Neurohormones and the Progression of Cardiovascular Disease: What's Behind High Risk?

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Cardiovascular (CV) events are the leadingcause of morbidity and mortality in theUnited States and throughout the Westernworld, accounting for approximately 40% of alldeaths in the United States. They are a majorcause of long-term disability, lost productivity,and diminished quality of life and therefore areassociated with a staggering economic cost tothe healthcare industry and to the US economyin general.

Impact of Multiple Risk Factors

It is clear that CV disease seldom presents asa single risk factor. Instead, most patients presentwith multiple risk factors, which collectivelycause progression of disease culminatingin an eventual CV event, namely, stroke,myocardial infarction (MI), heart failure (HF),or sudden death. Independent modifiable riskfactors include insulin resistance, diabetes,hyperlipidemia, ischemic heart disease, renaldysfunction, hypertension, and obesity. Theserisk factors are additive, and the presence ofmultiple risk factors in individual patients confersincreased risk for CV events.

Data from the Framingham study looking at8-year probability for major CV events clearlyillustrate this.For example, the patient who hassimply high cholesterol without other risk factorsis at relatively low risk. In contrast,patients in a high hypercholesterolemia groupwith additive risk factors of glucose intolerance,hypertension, cigarette smoking, or diabeteshave a > 60% increased risk of a majorCV event over an 8-year follow-up period(Figure 1).1

Treatment programs aimed at attenuatingdisease progression need to consider the spectrumof risk factors rather than focusing on anysingle item. Of the modifiable CV risk factors,hypertension is perhaps the most influentialand most prevalent. Nonetheless, most patientswith hypertension are not optimally managed.Both the level of awareness and adequacy oftherapy for hypertension remains poor. Of themore than 50 million patients with hypertensionin the United States, > 50% of them haveat least 3 metabolic abnormalities. Uncomplicatedhypertension is, in fact, uncommon.

High-risk hypertensive patients are at riskfor ultimately developing HF. Again, data fromthe Framingham study have shown that > 90%of patients with HF have antecedent hypertension.Levy and colleagues studied risk factorsfor congestive HF (CHF) among patients withhypertension. As shown in Figure 2, MI, anginapectoris, diabetes, left ventricular (LV) hypertrophy,and valvular heart disease have beenidentified as independent risk factors for CHFin hypertensive patients. Based on hazardratios, it is obvious that most potent amongthese is MI, followed by diabetes.2

Patients with diabetes represent a group ofspecial concern. A diabetic patient with multiplerisk factors has a disproportionate increasein risk of coronary heart disease and death.Diabetic patients without previous MI have ashigh a risk of MI as nondiabetic patients with aprevious MI.3

The major causes of mortality in patientswith diabetes are coronary heart disease andHF—far outstripping other causes, such as cancer,stroke, and infection.4

Recommendations from the Joint NationalCommittee on Prevention, Detection, Evaluation,and Treatment of High Blood Pressure(JNC VI),5 American Diabetes Association,6and the National Kidney Foundation,7 basedon data from the United Kingdom ProspectiveDiabetes Study (UKPDS)8 and HypertensionOptimal Treatment (HOT)9 trials suggestthat the ideal target blood pressure in a patientwith diabetes and hypertension is 120to 130/80 mm Hg. A high normal blood pressureor stage 1 hypertension is no longer consideredto be acceptable in these patients.

CV risk factors, many of which are oftenasymptomatic, may lead directly to the onsetand progression of HF and acute MI. It is thisprogression of heart disease that we attempt tointerrupt with early and aggressive therapy inhigh-risk hypertensive patients.

Pathological Basis for CV Disease:Neurohormonal Imbalance

The metabolic syndrome is central to theprogression of CV disease. Hypertension playsa key role in activation of the sympathetic nervoussystem (SNS) and the renin-angiotensin-aldosteronesystem (RAAS). A patient with themetabolic syndrome may progress down oneof many pathways to MI or cardiomyopathyand, ultimately, the development of CHF unlessthere is an intervention that can block orantagonize the deleterious effects of SNS orRAAS activation. Drugs that treat the metabolicsyndrome, diabetes, hypertension, or atherosclerosismay all interrupt or improve thisprocess.

