Utility of serum blood ketone levels and other risk factors for inadequate myocardial glucose suppression ketogenic FDG-PET/CT: a prospective and retrospective cohort study

doi:10.21203/rs.3.rs-7776884/v1

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Utility of serum blood ketone levels and other risk factors for inadequate myocardial glucose suppression ketogenic FDG-PET/CT: a prospective and retrospective cohort study

https://doi.org/10.21203/rs.3.rs-7776884/v1

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published 15 Dec, 2025

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OBJECTIVES

Incomplete myocardial glucose suppression (MGS) in ketogenic 18F-FDG-PET/CT is a common problem that reduces the diagnostic accuracy in detecting myocardial inflammation. This study assesses the usefulness of a dietary logbook, blood ketone testing and risk factors for inadequate MGS.

METHODS

Retrospective (2022–2024) and prospective (2024–2025) analysis was performed on all patients who underwent a ketogenic 18F-FDG-PET/CT. In April 2024, blood ketone testing, a dietary logbook, and improved dietary guidelines were introduced. All patients were instructed to follow > 24-hour ketogenic diet and > 12-hour fast before imaging.

RESULTS

After introducing the dietary logbook and guidelines, inadequate MGS rates decreased from 26% to 17% (95 patients 2022–2024 vs 92 patients 2024–2025)(p-value 0.14). Mean blood ketones were significantly lower in patients with incomplete MGS (0.34mmol/L vs 0.76mmol/L, p-value 0.04). On univariate analysis, significant risk factors for inadequate MGS included prednisolone use (75% vs 14.9%, OR: 17.1 [95%CI 1.65-177.04], p = 0.009), low blood ketones (≤ 0.3mmol/L)(OR: 5.77 [95%CI 1.69–19.68], p = 0.003) and female sex (7.5% vs 9.6% in males, OR: 3.57 [95%CI 1.12–11.3], p = 0.025). Multivariate analysis confirmed prednisolone use, low ketones (≤ 0.3mmol/L) and < 24-hour ketogenic diet as independent risk factors. Rates of inadequate MGS were 50%, 26% and 7% for patients with blood ketone levels of 0.1, 0.2–0.3 and ≥ 0.4mmol/L, respectively. All patients on prednisolone with ketones ≤ 0.3mmol/L had inadequate MGS.

CONCLUSIONS

Dietary logbook and clear instructions improve adherence. Low ketones, prednisolone use and short ketogenic preparation are risk factors for inadequate MGS.

Ketogenic

PET/CT

cardiac sarcoidosis

ketone

β-hydroxybutyrate

myocardial glucose suppression

The ketogenic diet (KD) is an effective preparatory strategy for suppressing physiological myocardial glucose uptake prior to 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), particularly in the evaluation of inflammatory cardiac conditions such as cardiac sarcoidosis [1]. Under normal metabolic conditions, myocardium primarily utilizes glucose and free fatty acids for energy. This leads to significant physiological 18F-FDG uptake in healthy myocardial tissue, which can obscure pathological uptake and reduce diagnostic accuracy [1].

A high-fat, low-carbohydrate KD induces a metabolic shift from glucose metabolism to fatty acid oxidation and ketone body utilization. This shift suppresses myocardial glucose uptake, effectively reducing background FDG signal and enhancing the contrast between normal and inflamed myocardium. As a result, pathological foci—such as those seen in cardiac sarcoidosis—can be more clearly visualized [1, 2].

The efficacy of KD preparation has been supported by several studies. For example, Özütemiz and colleagues demonstrated a 72-hour KD with overnight fasting achieved complete myocardial suppression in 96.9% of cases, compared to 68.1% with a 24-hour KD and 52.3% with an 18-hour fasting protocol [1]. These findings highlight the importance of both the duration and adherence to ketogenic protocols for optimal image quality. However, the duration of the ketogenic diet varies considerably between hospitals, with many adopting a shorter 24-hour protocol due to patient compliance, time constraints, and logistical challenges.

