Why low ideal cardiovascular health & sub clinical disease

Over my lifetime there has been an avalanche of research into the pathophysiology of atherosclerotic cardiovascular disease.  As many of my previous blogs have indicated the precise mechanisms underlying the initiation and progression of cardiovascular disease are pretty clearly understood:

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The process of pathological ageing of our arterial vasculature begins with trapping (oxidised) atherogenic lipoproteins (LDL; IDL and VLDL) in the sub endothelial space of the artery.  Oxidative modification of the atherogenic lipoproteins sets up a cascade activation of the inflammatory and cytokine immune system to potentiate the progression and instability of the atherosclerotic plaque in the vascular wall.

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Plaque instability is governed by many factors but chiefly driven by activation of the thrombotic and inflammatory systems exacerbated by the hydrostatic forces (blood pressure tearing plaque) in the artery leading to progressive end organ damage which we can monitor clinically as:

  1. Endothelial dysfunction
  2. Sub clinical atherosclerosis (thickened irregular Intima-Media and plaque formation)
  3. Micro and macro protein leak though the glomerulo capillary network (micro and macro albuminuria)
  4. Increased vascular rigidity (loss of vascular compliance)
  5. Development of systemic hypertension
  6. Left ventricular hypertrophy (with loss of LV compliance)
  7. Presence of left ventricular diastolic dysfunction systolic dysfunction
  8. Vascular retinopathy
  9. Overt vascular disease
  10. Overt conductive system disease

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The mechanism by which OPTIMAL MEDICAL THERAPY (OMT) improves morbidity and mortality and can postpone clinical events can be demonstrated in this Intravascular Ultrasound (IVUS).  This is the typical graphic generated by an intravascular ultrasound guidewire down a major epicardial coronary artery (in this case the proximal left anterior descending coronary artery – LAD).  The “black dot” in the centre of the two pictures is the ultrasound guidewire in the lumen of the LAD with the eccentric plaque noted extending from 11 o’clock to 4 o’clock.  Although the plaque volume is similar in the two arteries the plaque on the left is a typical “stable” plaque verses the “unstable” plaque on the right graphic.  The stable plaque is generally seen in patients on OMT with little residual risk and is characterised by a thick fibrous capsule and very little intra plaque inflammatory content (low cytokines and inflammatory cells) whereas the right plaque has a very thin capsule separating the blood from the plaque content which has a high content of oxidised free atherogenic lipoproteins, cytokines and cells , increased thermal temperature all contributing to plaque instability.

Relevant to the two plaques above the people harbouring these vessels will both be asymptomatic as the lumen of the vessels are “wide open”; they would both have negative exercise stress tests and both individuals may be excellent athletes. But the plaque instability on the right will explain the sudden cardiovascular events in an otherwise asymptomatic individual.

These plaques typically rupture or fissure at the shoulder of the plaque exposing the inflammatory content of the plaque to the circulating blood causing immediate intravascular thrombosis and blockage of the artery.

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At LDL levels < 1.8 the average plaque regression is approximately 1-2% per 18 months with plaque stability usually clinically apparent after only 6 months of high dose potent Statin therapy.

The STENO -2 trial is a good example of aggressive multiple risk intervention in a high risk “healthy” Type 2 diabetic.

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Aggressive risk factor management with a combination of Statin therapy to keep LDL 1.8-2.5; HDL > 1.2; TG < 1.7; BP ~ 130/70; glucose control to HbA1c < 6.5%; low BMI and exercise:

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Typical for the OMT/ Statin trials the separation of the Kaplan Meyer curves occurs early around 6 months of therapy with progressive separation of the curves thereafter.  In this trial there were approximately 50% less hard clinical events on the intensive treatment arm verses conventional treatment at 8 years.

Many different classes of drugs that are used in optimal medical therapy in the prevention of cardiac disease and the management of patients with vascular disease are “anti-atherosclerotic”.

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So if we have all this information why the high rates of poor health and sub clinical vascular disease in otherwise “healthy people”?

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I believe rather that slating the theory of the mechanism and causes of cardiac disease, the real stumbling blocks to prevent and manage heart disease are contained in my graphic above.

Starting at the centre is the PATIENT for if we can’t motivate the patient to stick to the rules with lifestyle diet and exercise and compliance with all anti atherosclerotic therapy then we expect poor health and high levels of sub clinical disease.

