⁶⁸Ga-DOTATATE Measurements Predict Progression of Aortic Valve Calcification in Humans

Abstract

BACKGROUND:

Inflammation potentiates aortic valve calcification (AVC). ⁶⁸Ga-DOTATATE (gallium-68 DOTA-(Tyr³)-octreotate), a positron emission tomography tracer that binds to somatostatin receptors, provides a measure of tissue inflammation. However, the diagnostic and prognostic values of aortic valve (AV) ⁶⁸Ga-DOTATATE uptake in AVC remain unexplored. Here, we tested whether AV ⁶⁸Ga-DOTATATE uptake predicts the progression of AVC.

METHODS:

A total of 683 individuals (median age, 63 years; 46% male) underwent clinical ⁶⁸Ga-DOTATATE positron emission tomography/computed tomography imaging from 2017 to 2023; 209 had follow-up imaging (median, 1.3 years interval). AV inflammation was measured as the maximum standardized uptake value of ⁶⁸Ga-DOTATATE uptake within the AV on baseline positron emission tomography/computed tomography. AVC was quantified on baseline and follow-up computed tomography scans (Hounsfield units >130). AVC progression was assessed as the difference between baseline and follow-up AVC. Individuals with a square root difference of annualized AVC change ≥2.5 were characterized as progressors and <2.5 as nonprogressors. Demographic and clinical data were collected from medical records.

RESULTS:

Baseline AV ⁶⁸Ga-DOTATATE uptake correlated with baseline AVC (standardized ρ=0.12; P=0.002). Furthermore, baseline AV ⁶⁸Ga-DOTATATE uptake associated with AVC progression (odds ratio [OR], 3.0 [95% CI, 1.4–6.4]; P=0.004) and remained significant after separately adjusting for baseline AVC (OR, 3.1 [95% CI, 1.5–6.6]), sex (OR, 4.0 [95% CI, 1.7–9.0]), hypertension (OR, 2.8 [95% CI, 1.3–6.2]), diabetes (OR, 3.0 [95% CI, 1.4–6.4]), hyperlipidemia (OR, 2.4 [95% CI, 1.1–5.3]), smoking (OR, 3.1 [95% CI, 1.5–6.7]), chronic kidney disease (OR, 2.9 [95% CI, 1.4–6.3]), and body mass index (OR, 3.0 [95% CI, 1.4–6.3]), became insignificant when adjusting to age (OR, 1.9 [95% CI, 0.8–4.3]).

CONCLUSIONS:

Our study highlights the use of ⁶⁸Ga-DOTATATE for assessing AV inflammation and predicting AVC progression. These findings underscore the role of inflammation in AVC progression and have potential implications for risk assessment and evaluating therapies in AV disease.

Calcific aortic valve disease (CAVD) is the most common valvular heart disease worldwide, and its prevalence is anticipated to rise with the aging population.¹ The prevalence of CAVD increases markedly with age, affecting ≈25% of individuals over 65 years old and up to 50% of those over 85 years old.² Although the spectrum of the disease ranges from asymptomatic aortic sclerosis to overt aortic stenosis (AS), the presence of calcification is a critical risk factor for disease progression and is associated with increased morbidity and mortality.³

CAVD is a progressive chronic disease characterized by the calcification and thickening of the aortic valve (AV) leaflets, which can impair valve function over time. Inflammation plays a pivotal role in its pathogenesis.³ The disease process is initiated by endothelial dysfunction, lipid infiltration, and mechanical stress.⁴ These factors trigger an inflammatory response involving activated macrophages and other immune cells, leading to the secretion of proinflammatory cytokines and the transformation of valvular smooth muscle cells into osteoblastic precursors. This cascade results in calcium deposition within the valve, progressive leaflet stiffening, and subsequent orifice narrowing, raising the pressure gradient across the valve over time. Such hemodynamic consequences prompt left ventricular hypertrophy, diastolic dysfunction, and eventual heart failure with potential obstruction of blood flow from the left ventricle to the aorta.^5,6 Surgical and transcatheter AV replacement represent the most accepted interventions for managing the disease.^7,8 However, new strategies are needed to identify drivers of CAVD progression, which may in turn enable earlier interventions.

Molecular imaging has emerged as a promising tool for the noninvasive assessment of valvular inflammation. Previous studies utilizing ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) have established the inflammatory nature of CAVD.^9,10 However, ¹⁸F-FDG, a glucose analog tracer used to quantify metabolic activity, has limitations in cardiac imaging due to high background myocardial glucose uptake, which can obscure valvular inflammation signals.¹¹ This background uptake reduces the specificity and sensitivity of ¹⁸F-FDG PET/CT in detecting AV inflammation, thus heightening the need for alternative imaging agents.