Serum ketone β-hydroxybutyrate levels have emerged as a useful biomarker for assessing the adequacy of myocardial glucose suppression. Elevated serum ketone β-hydroxybutyrate concentrations are associated with successful suppression, whereas lower levels may reflect suboptimal dietary adherence or insufficient metabolic transition to ketosis [2, 3] Although heparin administration has been proposed to improve suppression, there are limitations for patients with inadequate ketone levels [4].

Despite these advances, inadequate myocardial suppression remains a challenge in a subset of patients, with reported rates of non-diagnostic scans as high as 7.1% even after ketogenic preparation [5]. Contributing risk factors include poor compliance with dietary protocols, inadequate preparation time and individual metabolic variability. These limitations underscore the need for standardized preparation protocols and objective biomarkers to guide and assess readiness for PET/CT imaging.

This study aims to investigate clinical and metabolic risk factors for inadequate suppression by comparing cohorts before and after the implementation of enhanced dietary protocols—including a standardized ketogenic diet guide, dietary logbook, patient questionnaire, and point-of-care blood ketone testing to further improve patient selection and preparation strategies for cardiac PET imaging. The study will also evaluate an optimal blood ketone level threshold that best predicts adequate myocardial glucose suppression (MGS) in patients undergoing a 24-hour KD preparation for 18F-FDG PET/CT.

This was a combined retrospective and prospective observational study conducted at two tertiary hospitals to assess the utility of blood ketone levels and other clinical factors in predicting adequate MGS in patients undergoing 24-hour ketogenic preparation for 18F-FDG PET/CT scans. The retrospective component included all patients who underwent ketogenic PET/CT imaging between August 2022 and April 2024. No patients were excluded. The prospective arm of the study included all patients scanned from April 2024 to January 2025, during which time new preparation protocols were introduced in April 2024.

For the retrospective cohort, data was extracted from patient records, including demographic data such as age, gender, inpatient or outpatient status, scan indication, and the adequacy of myocardial suppression as determined on PET/CT review. Adequate suppression was defined as myocardial 18F-FDG uptake lower than blood pool activity. Cases with higher or heterogeneous myocardial uptake without known pathology were classified as having inadequate suppression.

For the prospective cohort, a new departmental protocol was implemented to improve myocardial suppression in April 2024. Patients in the prospective arm received revised dietary instructions that emphasized strict adherence to a high-fat, low-carbohydrate ketogenic diet for a minimum of 24 hours prior to the scan and fasting 12 hours prior to the study. These instructions, along with a newly introduced patient questionnaire and a dietary logbook, were emailed to all patients at least 72 hours in advance of their scheduled scan. Upon arrival on the day of imaging, patients underwent point-of-care testing of capillary blood β-hydroxybutyrate (ketone) and glucose levels using handheld meters (Abbott Freestyle Optium Neo). These biochemical parameters were recorded in addition to the patient’s age, gender, BMI, inpatient or outpatient status, exercise level, diabetic status, dietary adherence (as per the logbook), and any recent use of immunosuppressive medications, including corticosteroids.

Myocardial glucose suppression was assessed visually by experienced nuclear medicine physicians. Myocardial glucose suppression was considered adequate when normal myocardial FDG uptake was lower than the blood pool—defined as a negative study if all LV wall segments showed uptake equal to or less than the blood pool, and a positive study if focal or multifocal uptake was present or if corresponding regions demonstrated late gadolinium enhancement on cardiac MRI (when available). Scans not meeting these criteria—such as those showing diffuse LV uptake, basal LV ring uptake, lateral LV wall uptake, or patchy uptake exceeding blood pool activity—in the absence of known myocardial inflammation, were classified as inadequate myocardial glucose suppression (Fig. 1). Scans were correlated with clinical notes as well as cardiac MRI findings where available. Blood ketone levels were analyzed to determine if they correlated with suppression outcomes, with the aim of identifying a minimum threshold predictive of successful suppression.

