Structural remodeling processes of the vasculature and heart underlie most of the clinical events that treatment aims to prevent. Improved understanding of the contributors to these structural processes, such as endothelial dysfunction and neurohormonal activation, is needed. The atherosclerotic process, the predominant factor in the vasculature, is partly genetic and partly environment; factors that contribute to endothelial dysfunction, which in turn is prerequisite for the development of atherosclerosis. The atherosclerotic process leads to the cardiovascular (CV) events that mostly occur in the Western world.

Aging is a known contributor to atherosclerosis, which smoking aggravates. Elevated blood pressure, elevated LDL, low HDL, diabetes and oxidative stress injure the endothelium. Once injured, an increase in blood pressure and in the LDL-HDL ratio, and perhaps inflammation, contribute to progression of the atherosclerotic process. These represent a number of therapeutic targets to slow this atherosclerotic process.

The manifestations of large artery disease are seen after atherosclerosis develops: widening pulse pressure, increased pulse wave velocity, reduced large artery elasticity. All are markers for disease in the large conduit artery wall and is preceded by a reduction of small artery elasticity, which appears to be a marker for endothelial dysfunction, providing a method for early identification of alterations of the endothelium that lead to the progressive atherosclerotic process and places the patient in the cardiovascular continuum.

Genes and environment contribute to endothelial dysfunction and diabetes, and may contribute to myocardial disease. Hypertension develops at least in part as a manifestation of the endothelial dysfunction and contributes to myocardial disease. Left ventricular (LV) dysfunction, remodeling of the left ventricle, and progressive heart failure are natural evolutions of myocardial disease. Atherosclerosis, a systemic disease that leads to claudication, stroke, renal failure and coronary disease, may occur very early. Endothelial dysfunction is thought to contribute to nitric oxide deficiency in all of the structural remodeling processes in the left ventricle and vasculature and contributes to hypertension. The renin angiotensin system (RAS) contributes to progressive remodeling of the left ventricle, the atherosclerotic process and hypertension. The balance between the RAS and the nitric oxide system may be critical to define the early progression of cardiac and vascular disease that is termed the cardiovascular continuum.

The syndrome of heart failure has provided the opportunity to conduct rather careful studies of the natural history of the disease. The structural remodeling process, which occurs after disease has influenced LV function, leads to progressive enlargement of the chamber and a reshaping of the chamber to a larger transverse diameter. This process involves myocyte growth, lengthening of the myocytes due to sarcomere growth in series, and a change in the interstitium to allow the myocytes to enlarge.

An enlarged chamber and reduced ejection fraction result from matrix and myocyte changes. The falling ejection fraction observed in progressive heart failure is in large part a manifestation of a remodeling of the chamber, not necessarily of contractile dysfunction. The hormonal system is thought to be critically involved in this process since it is activated in most patients studied. Plasma norepinephrine, plasma renin activity, arginine vasopressin, atrial and natriuretic peptide and B-type natriuretic peptides are increased and endothelin-1 levels are elevated persons with heart failure compared to age matched, normal subjects. Most of these hormones are important factors causing vasoconstriction and thus increasing impedance to left ventricular ejection, and causing growth and remodeling of the myocytes and the interstitium.

In the CONSENSUS I trial patients presenting with hormone levels (norepinephrine, angiotensin II, aldosterone, atrial natriuretic peptide) above the median had a much higher mortality than those who presented with hormone levels below the median. Norepinephrine, angiotensin II and aldosterone are thought to contribute to disease progression, which has led to the hypothesis that LV dysfunction is associated with neurohormonal stimulation, which raises impedance to LV ejection and further impairs the function of the left ventricle. A vicious circle ensues that makes the left ventricle progressively worse. This neurohormonal stimulation also leads to ventricular remodeling with myocyte and matrix growth, further aggravating the neurohormonal stimulation and LV dysfunction. The structural remodeling is the major determinant of the long-term poor outcome in patients with heart failure.

Growing evidence points to the RAS as responsible for most of the adverse effects of the progressive structural process in the left ventricle and probably in the vasculature. Renin angiotensin, a potent constrictor, raises impedance and is a potent mitogen for stimulating the remodeling process in the left ventricle and vasculature.

Angiotensin II has a series of deleterious effects in the vasculature and heart. It is a potent vasoconstrictor, activates other hormonal systems which may be equally adverse in patients with heart failure, and is a potent stimulator of myocyte growth, vascular smooth muscle growth, and collagen synthesis; all components of the remodeling process in the vasculature and heart. Furthermore, it stimulates oxidative stress, platelet aggregation and thrombosis. The potent adverse effects of angiotensin II may play a role in the progressive cardiovascular continuum, not only in heart failure as a late manifestation.