In this context, ⁶⁸Ga-DOTATATE (gallium-68 DOTA-(Tyr³)-octreotate), a PET tracer that binds with high specificity to SSTR2 (somatostatin receptor subtype 2), which is overexpressed on activated macrophages, is a key mediator of inflammation in CAVD.^11,12 The high affinity of ⁶⁸Ga-DOTATATE for SSTR2 allows for targeted imaging of inflammatory processes with minimal background myocardial uptake, enhancing image quality and diagnostic accuracy.¹³ Unlike ¹⁸F-FDG, which requires strict fasting preparation, ⁶⁸Ga-DOTATATE does not need to have baseline control of blood glucose levels, and the image quality won’t be affected by the patient’s glycemic status.¹⁴ Recent studies have successfully used somatostatin receptor tracers to assess vascular inflammation in atherosclerosis within coronary arteries¹⁵ and major vessels, such as the aorta and carotids, as well as in conditions like myocardial infarction,¹⁶ large vessel vasculitis,¹² and ischemic strokes.¹⁷

Despite the potential advantages of ⁶⁸Ga-DOTATATE over ¹⁸F-FDG, its diagnostic and prognostic value in CAVD remains unexplored. Understanding whether ⁶⁸Ga-DOTATATE uptake correlates with baseline AV calcification (AVC) and predicts its progression could provide valuable insights into disease mechanisms and help identify patients at higher risk for AS progression. Accordingly, we aimed to investigate the relationships between baseline AV ⁶⁸Ga-DOTATATE uptake, baseline AVC, and AVC progression over time. We hypothesized that increased baseline ⁶⁸Ga-DOTATATE uptake in the AV is associated with higher baseline AVC and predicts the progression of AVC.

METHODS

Data Availability

The data that support the findings of this study are available from the corresponding author on reasonable request.

Study Population and Design

Our study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology Guideline for reporting human samples.

We retrospectively analyzed data from 698 individuals who underwent at least 1 nongated ⁶⁸Ga-DOTATATE PET/CT scan for the diagnosis or follow-up of neuroendocrine tumors at Mass General Brigham hospitals between 2017 and 2023. Fifteen subjects were excluded due to uninterpretable images caused by artifacts in the AV area, resulting in a final cohort of 683 participants. Among these, 209 individuals had additional follow-up scans during the same period (median interval of 1.3 years).

Demographic and clinical data—including age, sex, hypertension, hyperlipidemia, diabetes, chronic kidney disease, smoking status, and body mass index—were collected from electronic medical records. The study was conducted with the approval of the Mass General Brigham Institutional Review Board, and the requirement for informed consent was waived due to the retrospective nature of the study.

Assessment of AV Inflammatory Activity and Calcification

To ensure unbiased analysis, all images were deidentified before assessment. Two independent investigators, blinded to each other’s evaluations and to clinical data, performed the imaging analyses. One investigator assessed baseline AV ⁶⁸Ga-DOTATATE uptake, whereas the other quantified AVC on both baseline and follow-up CT scans.

Measurement of AV ⁶⁸Ga-DOTATATE Activity

The assessment of ⁶⁸Ga-DOTATATE uptake in the AV was conducted using methods previously applied for measuring ¹⁸F-FDG activity in the AV.^9,10 Imaging analysis was performed on axial sections using OsiriX MD software (version 13). After coregistering the PET and CT images, a circular region of interest with a diameter of 5 mm was placed to encompass the AV while minimizing spillover from the adjacent myocardial activity. From this region of interest, we measured the mean standardized uptake value (SUV) and maximum SUV (as the primary measure) of ⁶⁸Ga-DOTATATE within the central portion of the AV. To avoid potential confounding of PET signal interpretation, individuals with cardiac metastases or metastases in close proximity to the heart were excluded.

