Coronary Artery Calcium (CAC) scoring and Coronary Computed Tomographic Angiography (CCTA) in Men with Low Testosterone

Diagnostic Assessment Strategy: Cardiovascular Risk & Systemic Health in Hypogonadal Patients​

1. Strategic Framework for Cardiovascular Risk in the Hypogonadal Male​

In the contemporary clinical landscape, the management of the hypogonadal male demands a multi-modal assessment strategy that transcends the narrow focus of hormone replacement. Testosterone deficiency is not merely an endocrine deficit; it is a sentinel biomarker for "arterial age" and a strategic integrator of cumulative systemic health. For the specialist, a low testosterone level must be viewed as an imperative for a rigorous diagnostic investigation into the patient's cardiovascular and metabolic architecture.
The historical presumption that testosterone therapy (TTh) exerts deleterious effects on the cardiovascular system is a vestige of mid-20th-century medicine, dating back to the 1940s. We have since undergone a definitive paradigm shift. Modern evidence overwhelmingly demonstrates a clear inverse relationship between serum testosterone and all-cause mortality. Modern registries—most notably the 8-year longitudinal data from Haider—demonstrate that higher endogenous testosterone levels are associated with significantly longer survival and reduced major adverse cardiovascular events (MACE). To provide a higher tier of care, clinicians must move beyond traditional risk calculators and utilize advanced imaging to quantify actual disease burden.

2. Comparative Analysis of Imaging Modalities: CAC vs. CCTA​

Strategic risk stratification in the hypogonadal population relies on Coronary Artery Calcium (CAC) scoring and Coronary Computed Tomographic Angiography (CCTA). While both are CT-based, their clinical utility is distinct and requires a nuanced understanding of their technical constraints.

Clinical Utility: CAC vs. CCTA	Coronary Artery Calcium (CAC)	Coronary Computed Tomographic Angiography (CCTA)
Primary Metrics	Agatston Score (quantifies calcified plaque burden).	Non-Calcified Plaque (NCP) Volume, composition, and stenosis.
Predictive Robustness	Highly robust; validated risk charts provide established 10-year event rates.	Controversial/emerging; currently not recommended as a standalone tool for risk stratification.
Technical Limitations	Cannot identify soft/vulnerable (non-calcified) plaque.	High CAC (>400) generates streak artifacts, reducing diagnostic specificity to 18%–44%.

The finding of CAC = 0 defines the "Healthy Ager" phenotype. Long-term follow-up data (42 months) demonstrates that this group has a substantially lower risk of cardiac events compared to low-score groups (0.27% vs 2.6%). Conversely, discordant results in recent literature—where calcium scores and NCP volume trend in opposite directions—demand a critical eye. This ambiguity, notably seen in the 2017 Budoff study, highlights the potential for diagnostic failure when imaging is applied without context.

3. Evaluating the Testosterone-Plaque Progression Controversy​

The clinical conversation surrounding TTh and plaque progression is dominated by the conflicting results of the Basaria (TEAAM, 2015) and Budoff (2017) trials. A strategic analysis reveals that the Budoff study, which suggested TTh increases NCP volume, is hampered by four fundamental flaws:

1. Randomization Failure: The study groups were fundamentally mismatched at baseline. The placebo group had a median calcium score of 454 compared to 255 in the testosterone group; the placebo group effectively began the study with nearly double the baseline calcification, making any comparison of progression inherently flawed.
2. Technical Inaccuracy: In arteries with high calcium scores (>400), streak artifacts make the accurate reading of non-calcified plaque technically difficult and prone to false positives.
3. Clinical Event Gap: Despite the reported increase in plaque volume over 12 months, there were zero cardiovascular events in the testosterone group, undermining the "harm" hypothesis.
4. Registry Contradiction: These findings conflict with Haider’s 8-year registry of 77 men with established coronary artery disease receiving Testosterone Undecanoate (Nebido). Over the 8-year observation period, this high-risk cohort experienced zero MACE.

Crucially, the Basaria (2015) study provides a vital "statin masking" insight. In a post-hoc exploratory analysis of statin non-users, the annual rate of change in coronary calcium was significantly lower in the testosterone group (mean difference -30.1; P= .04). This suggests that testosterone may exert a protective effect on the arterial wall that is masked by the aggressive use of statins.

4. CAC as a Multi-Systemic Prognostic Marker: The "Arterial Age" Concept​

CAC scores provide a superior estimate of mortality risk because they represent a physiological "biologic age" rather than chronological years. An elevated CAC score is a high-risk phenotype; in the MESA cohort (Handy et al., 2016), approximately 20% of first non-cardiovascular events occurred within the 10% of the population with a CAC >400.
Based on the MESA data, a CAC score >400 is a potent predictor of systemic morbidity, associated with the following Hazard Ratios (HR):

• Cancer: HR 1.53
• Chronic Kidney Disease (CKD): HR 1.70
• Pneumonia: HR 1.97
• COPD: HR 2.71
• Hip Fracture: HR 4.29

Strategically, identifying the CAC = 0 "Healthy Ager" allows for the prevention of over-medicalization. However, in men with high CAC, we must look deeper into the underlying physiological drivers of low testosterone, which often share a common inflammatory root.