Statistical analysis was performed using SPSS 27 (IBM Corp., Armonk, NY). For univariate analysis, the chi-squared test was used for categorical variables and the independent t-test for continuous variables. Variables with a p-value < 0.20 in univariate analysis were entered into a multivariate logistic regression model to identify independent predictors of inadequate myocardial suppression. A p-value < 0.05 was considered statistically significant.

Ethics approval was obtained from the institutional Human Research Ethics Committee. As this study evaluated routine clinical practice, informed consent was waived for the retrospective data and deemed not required for the prospective observational data collection.

There was a total of 95 patients from Aug 2022 - April 2024 in the retrospective cohort and 92 patients from April 2024 - January 2025 in the prospective cohort. The demographic data for the cohort are summarized in Table 1. There were no significant differences between the demographic data between the retrospective and prospective cohort.

Table 1
Demographic and Clinical Characteristics of participants
	Retrospective Cohort	Prospective Cohort	p-value*
Number of patients (n)	95	92
Age (mean)	62.3 years	60.2 years	0.95
Gender (n)
Male	52	52
Female	43	40	0.81
Patient Location
Outpatients	45	57
Inpatients	40	35	0.57
PET Indication
Sarcoid assessment	57	49
Non-sarcoid	38	46	0.35
*P-value for difference between subgroups with dichotomous factors (Chi-squared) or means (Independent T-test)

Following the introduction of improved dietary guidelines and logbook in April 2024, the rate of inadequate MGS reduced from 26% down to 17% (9% decrease, p = 0.14). The overall rate of inadequate MGS was 22% (retrospective and prospective cohort study combined).

On univariate analysis of dichotomous variables, significant risk factors for inadequate MGS included prednisolone use (75% vs 14.9% for no prednisolone use, OR: 17.1 [95%CI 1.65-177.04], p = 0.009), low blood ketone level (≤ 0.3 mmol/L)(OR: 5.77 [95%CI 1.69–19.68], p = 0.003) and female sex (27.5% vs males 9.6%, OR: 3.57 [95%CI 1.12–11.3], p = 0.025) (Table 2).

Table 2
Univariate analysis of dichotomous factors associated with incomplete MGS in the Prospective cohort
	Inadequate myocardial glucose suppression OR (95% CI)	p-value
Female vs Male	3.57 (1.12–11.3)	0.025
Current Prednisolone use vs No prednisolone use	17.1 (1.65-177.04)	0.009
Blood ketone level
≤ 0.3 vs > 0.4 mmol/L	5.77 (1.69–19.68)	0.003
≤ 0.4 vs > 0.5 mmol/L	4.11 (1.08–15.6)	0.028
Ketogenic diet duration < 24hrs vs ≥ 24hrs	4.72 (1.08–20.6)	0.049
Inpatient vs Outpatient	1.33 (0.45–3.97)	0.61
Sarcoid vs non-sarcoid assessment	1.58 (0.52–4.79)	0.42
Poor Keto diet adherence vs Good keto diet adherence	2.09 (0.64–6.83)	0.22
Diabetic vs non-diabetic	0.39 (0.05–3.37)	0.35

Univariate analysis of the continuous variables associated with inadequate MGS are outlined in Table 3. Mean blood ketone levels were significantly lower in patients with incomplete MGS (0.34 mmol/L vs 0.76 mmol/L, p-value 0.04). The ketogenic diet duration was lower in patients with incomplete MGS (20.9 hrs vs 29.6 hrs, p = 0.07).

Table 3
Univariate analysis of continuous factors associated with incomplete MGS in prospective cohort
Characteristic	Inadequate Cardiac Suppression	Adequate Cardiac Suppression	P-value
Age	55.9 years	61.1 years	0.22
Weight	88.9 kg	88.0 kg	0.87
BMI	30.3	29.6	0.78
Blood Glucose Level	5.3 mmol/L	5.4 mmol/L	0.89
Blood Ketone Level	0.34 mmol/L	0.76 mmol/L	0.04
Ketogenic Diet Duration	20.9 hrs	29.6 hrs	0.07
Fasting Duration	16.7 hrs	17.2 hrs	0.88

Multivariate analysis demonstrated prednisolone use, low blood ketone levels (≤ 0.3 mmol/L), female gender and < 24hr ketogenic diet remained significant risk factors for inadequate MGS (Model 2, Table 4). Model 1 multivariate analysis demonstrated female was a risk factor for inadequate MGS however became non-significant after the addition of a ketogenic diet duration < 24hrs as a variable (Table 4).