Measurement of AVC and Progression

AVC was quantified on the nongated attenuation-corrected CT component of the ⁶⁸Ga-DOTATATE PET/CT scans using the same software. Calcifications were identified on axial sections using a predefined threshold of ≥130 Hounsfield units. AVC was defined as any calcification of the AV leaflets and annulus, with care taken to exclude nonvalvular calcifications.¹⁸

AVC progression was evaluated using the Hokanson method, as described previously for both coronary artery progression¹⁹ and AVC.¹⁰ This approach involves calculating the annualized square root–transformed difference between baseline and follow-up calcium scores. A cutoff value of 2.5 (which exceeds measurement error) was used to define significant progression. Participants with a square root–transformed difference ≥2.5 were classified as progressors, while those with a difference <2.5 were considered nonprogressors. This method is based on individual linear regression of AVC over time, to account for the variability in both baseline AVC load and the time interval between the baseline and follow-up images. This approach limits the impact of the nonuniform structure in raw calcium scores and improves the comparability across different scanner generations.¹⁹

Statistical Analysis

Continuous variables are presented as median (interquartile range), and categorical variables are expressed as counts and percentages. Comparisons between groups were performed using the independent samples t test for continuous variables if normally distributed, or the Mann-Whitney U test if not, and the χ² test was used for categorical variables. Spearman correlation analyses were utilized to assess the relationship between baseline AV ⁶⁸Ga-DOTATATE uptake and baseline AVC, both as a continuous calcium score and as a binary variable (presence versus absence of AVC). Correlation coefficients (ρ) and P values were reported for these associations.

Logistic regression analyses were used to assess the association between baseline AV ⁶⁸Ga-DOTATATE uptake and subsequent AVC progression. Odds ratios (ORs) with 95% CIs and corresponding P values were reported. Univariable regression models were adjusted individually for key potential confounders, including age, sex, hypertension, hyperlipidemia, diabetes, chronic kidney disease, smoking status, body mass index, and baseline AVC, where appropriate. In addition, 2 multivariable analyses were constructed; model 1 includes demographics (age and sex), baseline AVC, and body mass index, and model 2 includes traditional cardiovascular comorbidities (ie, hypertension, hyperlipidemia, diabetes, smoking status, and chronic kidney disease). Given that only 49 individuals met the definition for AVC progression, multivariable models were limited to a maximum of 5 predictors per model to minimize model overfitting.

To further explore potential effect modifiers, we conducted subgroup analyses stratified by the cohort median age (62 years), comparing older (>62 years) and younger (≤62 years) individuals. We also conducted an exploratory analysis to assess whether baseline AVC burden influenced the predictive value of AV ⁶⁸Ga-DOTATATE uptake by stratifying participants based on baseline AVC levels (≤ versus >median). All statistical analyses were performed using [SPSS version 28]. A 2-tailed P value of <0.05 was considered statistically significant.

RESULTS

Baseline Characteristics

Subject characteristics at baseline (n=683) are summarized in Table 1. The median age was 62.9 years (interquartile range, 53–71). Among the 209 subjects with follow-up scans, 45 exhibited progression of AVC (progressors), whereas 164 did not (nonprogressors). Progressors were older and had a higher prevalence of male sex, hypertension, hyperlipidemia, and a higher ⁶⁸Ga-DOTATATE signal (as both mean SUV and maximum SUV) compared with nonprogressors (Table 1).

Table 1.

Demographic Characteristics of the Total Population, Subjects With Baseline-Only Scans, and Those With Follow-Up Scans

Characteristics	Total population (N=683)	Baseline-only cohort (n=474)	Follow-up cohort
			Overall (n=209)	Progressors (n=45)	Nonprogressors (n=164)	P value
Age, y	62.9 (53–71)	63.5 (52.4–71.8)	62.1 (54.2–69.6)	69.9 (65.6–73.3)	59.6 (52.3–66.4)	<0.001*
Male, %	45.6	45	46.9	73.3	26.7	<0.001*
Hypertension, %	57.9	58.1	57.4	84.4	15.6	<0.001*
Diabetes, %	24.1	25.2	21.5	28.9	71.1	0.189
Hyperlipidemia, %	50.9	51.7	48.8	80	20	<0.001*
Chronic kidney disease, %	9.9	9.6	10.5	22.2	77.8	0.004*
Smoking, %	38.4	38.4	38.3	46.7	53.3	0.212
Body mass index	27.2 (23.5–31.2)	27.5 (24–32.5)	26.3 (23–29.8)	25.3 (21.9–30.2)	26.6 (23.2–29.8)	0.610
Baseline AVC	0 (0–14)	0 (0–23)	0 (0–0)	20 (65–242)	0 (0–0)	<0.001*
Baseline SUVmax	1.13 (0.92–1.43)	1.11 (0.92–1.39)	1.19 (0.94–1.52)	1.46 (1.13–1.85)	1.12 (0.92–1.44)	<0.001*
Baseline SUVmean	0.78 (0.64–0.96)	0.76 (0.64–0.95)	0.81 (0.65–1.02)	0.90 (0.69–1.12)	0.79 (0.64–0.96)	0.033*

The P value represents the difference between the progressors vs nonprogressors. Continuous data are presented as median (interquartile range). Categorical data are presented as %. AVC indicates aortic valve calcification; SUVmax, maximum standardized uptake value; and SUVmean, mean standardized uptake value.

