise testing is ideal if the patient can achieve adequate exercise capacity.

4. Ensuring adequate hydration, careful monitoring of hemodynamic changes and vital signs, and extended observation can help in the detection and management of delayed complications.

DECLARATION OF CONFLICT OF INTEREST

All authors declare no conflicts of interest.