Cardiovascular disease (CVD) continues to be the leading cause of death in Western societies, exacting a devastating toll on individuals, families, and our healthcare systems. Despite extensive knowledge about its epidemiology, development, and preventative treatments, this epidemic stubbornly persists. A key reason for this ongoing challenge is the persistent uncertainty surrounding the primary cause of atherosclerotic cardiovascular disease (ASCVD).

The Elephant in the Artery: Is LDL the Culprit?

For many in the medical community, low-density lipoprotein (LDL) is considered the leading suspect. This circulating lipid particle is known to deposit cholesterol into the arterial wall, initiating a process that leads to the formation of atherosclerotic plaque and, ultimately, life-threatening arterial thrombosis (blood clots).

So, if the evidence seems so clear, why isn’t LDL universally accepted as the definitive cause of atherosclerosis? The answer lies in the absence of a specific type of research: randomized controlled trials (RCTs) directly proving this causation. Due to ethical, financial, and practical scientific considerations, an RCT of sufficient duration to definitively prove or disprove this hypothesis may never be undertaken.

A Unique Approach: Applying the Bradford Hill Criteria

Faced with this challenge, a unique approach has been proposed to bolster the case for LDL’s critical role in ASCVD. This strategy employs criteria originally put forth by Sir Austin Bradford Hill, a renowned 20th-century British epidemiologist and statistician. Sir Hill recognized that not every disease cause could be established through an RCT. Therefore, he outlined nine criteria (now known as the Bradford Hill criteria) that, if met, strongly suggest an etiological factor is the likely cause of a disease.

This innovative approach organizes the vast body of scientific evidence supporting LDL as the primary cause of atherosclerosis according to these nine criteria. By systematically reviewing the data through this established epidemiological lens, the aim is to provide compelling evidence for LDL’s central role.

The Strong Case for LDL Reduction

The data, meticulously organized against the Bradford Hill criteria, strongly suggest that LDL is indeed the primary cause of atherosclerotic cardiovascular disease. This robust scientific backing leads to a powerful conclusion: sufficient reduction of LDL, specifically to levels below 70 mg/dl (<1.81 mmol/L), has the potential to make atherosclerotic cardiovascular disease a rare event.

This perspective offers a clear path forward in the fight against CVD. While direct RCTs proving LDL as the sole cause of atherosclerosis may be impractical, the overwhelming body of evidence, when viewed through the rigorous framework of the Bradford Hill criteria, points to LDL as the key driver.

What This Means for You:

• Understand Your LDL: Knowing your LDL cholesterol levels is a crucial step in assessing your cardiovascular risk.
• Prioritize LDL Management: Work with your healthcare provider to discuss strategies for managing your LDL levels, especially if they are elevated. This may involve dietary changes, lifestyle modifications, and, if necessary, medication.
• Embrace Prevention: The goal is not just to treat CVD, but to prevent it from occurring in the first place. Targeting LDL aggressively appears to be a highly effective preventive strategy.

By focusing on effective LDL reduction, we can move closer to eradicating this devastating disease and ensuring more productive, healthier lives for individuals and families.

Empower yourself with knowledge and take control of your heart health!

Disclaimer: This newsletter provides general information and does not constitute medical advice. Please consult with a qualified healthcare professional for personalized guidance regarding your health and treatment options.

The Heart of the Matter: Navigating the Latest Buzz on Keto Diets and Cholesterol

Cardiovascular disease remains a significant health challenge, and with ever-evolving dietary trends, it’s crucial to stay informed about what truly impacts our heart health. Recently, a study dubbed “KETO-CTA” has sparked considerable discussion, particularly on social media, regarding the long-established understanding of cholesterol and its link to atherosclerotic cardiovascular disease (ASCVD).

While some advocate for extremely low-carbohydrate (ketogenic) diets, leading to states of ketosis, these diets can also lead to a substantial rise in “bad” cholesterol — low-density lipoprotein cholesterol (LDL-C). This raises a critical question: how does a keto diet, and the associated lipid changes, truly impact our arteries?