^*Significant P values.

Association Between Baseline AV ⁶⁸Ga-DOTATATE Uptake and Baseline AVC

Baseline AV ⁶⁸Ga-DOTATATE uptake significantly correlated with baseline AVC in unadjusted analyses. This was evident when AVC was analyzed as a continuous calcium score (standardized ρ=0.128; P<0.001) and as a binary variable comparing the presence versus absence of calcification (standardized ρ=0.120; P=0.002, Table 2). This association remained significant after adjusting separately for sex (ρ=0.244; P<0.001), hypertension (ρ=0.190; P=0.007), hyperlipidemia (ρ=0.155; P=0.028), diabetes (ρ=0.209; P=0.003), smoking (ρ=0.215; P=0.002), and chronic kidney disease (ρ=0.0197; P=0.005). However, the association was attenuated and became nonsignificant after adjustment for age (ρ=0.123; P=0.083, Table 3). Figure 1 illustrates the baseline association between AV ⁶⁸Ga-DOTATATE activity and AVC. We also tested the same association between mean SUV and baseline AVC, and the results were inconsistent (Table S1).

Table 2.

Unadjusted Correlations Between Baseline AV ⁶⁸Ga-DOTATATE Signal Versus Baseline Calcification and Its Progression

Predictor		Outcome
		Baseline AV calcification						AV calcification progression
		Ca score			Present vs absent Ca			Progressors vs nonprogressors
		n	Correlation coefficient (ρ)	P value	n	Correlation coefficient (ρ)	P value	n	Correlation coefficient (ρ)	P value
Baseline AV 68Ga-DOTATATE Signal	SUVmax (primary measure)	681	0.128	<0.001*	681	0.120	0.002*	204	0.236	<0.001*
	SUVmean	681	0.101	0.008*	681	0.093	0.015*	204	0.149	0.033*

⁶⁸Ga-DOTATATE indicates gallium-68 DOTA-(Tyr³)-octreotate; AV, aortic valve; SUVmax, maximum standardized uptake value; and SUVmean, mean standardized uptake value.

^*Significant P values.

Table 3.

Adjusted Association Between Baseline Aortic Valve ⁶⁸Ga-DOTATATE Signal and Baseline Valvular Calcification

Predictor	Covariables	Outcome
		Baseline AV calcification
		Ca score		Present vs absent Ca
		Correlation coefficient (ρ)	P value	Correlation coefficient (ρ)	P value
Baseline AV 68Ga-DOTATATE SUVmax	Age	0.044	0.254	0.123	0.083
	Sex	0.095	0.014*	0.244	<0.001*
	Hypertension	0.082	0.033*	0.190	0.007*
	Diabetes	0.088	0.023*	0.209	0.003*
	Hyperlipidemia	0.071	0.066	0.155	0.028*
	Smoking	0.100	0.009*	0.215	0.002*
	Chronic kidney disease	0.090	0.020*	0.197	0.005*
	BMI	0.094	0.014*	0.089	0.021*

⁶⁸Ga-DOTATATE indicates gallium-68 DOTA-(Tyr³)-octreotate); AV, aortic valve; BMI, body mass index; and SUVmax, maximum standardized uptake value.

^*Significant P values.

Figure 1. Box plot showing the association between baseline aortic valve ⁶⁸Ga-DOTATATE (GA-DT; gallium-68 DOTA-(Tyr³)-octreotate) activity and baseline aortic valve calcification.

The error bars represent 1 SEM. AV indicates aortic valve; and SUVmax, maximum standardized uptake.