At 12 o’clock is the role of the DOCTOR where I see the following problems:

  1. Failure to risk stratify accurately risk burden for vascular disease
  2. Failure to manage the “global” risk spending too much time on individual risk factors (silo approach)
  3. The is a general resistance to aggressive global risk reduction leaving healthy people with considerable “residual risk”
  4. There is a fear of using multiple anti-atherosclerotic poly pharmacy
  5. There is a misguided opinion that invasive interventions are better and safer than aggressive optimal medical therapy (to stabilise plaques)

The INTERNET is a “double-edged sword” as although valuable information is present this is embedded in some seriously flawed; incorrect and frankly misleading junk. The internet for instance is full of absolute rubbish posted by cholesterol and statin skeptics contributing to much unwarranted anguish amongst those who don’t have the truth at their finger tips. Careful scrutiny of the misleading data will show that the authors often have unsubstantiated supplements; books and magic wands to prevent and treat vascular disease. 

THIRD PARTY FUNDERS are at times mischievous and meddlesome and contrary to popular opinion they are not in business to save lives but rather to protect shareholders.  The limited “formularies” and poor adherence to current international guidelines (2012 European Society of Cardiology) obstruct and pose major limitations to achieve optimal medical outcomes.

Finally the supplement industry is a major source of unsubstantiated claims to prevent and treat cardiovascular disease.  We have a ton of evidence based medicine from conventional cardiology double blinded placebo controlled trials. The efficacy and safety of treatments involving massive number of patients treated with various anti-atherosclerotic drugs is without question.

A wonderful example of evidence based medicine is the 2012 meta analysis of ALL the cholesterol lowering trials in relatively low risk individuals.

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The results slide shows on the extreme left the 5 year calculated risk of a major vascular event (MVE) of the groups from low risk <5% to the very high risk >30% (one-in-three risk of an event over 5 years).  I have just selected two outcomes namely coronary revascularization and major vascular events comparison for these risk groups on Statin therapy.  For each 1,0 mmol/l LDL reduction for each risk group we see an approximate 20% risk reduction in events compared to placebo.  This data is incredibly robust and supports all our information to date from Statin trials demonstrating survival proportional to LDL lowering (4 mmol/l LDL reduction = approximately 80% risk reduction once LDL approaches 1.8 mmol/l).

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I truly believe we are at the stage of preventing atherosclerosis completely and in individuals with either sub clinical or clinical vascular disease we can effectively switch off the process.  This entails sticking to the algorithm above keeping:

  1. BMI < 25
  2. LDL < 1.8
  3. HDL > 1.2
  4. Non-HDL < 2.0
  5. BP < 130/80
  6. us-CRP < 1.0
  7. HbA1c < 6.5%
  8. and resting HR < 70

I see confirmation of this daily with true health free of sub clinical disease if the 8 boxes are ticked.

Proverbs 10:17

Whoever heeds discipline shows the way to life,but whoever ignores correction leads others astray.

Yours in health



Are we failing the cardiovascular epidemic


I recently presented my thoughts at a conference at the Cape Town International Conference Centre in response to an article published in “health24”.


I challenged the concept that the “heart disease theory had failed” and based my conclusions on the following:            

CVD 10Deaths per 100 000 population in the USA for ALL forms of cardiovascular disease have fallen progressively from 1960 to 1997.

CVD 11Interestingly death from CVD per 100 000 population has fallen in MEN from 1979 to 2008 whist in WOMEN the success in palliating CVD has only occurred since 2000.  I believe this is due in part to the previous perception by women that they were immune to heart disease and their skeptical ethos to manage cardiovascular risk factors aggressively. 

I see this every day in clinical practise that women in general do not take care of their cardiac risk factors.  This is supported by a wonderful study published recently in CIRCULATION (one of the most respected cardiology journals).

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This study set out to assess “ideal cardiovascular health” in 1933 men and women average age 57 years who were “healthy” and seemingly free of heart disease.  Ideal cardiovascular heath is defined by the American Heart Association (AHA) as the “simple 7”.

CVD 20The simple 7 includes 4 ideal health behaviours:

  1. Not smoking (for a least a year)
  2. Body mass index < 25 kg/m2
  3. Moderate physical activity for 150 minutes/ week
  4. Intake of 4-5 key components of the AHA diet guidelines 

And 3 health characteristics:

  1. Total cholesterol < 5.0
  2. BP < 120/80
  3. Fasting glucose < 6.0

So out of the cohort of “healthy” 57 yr men and women what percentage do you think could tick ALL 7 boxes?

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The graphic is taken directly from the publication and shows a staggering 0.05% of the cohort fulfilled the criteria for “ideal CV health”.  Contrary to popular opinion women are just a bad (unhealthy) as men.

In a second study again published in CIRCULATION the authors studied a cohort of “healthy” men and women for the presence of SUB CLINICAL cardiovascular disease.  Sub clinical disease is “hidden” disease in otherwise healthy asymptomatic individuals and comprises:

  1. ECG evidence for left ventricular hypertrophy
  2. ECG evidence for left bundle branch block
  3. Presence of micro albuminuria in the urine
  4. Vascular changes on retinal exam with a opthalmoscope
  5. Carotid atherosclerosis as indicated by abnormal Intima-Media and or carotid plaque

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Sub clinical cardiovascular disease (target organ damage) was assessed in healthy normal weight; overweight and obese individuals and men and women with normal waist  circumference (< 88 cm for women and < 102 cm for men) and those with waist circumference > 88 cm and 102 cm respectively.