5. The Root Cause Hypothesis: Leaky Gut, HPA Dysfunction, and Atherosclerosis​

The "Leaky Gut" hypothesis suggests that atherosclerosis and hypogonadism may both be downstream manifestations of low-level endotoxemia. Lipopolysaccharides (LPS) leaking from the gut trigger systemic inflammation, which in turn causes hypothalamic-pituitary-adrenal (HPA) axis dysfunction.
In this framework, atherosclerotic plaque may be viewed as an infected biofilm—an inflammatory response to circulating endotoxins. This implies that low testosterone is often a marker of overall health quality rather than a primary cause of disease. For younger males presenting with HPA dysfunction, the primary directive is to avoid exogenous testosterone, which further suppresses an already compromised HPA axis. Instead, clinicians should prioritize the use of clomiphene or HCG to restore endogenous production while aggressively managing gut permeability and systemic inflammation.

6. Integrated Diagnostic Assessment Protocol​

Clinicians must adopt a unified protocol that bridges the gap between endocrinology and cardiovascular imaging.

Hypogonadal CV Risk Assessment Checklist​

• Imaging Requirements:
  • [ ] CAC Scoring: Essential baseline for determining "arterial age."
  • [ ] CCTA: Selective use for patients with low CAC to investigate NCP burden.
• Biomarker Panel:
  • [ ] Hormonal: Total, Free, and Bioavailable Testosterone.
  • [ ] Metabolic: HbA1c, Hematocrit, and full Lipid Profile (specifically LDL-C and Triglycerides).
  • [ ] Strategic Data: Statin Status (to account for potential masking of TTh benefits).
• Systemic Screens:
  • [ ] Gut Health: Assessment for intestinal permeability/endotoxemia.
  • [ ] Inflammation: High-sensitivity C-Reactive Protein (hs-CRP).
  • [ ] Anthropometrics: BMI and Waist Circumference.

Strategic Interpretation: The "So What?" The diagnostic path is clear: If CAC >400 and T is low, the clinician must prioritize gut-health and inflammation management either prior to or alongside TTh. If CAC = 0 and T is low, the focus shifts to investigating HPA axis dysfunction and lifestyle-driven endocrine suppression.

A "critical eye" is non-negotiable. We must reject the simplified narrative of testosterone-driven risk and instead embrace a model of integrative cardiovascular health that addresses the root drivers of systemic aging.

 

Understanding Heart Plaque: A Primer on Scans, Scores, and Your Health​

1. The Basics: What is Heart Plaque?​

Coronary atherosclerosis is the process where plaque—a complex, dynamic buildup of fatty deposits, inflammatory cells, and minerals—accumulates within the walls of the heart’s arteries. It is not a static substance but a progression that often begins as "soft" (non-calcified) material and, over years or decades, matures into "hard" (calcified) deposits. For the older adult, monitoring this progression is the single most effective way to determine biological risk, as the presence of plaque is a direct window into the body's aging process.
Key Concept: Arterial Age vs. Chronological Age While your chronological age is determined by your birth date, Arterial Age reflects the actual "wear and tear" on your vascular system. Data from the Multi-Ethnic Study of Atherosclerosis (MESA) shows that because plaque levels vary so widely, an individual's equivalent biological age can vary by up to 30 years from their chronological age based on their heart scan results.
The physical state of this plaque—whether it remains soft or becomes hardened—dictates how we measure it and what it signifies for your clinical outlook.
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2. The Two Faces of Plaque: Non-Calcified vs. Calcified​

Clinicians categorize plaque into two primary types to better understand the stage of a patient's disease. Non-calcified plaque is often the focus of clinical trials because it represents the "active" or "vulnerable" phase of atherosclerosis. Calcified plaque represents the end stage of the process where the body has "scaffolded" the area with calcium, making it more stable but indicating a higher total burden of disease.

Feature	Non-Calcified (Soft) Plaque	Calcified (Hard) Plaque
Composition	Fatty deposits, cholesterol, and inflammatory debris.	Calcium-rich, hardened mineral deposits.
How It's Measured	Measured via CCTA (Coronary Computed Tomographic Angiography).	Measured via CAC (Coronary Artery Calcium) scan.
Clinical Significance	Measures disease "progression" or activity; used heavily in research.	Robust predictor of heart attack risk and "Arterial Age."