Association Between Baseline AV ⁶⁸Ga-DOTATATE Uptake and AVC Progression

Baseline AV ⁶⁸Ga-DOTATATE uptake was significantly associated with subsequent AVC progression in an unadjusted analysis (standardized ρ=0.236; P<0.001, Table 2). This association remained significant after adjusting separately for baseline AV calcium score (OR, 3.113 [95% CI, 1.469–6.596]; P=0.003), sex (OR, 4.010 [95% CI, 1.772–9.071]; P<0.001), hypertension (OR, 2.799 [95% CI, 1.270–6.171]; P=0.011), hyperlipidemia (OR, 2.4 [95% CI, 1.082–5.324]; p 0.031), diabetes (OR, 2.994 [95% CI, 1.41–6.359]; P=0.004), smoking (OR, 3.139 [95% CI, 1.497–6.665]; P=0.003), and chronic kidney disease (OR, 2.944 [95% CI, 1.369–6.331]; P=0.006) but was attenuated by adjustment for age (OR, 1.869 [95% CI, 0.806, 4.337]; P=0.145, Table 4). In addition, the association between baseline AV ⁶⁸Ga-DOTATATE uptake and AVC progression remained significant after multivariable adjustments for age, sex, baseline AVC and body mass index (OR, 4.113 [95% CI, 1.030, 16.427]; P=0.045) and for hypertension, hyperlipidemia, diabetes, smoking, and chronic kidney disease (OR, 2.304 [95% CI, 1.007, 5.274]; P=0.048, Table 4). Figure 2 shows the association between baseline AV ⁶⁸Ga-DOTATATE activity and subsequent AVC progression, and Figure 3 shows an example of an individual who shows progression of their AVC versus an individual who did not show AVC progression relative to their AV ⁶⁸Ga-DOTATATE activity.

Table 4.

Association Between Baseline Aortic Valve ⁶⁸Ga-DOTATATE Signal and Subsequent Valvular Calcification

Predictor	Covariables	Outcome
		AV calcification progression (progressors vs nonprogressors)
		OR (95% CI)	P value
Baseline AV 68Ga-DOTATATE SUVmax	Unadjusted	3.006 (1.422–6.353)	0.004*
	Age	1.869 (0.806–4.337)	0.145
	Sex	4.010 (1.772–9.071)	<0.001*
	Hypertension	2.799 (1.270–6.171)	0.011*
	Diabetes	2.994 (1.410–6.359)	0.004*
	Hyperlipidemia	2.400 (1.082–5.324)	0.031*
	Smoking	3.139 (1.497–6.665)	0.003*
	Chronic kidney disease	2.944 (1.369–6.331)	0.006*
	BMI	3.008 (1.427–6.343)	0.004*
	Baseline Ca score	3.113 (1.469–6596)	0.003*
	Model 1	4.113 (1.030–16.427)	0.045*
	Model 2	2.304 (1.007–5.274)	0.048*

Model 1 includes age, sex, baseline calcification, and BMI. Model 2 includes hypertension, hyperlipidemia, diabetes, smoking, and chronic kidney disease. Cardiovascular disease risk factors: combined variable includes hypertension, diabetes mellitus, hyperlipidemia, smoking, and chronic kidney disease. ⁶⁸Ga-DOTATATE indicates gallium-68 DOTA-(Tyr³)-octreotate; AV, aortic valve; BMI, body mass index; OR, odds ratio; and SUVmax, maximum standardized uptake value.

^*Significant P values.

Figure 2. Boxplot showing the association between baseline aortic valve ⁶⁸Ga-DOTATATE (GA-DT; gallium-68 DOTA-(Tyr³)-octreotate) activity and subsequent aortic valve calcification.

The error bars represent 1 SEM. AV indicates aortic valve; and SUVmax, maximum standardized uptake.

Figure 3. Imaging examples of a “progressor” and a “non-progressor” subjects with baseline CT, baseline ⁶⁸Ga-DOTATATE (gallium-68 DOTA-(Tyr³)-octreotate) PET/CT, and subsequent follow-up CT highlighting the calcification progression.

A, Baseline scan of a progressor subject with an aortic valve calcium score of 2788. After almost a year and a half, the subject’s aortic valve calcification (AVC) progressed to 4394. B, Baseline scan of a progressor subject with an aortic valve calcium score of 353. After almost a year and a half, the subject’s AVC progressed to 490. C, Baseline scan of a progressor subject with an aortic valve calcium score of zero. After almost 2 and a half years, the subject’s AVC progressed to zero. Studies were reoriented into the cardiac short axis and windowed individually to demonstrate specific examples of valvular ⁶⁸Ga-DOTATATE activity and AVC progression. CT indicates computed tomography; and PET, positron emission tomography.

In a sensitivity analysis, we tested the same association between baseline AV ⁶⁸Ga-DOTATATE (using mean SUV and TBR max) and AVC progression, and the results were insignificant (Tables S2 and S3).