Table 4
Multivariate analysis of factors associated with incomplete MGS
	Odds Ratio for Incomplete MGS (95% CI)	P-value
Model 1
Low Blood Ketone level (≤ 0.3mmol/L)	4.04 (1.09–14.98)	0.037
Female Gender	4.50 (1.11–18.26)	0.036
Prednisolone use	26.97 (91.84-396.25)	0.016
Model 2
Low Blood Ketone level (≤ 0.3 mmol/L)	7.1 (1.2–41.4)	0.029
Female Gender	4.49 (0.79–25.64)	0.09
Prednisolone use	51.03 (2.55-1023.3)	0.01
Ketogenic diet duration < 24hrs	20.08 (2.28-176.47)	0.007

The rates of inadequate MGS were 50%, 26% and 7% for patients with blood ketone level of 0.1 mmol/L, 0.2–0.3 mmol/L and ≥ 0.4 mmol/L, respectively (Table 5). If patients were on prednisolone, 100% had inadequate MGS if the blood ketone level was 0.3 mmol/L or lower. There were two patients who were on prednisolone (10mg daily and 25mg daily) had a low blood ketone level of 0.1 mmol/L and had inadequate MGS, despite adherence to the ketogenic diet for 24hrs. There was one patient on prednisolone (10mg daily) who had a borderline blood ketone level of 0.3 mmol/L and had inadequate MGS. There was one patient on prednisolone (10mg) who had a blood ketone level of 0.4 mmol/L and had adequate MGS.

Table 5
Ketone level and association with incomplete MGS
	Blood Ketone Level (mmol/L)
	0.1	0.2–0.3	≥ 0.4
Risk of inadequate MGS	50%	26%	7%
+ Poor Ketogenic diet adherence	100%	50%	18.8%
+ On Prednisolone	100%	100%	0%
+ Female	100%	28%	16%
+ Male	29%	22%	3%

There were four patients who had high blood ketone levels (> 0.3 mmol/L) but had inadequate cardiac suppression. One patient had a high ketone level of 1.4 mmol/L however they reported that they consumed mashed pumpkin and crackers the day prior to the scan. Another patient had a ketone level of 0.6 mmol/L but reported they ate potato soup and bread the day before. Another patient had a ketone level of 0.4 mmol/L but had crackers at 10pm the night before. One patient had a ketone level of 0.7mmol/L but denied having carbohydrates the day before.

This present study reinforces the clinical utility of ketogenic preparation for cardiac FDG PET/CT to suppress physiological myocardial glucose uptake, thereby enhancing diagnostic accuracy in evaluating inflammatory cardiac pathologies such as sarcoidosis. Our findings suggest that emailing patients clear ketogenic dietary instructions along with a dietary logbook significantly improves adherence to the ketogenic protocol. It clarifies adherence to the ketogenic diet prior to the scan. This simple intervention may optimize myocardial suppression and improve scan interpretability.

This study also demonstrated that measuring serum ketone levels remains a valuable adjunct, providing objective insight into the patient's metabolic state. In our cohort, the rates of inadequate MGS were 50%, 26% and 7% for patients with blood ketone levels of 0.1, 0.2–0.3 and ≥ 0.4 mmol/L, respectively. This is consistent with a previous study which demonstrated a ketone level cut-off value of 0.35 mmol/L to predict adequate myocardial suppression, with a specificity of 90% and sensitivity of 56% in patients with 24–48 hrs of a ketogenic diet [6]. In comparison, another study including patients on a 24-hour or 72-hour ketogenic diet, or given a ketogenic drink, found that a ketone threshold of ≥ 0.58 mmol/L correctly classified 92% of scans [7]. The differences in ketone levels across studies is attributable to the variable duration of the ketogenic diet, with studies showing significantly higher ketone levels after a 72-hour regimen compared to a 24-hour ketogenic diet protocol (0.3 ± 0.4 versus 1.0 ± 0.7 mmol/L; p < 0.001)6.