The transition from soft to hard plaque is a hallmark of the disease's lifecycle, and quantifying this transition requires specific imaging technology.
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3. Measuring the Risk: Calcium Scores and Agatston Units​

To turn an image into a medical plan, we use two distinct measurements. The Agatston unit is the global standard for the Coronary Artery Calcium (CAC) scan. It provides a numerical score based on the density and area of calcification. In contrast, the CCTA uses contrast dye to measure the volume of both soft and hard plaque in cubic millimeters (mm^3).
The Three Main Measurements:

• Non-calcified volume (mm^3): Tracking the "soft" plaque that has not yet hardened.
• Total plaque volume (mm^3): The combined sum of all arterial buildup.
• Calcium score (Agatston): The standardized score used for routine risk prediction.

The Clinical "So What?": While CCTA is a powerful research tool, the CAC scan (Agatston) remains the preferred choice in routine clinical practice. This is because its predictive ability is backed by decades of data—such as the CONFIRM registry—showing a direct link between the score and future events. Organizations like the ACC/AHA do not currently recommend CCTA for risk stratification in asymptomatic individuals due to a lack of evidence that it improves clinical outcomes compared to standard testing.

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4. Interpreting Your Score: What the Numbers Tell You​

Based on the MESA and Budoff studies, your Agatston score places you into specific risk tiers. A score of zero is the gold standard for "Healthy Agers"—individuals who, despite their chronological age, show no evidence of coronary calcification and possess a significantly lower risk for systemic disease.

Risk Categorization Table

Agatston Score	Risk Category	Clinical Meaning
0	Low Risk	"Healthy Agers"; extremely low risk of cardiovascular events.
1–400	Moderate Risk	Evidence of atherosclerosis; requires proactive risk management.
>400	High Risk	Extensive calcification; severe atherosclerosis and high risk of events.

Recent research shows that these scores are "risk integrators," signaling health outcomes that extend far beyond the heart.
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5. Beyond the Heart: The "Arterial Age" Connection​

A high calcium score (>400) is a potent signal of systemic aging. The Handy et al. (MESA) study demonstrated that individuals with extensive calcification are at a significantly higher risk for non-cardiovascular, age-related conditions. This suggests that the heart scan is actually a report card for your body’s overall biological resilience.

Non-Heart Risks Associated with a CAC Score >400:

1. Hip Fractures: HR 4.29 (429% increased hazard)
2. COPD: HR 2.71 (271% increased hazard)
3. Pneumonia: HR 1.97 (197% increased hazard)
4. Chronic Kidney Disease (CKD): HR 1.70 (70% increased hazard)
5. Cancer: HR 1.53 (53% increased hazard)

Conversely, "Healthy Agers" (CAC=0) had a significantly lower risk across the board, including a 69% lower risk of hip fractures (HR 0.31) and a 24% lower risk of cancer (HR 0.76) compared to those with any plaque.
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6. Factors Influencing Plaque: The Testosterone and Statin Debate​

The impact of therapies like Testosterone Replacement Therapy (TRT) on plaque remains a subject of intense clinical scrutiny. The Budoff (2017) study reported that older men on testosterone saw an increase in non-calcified plaque volume (a 41 mm^3 difference over placebo).

However, many clinicians, including Dr. Jeffrey Dach, view the Budoff results as suspect due to significant methodological flaws:

• Failure of Randomization: The groups were imbalanced from the start; the testosterone group began with a median calcium score of 255, while the placebo group was nearly double at 494.
• Streak Artifacts: In patients with scores >400 (which described half the study participants), heavy calcification causes "streak artifacts" that limit the accuracy of CCTA in measuring soft plaque, leading to potential technical errors.

Furthermore, the Basaria (2015) study found that the annual rate of change in coronary calcium was significantly lower in the testosterone group, but this benefit was specifically observed in statin non-users. This suggests a "statin masking effect," where statins may alter the observable cardiovascular benefits of testosterone.

Doctor's Note As a clinician, I treat the patient, not just the scan. It is critical to note that in the Budoff study, despite the reported "increase in plaque," there were zero major cardiovascular events in the testosterone group. Contrast this with real-world data from Dr. Haider’s 8-year registry, where men on TRT saw significant improvements in weight, BMI, blood pressure, and HgbA1c (blood sugar), with zero cardiovascular events. We must balance small changes in plaque volume against these robust "secondary prevention" benefits.

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7. Summary Checklist for Older Adults​

• [ ] Identify your Agatston Score: Know if you are a "0" (Healthy Ager) or if you have "Extensive Calcification" (>400).
• [ ] Understand the measurement: Remember that Agatston scores (CAC) are the clinical gold standard, while mm^3 volume (CCTA) is primarily used in research.
• [ ] Acknowledge the "30-year variance": Use your scan to determine your true "Arterial Age" rather than relying on your birth date.
• [ ] Monitor systemic health: If your score is >400, work with your doctor to screen for non-heart risks like CKD, COPD, and bone density.
• [ ] Contextualize TRT and Statins: If you are on TRT, discuss the "statin masking effect" with a specialist and focus on overall metabolic markers like blood pressure and HgbA1c.