Figure 3 illustrates the interrelationshipbetween insulin resistance, angiotensin II, andnorepinephrine in the metabolic syndrome,starting at the top with insulin resistance.10Insulin resistance leads to hyperinsulinemia,which, in turn, is a stimulus for increased norepinephrineand angiotensin II. Together, thesefactors contribute to increased CV risk. Forexample, hyperinsulinemia influences aldosteroneand angiotensin II levels, which, inturn, can lead to fibrosis and hypertrophy notonly of the heart or the myocardium, but alsoof blood vessels, leading to vascular remodelingand arteriosclerosis.

The Role of the SNS

An increase in central nervous system (CNS)sympathetic outflow results in an increase insympathetic activity to blood vessels and the kidneys,acting mainly via peripheral alpha1 receptorsto promote vasoconstriction and sodiumand water retention in the kidney. In addition,activation of beta1 receptors in the kidney leadsto an increase in renin release.Thus, activation ofthe SNS leads to activation of the RAAS.

But perhaps most important, this increase inCNS sympathetic outflow occurring in the settingof CV disease leads to an activation of cardiacsympathetic activity, which may act viabeta1, beta2, and alpha1 receptors—all ofwhich are present in the human heart—to promotedisease progression (Figure 4). Amongthe consequences of increased cardiac sympatheticactivity are an increased risk of ventriculararrhythmias and LV hypertrophy oradverse remodeling.

Remodeling is of particular interest becauseit ultimately defines the progression of CV disease.Remodeling is a process by whichmechanical, neurohormonal, and possiblygenetic factors alter ventricular size, shape, andfunction. It occurs in most heart diseases,including MI, cardiomyopathy, hypertension,aging, diabetes, and valvular heart disease.Remodeling can be reversed, or at leastdelayed, and an improvement in this remodelingprocess may be associated with animprovement in patient outcomes.

There are 2 pathways for adverse remodeling.One is a hypertrophic pathway, the other,a dilated pathway. In response to chronicpressure overload, concentric LV hypertrophyis associated with normal cavity size, but astiff ventricle and diastolic dysfunction ultimatelyprogresses to the onset of diastolic HF.Conversely, progressive LV dilation and dysfunctionassociated with the development ofa globular heart with systolic dysfunctionwith mitral regurgitation can ultimately leadto the onset and progression of symptomaticHF as well.

Figure 5 shows LV mass, specifically LVmass index, in normotensive individuals,patients with hypertension alone, and patientswith hypertension plus diabetes. Comparedwith normotensive persons, hypertensivepatients have an increased LV mass index.

In patients with both hypertension and diabetes,the increase in LV mass index is muchgreater than that seen in those with hypertensionalone.11

Reversing Remodeling

Adverse remodeling of the heart defines diseaseprogression. At the cardiac, cellular, andmolecular levels, neurohormonal activationdrives this adverse remodeling process. Thisprocess can be reversed by neurohormonalinterventions, such as angiotensin-convertingenzyme (ACE) inhibitors, angiotensin receptorblockers, and beta blockers.

For instance, in an echocardiographic substudyof the Carvedilol Post Infarct SurvivalControl in LV Dysfunction (CAPRICORN) trial,the effects of carvedilol (a nonselective alpha1,beta1, and beta2 adrenergic blocking agent) orplacebo in addition to standard treatment withan ACE inhibitor and aspirin on LV remodelingpost MI were studied. Both groups showedimprovement from baseline because eachgroup received a neurohormonal blockingdrug. The group receiving carvedilol as well asstandard treatment, however, showed greaterimprovement than the group receiving standardtherapy alone (Figure 6).12


Activation of the SNS and the RAAS plays acentral role throughout the CV disease continuum.Thus neurohormonal antagonists, such asbeta blockers and ACE inhibitors, may be thepreferred agents for preventing the developmentor progression of CV disease.

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