However, optimal myocardial suppression appears to require both biochemical ketosis and strict dietary compliance. This study demonstrated that relying solely on serum blood ketone levels can be insufficient without assessment of actual dietary adherence, as some patients demonstrated poor suppression despite adequate ketone levels. The specific example which highlights this was a patient with inadequate MGS with a blood ketone level of 1.4mmol/L but had mashed pumpkin and crackers 24hrs prior to the scan. This highlights the importance of a combined approach involving both metabolic (serum ketone) and behavioral (dietary log) assessment to determine true ketogenic adherence [9, 10]

These findings maybe particularly valuable in indeterminate cases wherein the combination of high serum ketone levels and good dietary adherence favors a highly likelihood of adequate myocardial glucose suppression and any uptake is likely pathological myocardial uptake, whereas low ketones and poor adherence favors a higher likelihood of inadequate myocardial glucose suppression. This distinction may help clinicians avoid misdiagnosis or unnecessary further testing [11].

This present study also highlights the increased difficulty for patients on prednisolone to achieve a ketogenic metabolic state and adequate MGS, even with adherence to a standard 24-hour ketogenic diet and fasting protocol. This contrasts with a previous study which demonstrated patients treated with systemic corticosteroids had adequate suppression (88%) compared to 57% without systemic corticosteroids (p = 0.096) [12].

Corticosteroids such as prednisolone are well-known to induce hyperglycemia and insulin resistance, which can impair the metabolic shift required for effective suppression of myocardial glucose uptake. Glucocorticoids upregulate hepatic gluconeogenesis and reduce peripheral glucose uptake, thereby sustaining elevated serum glucose levels and blunting ketogenesis [13, 14]. These metabolic effects directly oppose the physiologic conditions necessary for myocardial fatty acid utilization during FDG PET imaging.

In this present study, all patients on prednisolone demonstrated a markedly reduced ability to achieve adequate myocardial suppression when prepared with a 24-hour ketogenic protocol. Specifically, 100% of patients on prednisolone with a blood ketone level of ≤ 0.3 mmol/L failed to achieve adequate MGS. Two patients on prednisolone (10 mg and 25 mg daily) had low ketone levels of 0.1 mmol/L and demonstrated inadequate suppression, despite reportedly adhering to the prescribed ketogenic diet. Another patient, also on 10 mg daily of prednisolone, had a borderline ketone level of 0.3 mmol/L and similarly showed inadequate suppression. Notably, the only patient on prednisolone to achieve adequate MGS had a ketone level of 0.4 mmol/L, suggesting that higher ketone thresholds may be necessary in corticosteroid-treated individuals to compensate for glucocorticoid-induced metabolic derangements.

These findings suggest that shorter 24-hour ketogenic preparation protocols may be insufficient for patients receiving systemic corticosteroids. It is plausible that these patients require an extended ketogenic diet duration of 48 to 72 hours, with more stringent fasting, to overcome the counterregulatory effects of corticosteroids on glucose metabolism and to promote sufficient ketone production. Additionally, a higher minimum ketone threshold (e.g. >0.4 mmol/L) may be a more appropriate indicator of readiness for imaging in this subgroup.

These results are consistent with previous literature indicating that individual metabolic and pharmacologic factors can significantly influence FDG biodistribution and suppression protocols [15, 16]. Given the prevalence of corticosteroid use in patients undergoing inflammatory cardiac imaging, particularly for suspected sarcoidosis, our findings underscore the need for tailored preparation protocols for this high-risk group. Larger studies are warranted to define optimal ketogenic duration and ketone cutoffs in corticosteroid-treated populations, and to evaluate whether adjunctive strategies such as prolonged fasting or exogenous ketone supplementation could improve MGS outcomes.