Impact of Age and Baseline AVC on the Relationship Between Baseline ⁶⁸Ga-DOTATATE Uptake and Subsequent AVC Progression

Given that the burden of aortic valve disease increases substantially with age, and the findings that relationships were attenuated by the addition of age to the multivariable models,²⁰ we conducted subgroup analyses to test whether ⁶⁸Ga-DOTATATE uptake was a significant predictor of AVC progression among older individuals. In an analysis of subjects who entered with age greater than the median for our population (≥age 62 years), ⁶⁸Ga-DOTATATE predicted AVC progression (OR, 10.587 [95% CI, 1.330–84.293]; P=0.026, Table 5). On the contrary, ⁶⁸Ga-DOTATATE was not predictive of AVC progression in younger individuals (OR, 1.310 [ 95% CI, 0.182–9.432], P=0.789).

Table 5.

Association Between Baseline ⁶⁸Ga-DOTATATE Uptake and Aortic Valve Calcium Progression by Median Age Cutoff

Predictor	Age subgroups	AVC progression
		Cases (n)		OR (95% CI)	P value
		Progressors	Nonprogressors
AV 68Ga-DOTATATE SUVmax	>Population median (62 y)	39	63	2.811 (1.061–7.450)	0.038*
	≤Population median (62 y)	5	95	1.310 (0.182–9.432)	0.789

Analyses are adjusted for baseline Ca (absent vs present). ⁶⁸Ga-DOTATATE indicates gallium-68 DOTA-(Tyr³)-octreotate; AV, aortic valve; AVC, aortic valve calcification; OR, odds ratio; and SUVmax, maximum standardized uptake value.

^*Significant P values.

In an exploratory analysis evaluating whether baseline AVC burden modified the association between baseline ⁶⁸Ga-DOTATATE uptake and subsequent AVC progression, participants were stratified by median baseline AVC score. Among individuals with lower baseline AVC (≤ median), ⁶⁸Ga-DOTATATE uptake was not significantly associated with future calcification progression (OR, 1.07 [95% CI, 0.38–2.98]; P=0.905). In contrast, in participants with higher baseline AVC (>median), ⁶⁸Ga-DOTATATE uptake was significantly associated with subsequent AVC progression (OR, 5.71 [95% CI, 1.43–22.76]; P=0.014). These associations remained robust after adjustment for individual covariates and in both multivariable models (Table 6).

Table 6.

Association Between Baseline Aortic Valve ⁶⁸Ga-DOTATATE Signal and Subsequent Valvular Calcification, Stratified by Baseline Valve Calcification (Around Median)

Predictor	Covariables	Baseline AV Ca ≤median		Baseline AV Ca >median
		AV calcification progression (progressors vs nonprogressors)
		OR (95% CI)	P value	OR (95% CI)	P value
Baseline AV 68Ga-DOTATATE SUVmax (Z score)	Unadjusted	1.065 (0.380–2.984)	0.905	5.709 (1.432–22.763)	0.014*
	Age	0.771 (0.238–2.493)	0.664	6.605 (1.428–30.556)	0.016*
	Sex	1.098 (0.417–2.893)	0.849	6.655 (1.676–26.424)	0.007*
	Hypertension	1.004 (0.368–2.740)	0.994	3.727 (1.010–13.746)	0.048*
	Diabetes	1.057 (0.381–2.927)	0.916	6.511 (1.409–30.100)	0.016*
	Hyperlipidemia	0.883 (0.287–2.716)	0.828	5.674 (1.229–26.191)	0.026*
	Smoking	1.071 (0.389–2.950)	0.894	5.588 (1.401–22.287)	0.015*
	Chronic kidney disease	1.087 (0.402–2.935)	0.870	5.713 (1.324–24.662)	0.020*
	BMI	0.967 (0.352–2.660)	0.949	5.722 (1.428–22.931)	0.014*
	Model 1*	0.594 (0.196–1.802)	0.358	7.726 (1.693–35.259)	0.008*
	Model 2*	0.099 (.006–1.655)	0.108	5.699 (1.240–26.193)	0.025*

Model 1: includes age, sex, and BMI. Model 2 includes hypertension, diabetes, hyperlipidemia, chronic kidney disease, and smoking. Cardiovascular disease risk factors: combined variable includes hypertension, diabetes mellitus, hyperlipidemia, smoking, and chronic kidney disease. ⁶⁸Ga-DOTATATE indicates gallium-68 DOTA-(Tyr³)-octreotate; AV, aortic valve; BMI, body mass index; OR, odds ratio; and SUVmax, maximum standardized uptake value.