CVD 23This is a typical carotid ultrasound of a “healthy” woman with advanced sub clinical carotid atherosclerosis.

CVD 24You can see the very high prevalence of sub clinical disease in normal weight, heathy individuals, increasing to ~ 50% of obese men and women with and without increased waist measurements. 

In other words “so-called” healthy people have neither “ideal cardiovascular health” nor are they free of sub clinical disease.  This therefore begs the question I posed previously as to why middle age men and women are extremely POOR in keeping themselves truly healthy and FREE of sub clinical disease.  Remember those individuals with sub clinical disease are on a continuum time scale representing pathological ageing.  In other words their biological age (age inside) is way older than their chronological age.

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I’m therefore not surprised with the publication I posted in my last BLOG. “Based on 2009 death-rate data, more than 2000 Americans die of cardiovascular disease every day, or approximately one death every 40 seconds. Every 25 seconds, one American will have a coronary event, and every minute one American will die from one. Coronary heart disease accounted for one in six deaths in the US in 2009, while stroke accounted for one in every 19 deaths. Every 40 seconds, somebody in the US has a stroke”.

But can we understand some of the reasons as to why “ideal cardiovascular health” and freedom from sub clinical disease is so elusive when we have a really good understanding of the pathogenesis of cardiac disease?

In my next blog I will try to address these issues.


No no

The real causes for the cardiovascular disease epidemic?

CVD Death Rate in US Declines, But One in Three Still Dying From Cardiac Causes

Published in MEDSCAPE Cardiology Dec 12, 2012

The American Heart Association (AHA) has released its most recent update on heart disease and stroke, estimating that the total direct and indirect costs of cardiovascular disease and stroke are more than $310 billion in the US. Although the relative rate of deaths attributable to cardiovascular disease declined from 1999 to 2009, cardiovascular disease still accounts for one in every three US deaths.

Based on 2009 death-rate data, more than 2000 Americans die of cardiovascular disease every day, or approximately one death every 40 seconds. Every 25 seconds, one American will have a coronary event, and every minute one American will die from one. Coronary heart disease accounted for one in six deaths in the US in 2009, while stroke accounted for one in every 19 deaths. Every 40 seconds, somebody in the US has a stroke.

Declining Death Rates, But Risk Factors Still Climbing

The 2009 overall rate of death attributable to cardiovascular disease was 236.1 deaths per 100 000 individuals. The rate of death was 281.4, 387.0, 190.4, and 267.9 per 100 000 white males, black males, white females, and black females, respectively. From 1999 to 2009, the relative rate of death attributable to cardiovascular disease declined by 32.7%, but cardiovascular disease still accounted for one-third of deaths in the US.

Regarding cardiovascular disease risk factors, the AHA estimates that 31.9 million adults have serum total-cholesterol levels > 6.0 mmol/l and 33.0% of US adults have hypertension, or approximately 78 million adults. African American adults have the highest prevalence of hypertension in the world, notes the AHA. In 2010, 19.7 million Americans had physician-diagnosed diabetes mellitus, or 8.3% of the population, while another 38.2% had prediabetes with abnormal fasting-glucose levels (glucose intolerance).

For smoking status, approximately one in five adult Americans continues to smoke, while 18.1% of students in grades 9 through 12 reported current cigarette use.

The percentage of young persons ( <18 years old) who engage in no regular physical activity is high, and this percentage increases with age. In 2011, 17.7% of girls and 10.0% of boys reported not participating in 60 minutes of moderate to vigorous physical activity even once during the previous seven-day period. One in three adults reported engaging in no aerobic leisure-time physical activity.

More than 150 million adults in the US were considered overweight or obese, or two out every three adults. More than one-third of US adults are obese, while 31.8% of children and adolescents aged two to 19 are overweight or obese, or 23.9 million kids. More than 12 million US children and adolescents are considered obese.

So the real causes for the cardiovascular epidemic are poorly understood and poor managed conventional cardiovascular risk factors.

Why is this, when we have such an enormous depth of knowledege and understanding the pathophysiological of cardiovascular disease and the role the cardiac risks in driving this epidemic?

In my next blog I will attempt to answer this question.


High dose potent Statin therapy and Inflammation

Lipid lowering with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or ‘statins’ has dramatically reduced morbidity and mortality in patients with established cardiovascular disease. Recently, there have been multiple studies investigating the role of high-dose potent statin therapy with more aggressive lipid lowering in this setting.