Previous study by Hartikainen and colleagues [6] also identified diabetes and obesity predicted adequate myocardial suppression. Our study did not identify diabetes or obesity (based on BMI) associated with myocardial suppression in our prospective cohort.

Cost Analysis

Implementing a streamlined ketogenic preparation protocol that includes blood ketone testing and emailed dietary instructions with a logbook presents a highly cost-effective strategy for ensuring adequate myocardial glucose suppression in cardiac FDG PET/CT imaging. A single ketone strip costs approximately $0.85 AUD and point-of-care testing typically requires only one minute of staff time to perform, often using the same glucose monitor and single skin prick. Emailing the dietary guidelines and logbook to patients takes about one minute, and patients typically spend around 10 minutes completing the logbook and adhering to the ketogenic diet.

In contrast, inadequate myocardial suppression can necessitate repeated PET/CT scans, leading to significant additional costs and resource utilization. The Medicare Benefits Schedule (MBS) fee for a whole-body FDG PET scan is $953.00 AUD, with Medicare covering 85% ($810.05 AUD) and patients potentially facing out-of-pocket expenses depending on the provider's billing practices. Repeat scans also impose further burdens, including extended dietary restrictions [up to 72 hours], increased patient inconvenience, and additional strain on departmental resources and scheduling. Therefore, pre-test qualitative and quantitative assessment of diet and ketones may be a practical method to improve resource utilization.

Limitations

This study has several limitations that may affect the generalizability of its findings. The external validity is constrained by the specific protocol used: a 24-hour ketogenic diet with a 12-hour fast prior to FDG injection. Other institutions employ longer preparation protocols — including 48- to 72-hour ketogenic diets — which have been shown to more consistently suppress physiological myocardial uptake [16, 17]. However, there are also many hospital departments which utlise a 24-hour ketogenic diet with a 12-hour fast to reduce patient scan delays. Moreover, the findings from this study may assist in identifying which patients may be suitable for earlier imaging at 24-hours rather than wait 72-hours.

Another limitation of our study was the low number of patients on corticosteroids, however despite the small numbers, it had an overt quantitative and qualitive impact on MGS. The metabolic impact of glucocorticoids may necessitate higher ketone thresholds (ie. >0.4mmol/L) or prolonged dietary preparation to achieve adequate myocardial suppression. Further research is warranted to determine the appropriate preparation strategy for this subgroup.

Another limitation was not utilising intravenous unfractionated heparin (50 IU/kg) approximately 15 minutes prior to FDG injection. While theoretically beneficial by inducing lipolysis and increase serum free fatty acids [18], clinical studies have shown mixed results regarding MGS and may have added confounding variables in this present study [15, 19, 20, 21]. A previous study demonstrated heparin did not significantly affect suppression in patients with a low ketone level [21].

This study also did not utilise exogenous ketone supplements, such as ketone esters or ketogenic formulas, to induce rapid ketosis in patients unable to adhere to dietary restrictions. Early data suggest these strategies may enhance myocardial suppression, but evidence remains limited and variable [23, 23]. Previous studies have also identified fatty liver predicted adequate myocardial suppression [6]. Our study did not assess the presence of fatty liver.

In conclusion, this study demonstrates providing patients clear ketogenic dietary instructions along with a dietary logbook improves dietary adherence prior to 18F-FDG PET/CT. Moreover, incorporating point-of-care ketone level testing can further refine patient preparation, ensuring higher rates of diagnostic-quality imaging. Future research should focus on exploring additional strategies to mitigate the identified risk factors for preparation of failure.

Sources of Funding: None

Disclosure of Potential Conflicts of Interest: None

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Utility of serum blood ketone levels and other risk factors for inadequate myocardial glucose suppression ketogenic FDG-PET/CT: a prospective and retrospective cohort study

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