The KETO-CTA Study: A Closer Look at “Lean-Mass Hyperresponders”

The KETO-CTA study focused on a subgroup of individuals on ketogenic diets, termed “lean-mass hyperresponders” (LMHRs). These are individuals who, despite having a low body mass index (BMI) and being metabolically healthy, experience a significant increase in LDL-C on a keto diet. The study’s authors suggested that this subgroup might be protected from atherosclerosis progression, even with very high LDL-C levels, a claim that challenges nearly 50 years of robust evidence.

The KETO-CTA study was a single-arm observational study involving 100 LMHR individuals who had been on a ketogenic diet for at least two years. To qualify, participants had to have a low BMI, specific lipid profiles (LDL-C ≥ 190 mg/dL, HDL-C ≥ 60 mg/dL, triglycerides ≤ 80 mg/dL), and signs of metabolic health. Coronary CT imaging was used to measure plaque progression over one year.

Key observations from the study:

• Participants, with an average BMI of 22, had striking mean LDL-C levels of 254 mg/dL.
• The study’s primary endpoint, the change in noncalcified plaque volume, showed an increase of 18.8 mm$^3$ over the year. Visual inspection of individual data also revealed that most participants experienced an increase in noncalcified plaque.
• The study surprisingly found no correlation between the change in ApoB (another marker of atherogenic particles) or LDL-C and the change in noncalcified plaque volume.

Based on these findings, the KETO-CTA authors proposed that LMHRs are unique, suggesting their elevated ApoB and LDL-C, while dynamic and diet-induced, do not drive atherosclerosis in the same way as in other populations. They even suggested that individuals with a baseline coronary artery calcium (CAC) score of zero, even with high LDL-C, might be a low-risk group.

Why the KETO-CTA Conclusions Are Problematic

While the KETO-CTA study generated significant discussion, it’s crucial to critically evaluate its conclusions, especially when they appear to contradict long-standing scientific understanding. Here are several reasons why the claims from KETO-CTA should be interpreted with significant caution:

1. The Primary Endpoint Increased: The study’s own primary endpoint — the change in noncalcified plaque volume — increased by 18.8 mm$^3$. This increase was actually 2.5 times higher than what the researchers predicted in their study protocol. If this imaging endpoint is a valid surrogate for atherosclerosis, these results are concerning, not reassuring.
2. Surrogate Markers Are Often Unreliable: Imaging tests, while useful, are often imperfect surrogates for clinical outcomes like heart attacks or strokes. To truly assess risk, we need studies that measure hard cardiovascular events, not just changes in plaque volume over a short period.
3. Decades of Causal Evidence for LDL-C: There are approximately 70 years of scientific data strongly supporting LDL-C as a causal factor for atherosclerosis. Nearly every one of the rigorous Bradford Hill criteria for causation is met for LDL-C and ASCVD. To claim an exception, especially one that contradicts such a robust body of evidence, requires far more rigorous proof than a small, observational study can provide.
4. Lack of a Control Group: The KETO-CTA study was a single-arm study, meaning it lacked a control group. Without comparing LMHRs to a group on a different diet (e.g., a Mediterranean diet), it’s impossible to draw definitive conclusions about the relative impact of the ketogenic diet on plaque progression.
5. Highly Selected Participants: The authors did not disclose how many individuals they screened to find the 100 LMHR participants. This raises concerns about how highly selected and potentially unrepresentative this group might be.
6. Complexities of Nutritional Studies: Understanding the true impact of specific diets on heart health is incredibly challenging. Long-term randomized trials with dietary adherence are difficult to conduct. Furthermore, individuals in the LMHR group likely engage in other healthy behaviors (e.g., exercise, not smoking) that can also influence heart disease risk, complicating the interpretation of findings.

The Bottom Line: Don’t Upend Decades of Evidence

The KETO-CTA study was a small, non-controlled observational study where the primary endpoint actually showed an increase in plaque burden. It does not provide sufficient evidence to overturn decades of causal evidence linking elevated LDL-C to the development and progression of atherosclerosis. The established understanding that high LDL-C drives atherosclerosis remains a cornerstone of cardiovascular prevention.

For optimal heart health, managing LDL-C levels, often to targets below 70 mg/dL (1.81 mmol/L), continues to be a critical strategy in preventing atherosclerotic cardiovascular disease.

Stay informed and always consult with your healthcare provider for personalized advice on your diet and heart health.

This newsletter provides an independent medical perspective on recent research and should not be considered medical advice. Always discuss your health concerns with a qualified healthcare professional.