^*Significant P values.

DISCUSSION

This study shows that a heightened local AV ⁶⁸Ga-DOTATATE PET/CT signal, a measure of inflammation, is associated with baseline AVC and its progression. The correlation between AV ⁶⁸Ga-DOTATATE uptake and baseline AVC remained significant after adjusting for several cardiovascular risk factors, though it was attenuated after adjustment for age. Furthermore, baseline AV ⁶⁸Ga-DOTATATE uptake was a significant predictor of AVC progression, even after adjusting for baseline calcium score and other potential confounders aside from age. These findings highlight the central role of inflammation—particularly SSTR2-expressing cells such as macrophages and pericytes—in the pathogenesis of AVC progression.¹² The findings suggest that ⁶⁸Ga-DOTATATE is a promising and specific marker for AV inflammation and may offer a targeted approach to risk stratification in patients with AS.

Notably, the predictive value of ⁶⁸Ga-DOTATATE uptake was more pronounced in older individuals (>population median age). Several factors may reconcile these findings. Age is a powerful integrator of cumulative exposure to proinflammatory, metabolic, and hemodynamic stressors; older valves contain a greater density of activated macrophages and pericytes that over-express SSTR2, the target of DOTATATE.²¹ Consequently, tracer uptake in older adults likely reflects cumulative exposure to proinflammatory stimuli or diminished regulatory mechanisms with aging, potentially heightening the relative importance of inflammation as a driver of calcification progression in this population. In contrast, the younger subgroup had modest calcific burden and fewer progression events, reducing statistical power and amplifying noise from physiological variations in tracer distribution or image resolution.

Further, in an exploratory subgroup analysis, DOTATATE was highly prognostic among those with a higher baseline calcium burden yet showed no signal in those with minimal or absent calcification. This finding may reflect a biological threshold phenomenon. Once microcalcification is established, inflammatory and osteogenic pathways reinforce one another: activated macrophages secrete pro-osteogenic cytokines, while nascent mineral deposits attract further inflammatory cells. This feed-forward loop amplifies SSTR2 expression and DOTATATE signal, making progression more detectable in the high-calcium group. By contrast, exceptionally early disease may involve intermittent or focal inflammatory activity below the spatial resolution of PET, limiting predictive value despite inflammation’s conceptual primacy. Technical considerations—nongated imaging and modest signal-to-background ratios—further dilute the tracer signal in low-calcium valves.

The natural history of CAVD involves 2 distinctive stages: the initiation phase and the propagation phase. CAVD is initiated, similar to atherosclerosis, by endothelial dysfunction, lipid deposition, and oxidative stress. The second phase, propagation, includes the osteogenic transformation of vascular interstitial cells into osteoblastic precursors, a process mediated by cytokines produced by inflammatory cells.^3,6 Macrophages and pericytes are major components of this inflammatory milieu and could serve as potential surrogates for quantifying this inflammatory process.¹² Because it is challenging to determine which patients will progress to overt AS, additional tools are needed to identify this higher-risk cohort.

Our findings align with previous studies that reported the association between valvular inflammation, progression of AVC, and AS.^10,22 Some of these studies leveraged ¹⁸F-FDG PET to show higher valvular uptake in AS and that higher uptake predicts future calcification.⁹ Subsequent studies have applied ¹⁸F-sodium fluoride (¹⁸F-NaF) to target microcalcification in the AV. These studies have shown that, like ¹⁸F-FDG, 18F-sodium fluoride effectively predicts disease progression and adverse clinical outcomes.^22,23 Because inflammation is an upstream and a more modifiable target than calcification, which is a fixed end point, imaging with ⁶⁸Ga-DOTATATE offers a better approach for risk stratification. It provides a more effective end point in clinical trials. Nevertheless, until now, no study has used ⁶⁸Ga-DOTATATE PET to evaluate CAVD.