There is increasing evidence implicating a role of inflammation in the pathogenesis of atherosclerosis. These high-dose potent statin trials and other studies have also provided a wealth of data suggesting that statins have anti-inflammatory and anti-oxidant properties that go beyond their lipid-lowering effects.

The role of inflammation in the pathogenesis of atherosclerotic coronary disease has been extensively investigated over my lifetime.  There is considerable evidence to implicate inflammation in each step of the atherosclerotic process, from the initial fatty streak formation to plaque progression and rupture (Figure 2).  


Statin and inflammation

Among the numerous circulating inflammatory biomarkers that have been found to be predictive of cardiovascular events, the most extensively studied has been the acute-phase reactant “high-sensitivity or ultra-sensitive C-reactive protein” (us-CRP).  Multiple studies, including several meta-analyses, have demonstrated us-CRP to be an independent predictor of cardiovascular risk.   Further, recent laboratory studies of intravenous C-reactive protein infusion in animal models and human volunteers demonstrated increased inflammation and atherosclerosis and activation of coagulation, providing evidence for a direct role of C-reactive protein in the pathogenesis of coronary artery disease.

Statins have been recognized to have anti-inflammatory and antioxidant properties, and it has been suggested that these so-called “pleiotropic” effects may account for some of the benefits of statins beyond LDL-C lowering alone.  Recent studies have shown that statins reduce inflammatory macrophage cell growth within atherosclerotic plaques, decrease superoxide (oxidative free radicals) production from NAD(P)H oxidase (nox1) in vascular smooth muscle cells, and increase endothelial nitric oxide production.  In addition, they promote potent systemic anti-inflammatory effects by inhibiting the isoprenylation and translocation of “Rac”, a key subunit of the NAD(P)H oxidase complex that catalyses the production of superoxide.

Are there any safety concerns of high-dose statin therapy?

Safety concerns surrounding high-dose statin therapy centre on the traditional liver or skeletal muscle-related disturbances seen at low rates with moderate-dose statin therapy, in addition to potential new risks related to ultra-low cholesterol and LDL-C levels. Major clinical trials, along with previously published data and ongoing trials, have addressed these safety concerns.

Atorvastatin (Lipitor) has been the most extensively studied at high doses (up to 80 mg/d) and so possesses the most data regarding safety and adverse effects.  The incidence of hepatic enzyme elevation (defined as ALT or AST > 3 x the upper limit of normal) in patients treated with high-dose atorvastatin, simvastatin, or fluvastatin in major trials is 0.5–3.0% only.  Discontinuation or dose reduction of the offending statin usually results in prompt resolution of the enzyme elevations.

The incidence of myopathy (defined as creatine kinase elevation of > 10 x upper limit of normal with muscle related myalgia symptoms) and frank rhabdomyolysis in controlled clinical trials employing the use of high-dose statin therapy is rare. In nearly 12 000 patients encompassing over 40 trials of high-dose atorvastatin, there were only two cases of myopathy, whereas no cases of myopathy have been reported in controlled trials of high-dose fluvastatin.  In contrast, high-dose simvastatin therapy seems to be associated with a perceptible increase, although small, in the risk of myopathy (0.4%).

Epidemiological and animal studies have suggested a link between low total cholesterol levels and risk for retinal and optic nerve damage, haemorrhagic stroke, and mortality. As a substantial proportion of patients treated with high-dose statin therapy will reach LDL-C levels far below 1.8 mmol/l, these potential hazards have come to the forefront.  The large trials has demonstrated no increase in the risk of these adverse events associated with ultra-low LDL-C levels.

So in summary:

heart attack

There is substantial support for the institution of high-dose potent  statin therapy in various clinical settings in the secondary prevention of coronary events. Two recent meta-analyses of high-dose statin trials have been able to quantify the benefit at an additional 16% reduction in coronary death or myocardial infarction with high dose compared with moderate-dose statin therapy.

High-dose statin therapy in the setting of “acute coronary  syndromes” (ACS), demonstrate a 22% reduction in all-cause mortality, as well as a 25% reduction in cardiovascular mortality.

This data provides further insight into the contributions of atherogenic lipoproteins (LDL; IDL and VLDL) and inflammation to atherosclerotic plaque burden through analysis of statin-mediated effects on these parameters. The data linking inflammation and oxidative damage with coronary artery disease and ACS are now mounting. Currently, C-reactive protein remains the most extensively studied marker of inflammation in coronary disease and adds incremental predictive power to traditional risk factors in predicting adverse cardiac events.

Additionally, after weight loss, exercise, and smoking cessation, statins remain the best therapeutic option to mitigate inflammation in coronary artery disease.

 Heart healthI hope this information adds to a growing data bank of safety and efficacy in the the rationale of using high dose potent Statins in reducing the devastating effects of progression of atherosclerotic vascular disease.

Blessings Cardiologdoc