In this issue of the Journal, Shlomai, Grassi, Grossman, and Mancia address the always “hot topic” of target organ damage in patients with hypertension in an article entitled “Assessment of Target Organ Damage in the Evaluation and Follow-Up of the Hypertensive Patients: Where Do We Stand?” The article is thoughtful and informative, considers the facts and takes away the fiction, and balances the totality of evidence to reach conclusions. It is a pleasure to offer my brief commentary from a different angle.

Hypertension is a well-known cardiovascular (CV) risk factor that contributes substantially to increased morbidity and mortality. High blood pressure (BP) can cause changes in many organs in the body, such as left ventricular hypertrophy (LVH), proteinuria and renal failure, retinopathy and vascular dementia, increased carotid intima-media thickness, and even increased calcium score. These changes are collectively called “target organ damage” (TOD) and are associated with increased risk for CV complications. There are many processes involved in the pathogenesis of TOD and these include endothelial activation, platelet activation, increased thrombogenesis, changes in the renin-angiotensin-aldosterone system (RAAS), and collagen turnover. Most of the changes early on affect the vasculature, cause endothelial dysfunction, vascular hypertrophy, arteriosclerosis, and atherosclerosis. For this reason, hypertension has also been called a vascular disease.

Endothelial dysfunction (or endothelial activation) is characterized by 3 distinct properties: inability to vasodilate, inability to prevent adhesion of inflammatory molecules, and loss of ability to prevent protein leak.

Endothelial dysfunction is associated with decreased production of nitric oxide (NO) and decreased NO bioavailability in the vessel wall[1] and has been linked to multiple CV risk factors including uncontrolled essential hypertension.[2]

The pioneering work of Furchgott and Zawadzki[3] first identified NO as an endothelium-derived relaxing factor that helps maintain the ability of the vessels to vasodilate. NO is generated by the action of endothelial NO synthase (eNOS). Shear stress is a key activator of eNOS in normal physiology, and this helps adapt organ perfusion to changes in cardiac output.

In disease states, most CV risk factors lead to increased production of reactive oxygen species (ROS), which, in turn, scavenges away NO and reduces NO bioavailability. Increased production of ROS and decreased NO bioavailability has been suggested as a hallmark of endothelial dysfunction and a pathogenetic mechanism in atherosclerosis and CV disease.[4]

Uncontrolled hypertension is one of many CV risk factors that leads to increased production of ROS and reduced NO bioavailability, leading to endothelial dysfunction, atherosclerosis, and TOD. Pressure overload leads to vascular and myocardial hypertrophy that can affect the function of the heart, the kidney, and many other organs with various sets of consequences. Uncontrolled hypertension has long been known to increase the risk of stroke, heart attack, kidney disease, and vascular insufficiency. We need to remember, however, that risk factors for atherosclerosis tend to cluster. Hypertension is often accompanied by the metabolic syndrome, which encompasses a cluster of factors such as obesity, dyslipidemia, glucose intolerance, and prothrombotic or proinflammatory states that also contribute to TOD.

Numerous studies have shown that effective treatment of hypertension can prevent many, but not all, of the CV complications of hypertension. These outcome studies, however, require large numbers of patients and long follow-up, are difficult to perform, and are expensive. Thus, intermediate or “surrogate” endpoints have been sought to assess effective treatment of hypertension.

TOD from uncontrolled hypertension has been shown to be a good surrogate for CV risk, but the value of target organ damage reversal has been debated. In this context, we also need to remember that TOD are not causally related to outcomes, ie, LVH and microalbuminuria are independently related to stoke, heart attack, and CV mortality, but it is not the leaking of albumin or the hypertrophy of the myocytes that cause the heart attacks and stroke. It is the association with vascular disease, unstable or vulnerable plaques, prothombotic state, and/or extent of vascular disease.

In the article,[5] the authors provide a critical review of the literature, examine the association of TOD with CV events, and the role of TOD reversal on health outcomes. In this context, the authors point out that subtle changes in various organs can be detected early, before the appearance of any CV events. Such early involvement of target organs corresponds to increased CV risk irrespective of whether it involves the structure or the function of the heart, brain, kidney, or vasculature. LVH is probably the best example of TOD that correlates with CV risk. Numerous studies have shown a strong association between both electrocardiographic or echocardiographic LVH and risk for CV events. The risk is graded, continuous, and almost linear, but most likely it is not causally related. Myocyte hypertrophy does not cause heart attacks and strokes. Although some prospective studies suggest that treatment-induced regression of LVH is associated with better prognosis, other studies failed to confirm such an association. At first glance, it seems to be a paradox but actually it makes a lot of sense: Along with LVH regression due to hypertension control, we need to address all other variables that contribute to CV risk, such as plaque stabilization with statins, antiplatelet therapy with aspirin, and increased inflammation.

The increased CV risk with LVH is not caused by myocyte hypertrophy per se. The increased risk is a result of the changes found in the coronary and brain circulation; the structure of the coronary, kidney, and brain vessels; adhesiveness of platelets; and vulnerability of plaques. The amount of fibrosis and interstitial changes is another variable that may play a role. LVH is just a surrogate marker. Thus, BP control leading to LVH regression does not necessarily mean improvement in the other conditions that lead to high CV risk. It is not surprising that a recent large meta-analysis that included 14 studies and 12,809 participants with 2259 events[6] failed to show a significant continuous relationship between LVH changes and clinical events and casts doubt on the importance of LVH regression as a predictor of CV events.

Albuminuria is another example of TOD with a strong correlation with CV risk. The same rules apply here. Protein leak, part of the endothelial dysfunction definition, occurs at the glomerular endothelium level. It likely occurs elsewhere, but proteinuria is just a marker of endothelial dysfunction in other vascular beds as well. Thus, proteinuria correlates with CV events because it is a marker of vascular dysfunction elsewhere. In contrast, improvement of proteinuria without correcting vascular damage in the heart and brain will not materially affect risk for heart attacks and stroke.

The same rules apply for carotid intima-media thickness, coronary calcium score, and arterial stiffness. Although TOD in many organ systems correlates with CV risk regression or improvement of TOD, it does not necessarily eliminate the risk. We still need to pay attention to TOD and take it into consideration in order to tailor our therapies, but we are far from making them therapeutic targets. To be successful in minimizing CV risk we need to target the cause(s) of vascular disease, ie, known or emerging CV risk factors, and we need to target and aggressively treat them all. Perhaps in the future we may uncover unifying markers of risk, such as inflammatory markers (eg, high-sensitivity C-reactive protein, vascular cell adhesion molecule) or mediating enzyme systems that modulate vascular damage. Until then it is wise to focus on things that we know work: high BP, high cholesterol, diabetes, smoking, and sedentary lifestyle, and manage them all as best as we can. Comprehensive risk factor modification seems to be the best strategy for now.


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  2. References
  • 1
    Vita JA, Keaney JF. Endothelial function: a barometer for cardiovascular risk? Circulation. 2002;106:640642.
  • 2
    Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801809.
  • 3
    Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373376.
  • 4
    Schulz E, Gori T, Münzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res. 2011;34:665673.
  • 5
    Shlomai G, Grassi G, Grossman E, Mancia G. Assessment of target organ damage in the evaluation and follow-up of the hypertensive patients: where do we stand? J Clin Hypertens (Greenwich). 2013; 15:742747.
  • 6
    Costanzo P, Savarese G, Rosano G, et al. Left ventricular hypertrophy reduction and clinical events. A meta-regression analysis of 14 studies in 12,809 hypertensive patients. Int J Cardiol. 2012;Jul12. [Epub ahead of print]