Despite the physiological expression of⁶⁸Ga-DOTATATE in other tissues^{24 68}Ga-DOTATATE remains a highly effective radiotracer for evaluating inflammation and offers more specificity than ¹⁸F-FDG in assessing cardiovascular inflammation.¹¹ Notably, inflammation may serve as the initiating process in AS and may precede microcalcification that can be quantified using ¹⁸F-sodium fluoride. ⁶⁸Ga-DOTATATE provides a more specific marker of macrophage activity that is not subject to the limitations of background myocardial uptake, like ¹⁸F-FDG, and may have heightened uptake before that observed using ¹⁸F-sodium fluoride. Furthermore, ⁶⁸Ga-DOTATATE has been shown to reliably discriminate between high-risk and low-risk coronary atherosclerotic lesions, making it a promising option for the assessment of CAVD.²⁵

These findings have several clinical implications. First, ⁶⁸Ga-DOTATATE PET imaging could serve as a noninvasive tool for risk stratification in patients with CAVD. Identifying individuals with heightened valvular inflammation may allow for closer monitoring and timely intervention before the development of symptomatic severe AS. Second, the results reinforce the importance of inflammation in the pathogenesis of CAVD, suggesting that anti-inflammatory therapies targeting activated macrophages or pericytes may have therapeutic potential.²⁶ As no medical therapy has been shown to slow or reverse CAVD progression, our findings offer a rationale for clinical trials targeting macrophage-driven inflammation as a modifiable driver of calcification.

Study Limitations and Future Directions

Several limitations of this study should be acknowledged. First, the retrospective observational design may introduce selection bias and limit the ability to establish causality. Second, the study population consisted of patients undergoing ⁶⁸Ga-DOTATATE PET/CT imaging for neuroendocrine tumor assessment, which may limit the generalizability of the findings to the broader population. Although we were unable to fully control for the potential impact of neuroendocrine tumors, we minimized confounding by excluding patients with cardiac metastases or any metastases in close proximity to the heart. Third, echocardiographic data were not consistently available, and the cohort primarily included individuals without clinically significant AS. As such, extrapolation of these findings to patients with moderate or severe AS should be made with caution. Nonetheless, our results offer insight into early valvular inflammation and calcification, likely preceding overt AS—an area where risk stratification tools are currently limited. Fourth, while the absolute differences in ⁶⁸Ga-DOTATATE uptake between groups were modest and some overlap was observed, the biologic signal remained statistically and mechanistically meaningful. This highlights the potential of ⁶⁸Ga-DOTATATE as a sensitive marker of early disease activity, even in preclinical stages of aortic valve disease. The absence of dedicated, gated CT scans optimized for calcium quantification may have affected the accuracy of AVC measurements. However, prior studies suggest that the CT component of hybrid PET/CT scans provides similar accuracy.²⁷ Furthermore, we did not fully account for potential confounders such as medication use (eg, statins, anti-inflammatory drugs) and other comorbid conditions that could influence calcification processes and inflammatory activity.

To address these limitations, future prospective studies with larger and more diverse populations are warranted to validate and expand on these findings. The inclusion of echocardiographic assessments would allow for a correlation of imaging findings with valvular function and clinical outcomes. Comparative studies evaluating ⁶⁸Ga-DOTATATE alongside other tracers like ¹⁸F-FDG could further establish its relative efficacy in CAVD. Overall, ⁶⁸Ga-DOTATATE PET imaging may serve a dual role in both identifying high-risk individuals and assessing response to emerging anti-inflammatory therapies targeting early stages of valve disease—shifting the paradigm from reactive to preventive care in CAVD.

Conclusions

In conclusion, our study indicates that ⁶⁸Ga-DOTATATE PET imaging is a promising tool for assessing AV inflammation and predicting the progression of AVC. These findings enhance our understanding of the relationship between inflammation and calcification in the AV, with potential implications for personalized treatment strategies and improved outcomes in patients at risk of CAVD.

Supplementary Material

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/ATVBAHA.125.322779.

Highlights.

• ⁶⁸Ga-DOTATATE (gallium-68 DOTA-(Tyr³)-octreotate) positron emission tomography can identify subclinical inflammation in the aortic valve.

• Higher baseline ⁶⁸Ga-DOTATATE uptake is independently associated with aortic valve calcification progression, with higher predictive value among older adults.

• These findings support valve inflammation as an early, measurable risk factor for calcific aortic valve disease.

Nonstandard Abbreviations and Acronyms

¹⁸F-FDG

¹⁸F-fluorodeoxyglucose

⁶⁸Ga-DOTATATE

gallium-68 DOTA-(Tyr³)-octreotate

AS

aortic stenosis

AV

aortic valve

AVC

aortic valve calcification

CAVD

calcific aortic valve disease

CT

computed tomography

OR

odds ratio

PET

positron emission tomography

SUV

standardized uptake value