The remodeling of the vasculature is less well understood. Small arteries remodel and hence reduce the lumen size, although smooth muscle mass is not increased. The remodeling process in the small artery raises impedance, resistance to flow and blood pressure. Vascular smooth muscle grows and the vascular wall will thickens as a result of an increase in smooth muscle mass due to activation of the growth stimulating effects of the renin angiotensin system. The rise in resistance and wall thickness reduces arterial elasticity and contributes to the impedance of the LV ejection.

Vascular structure and vascular tone can be viewed as dependent on the balance between the constrictor growth promotion of angiotensin II and the dilation and growth inhibitor effects of nitric oxide. The reduction of nitric oxide levels or increase of angiotensin II levels at the vascular site accelerates the abnormality of tone and structure of the blood vessel and contributes to the events that occur.

The remodeling process in the artery wall appears to be different in the large and small arteries. In the large arteries, the lumen size actually tends to increase, the wall becomes thicker, and the compliance or distensibility of the large arteries is reduced. As a result of this process, a consequence of endothelial dysfunction, there is lipid accumulation and plaque formation in the large conduit arteries that leads to acute events.

In the small arteries, compliance or elasticity of the small arteries is reduced. Flow inhibition and impairment of regional blood flow occurs because of the narrowing of the small nutritional arteries in the microcirculation. A growing body of data suggests that drugs that inhibit the renin angiotensin system (ACE inhibitors, angiotensin receptor blockers) will slow the progressive structural process occurring in the wall of the large and small arteries. Data from the SOLVD trial, in which left ventricular volume was monitored, show that enalapril produced a significant reduction in LV end diastolic and end systolic volume, compared to placebo. Data from the carvedilol trial conducted in Australia and New Zealand show that the LV volume increased in the placebo arm, but fell in the carvedilol group.

The favorable structural effect appears to be directly correlated with an improvement in outcome. The V-HeFT trials, in which ejection fraction as a surrogate for chamber dimension was monitored, showed that the changes in LV ejection fraction correlated very well with subsequent outcome. Mortality was very high in patients whose ejection fraction fell by more than five units during the study period. A lower rate of mortality was seen when the ejection fraction remained the same, an even lower mortality when the ejection fraction rose by more than five units, and a strikingly reduced mortality when the ejection fraction rose by more than 10 units.

Improvement in the structural abnormality is associated with an improved outcome; drugs with a favorable effect on structural remodeling have a favorable effect on outcome. Mortality was reduced with enalapril compared to placebo in the CONSENSUS trial and the SOLVD treatment trial, and in the post-MI trials (SAVE, AIRE, and TRACE). Ramipril reduced the event rate in patients with atherosclerotic disease or diabetes in the HOPE trial. ACE inhibitors protect the arterial vasculature and protect the left ventricle. Beta blockers produced a significant improvement in survival compared to placebo in the CIBIS II, MERIT-HF and Copernicus studies providing clear evidence that favorable structural effects on the left ventricle are associated with favorable outcomes.

Angiotensin contributes to the progression of disease in the setting of heart failure, even in the presence of therapy, as shown by the results from the ValHeFT trial. In patients with advanced heart failure on standard background therapy, valsartan, compared to placebo, produced a significant reduction in morbidity and mortality; a 13.3% risk reduction compared to placebo, added to background therapy, and a highly significant 27.5% reduction in the risk for hospitalization for adjudicated heart failure. All secondary markers were improved with valsartan, including an improvement in quality of life. Valsartan improved ejection fraction and LV dimensions and lowered norepinephrine and BNP.

Mortality was not reduced in the ValHeFT trial. This may be due to the late initiation of treatment, after patients have a dilated left ventricle and low ejection fraction and are clearly advanced in the cardiovascular continuum. Late intervention, as in the clinical trials, aims to delay the development of events. Instead, monitoring should begin earlier in the biological process to demonstrate a shift in the slope of the progression of disease. The biological process may involve structure of the left ventricle or arterial vasculature or endothelial dysfunction, neurohormonal activation, particularly the renin angiotensin system, and probably gene expression. Early disease detection provides the opportunity to slow the progressive diseases of atherosclerosis and LV dysfunction. Therapeutic intervention can slow progression in advanced disease like heart failure, renal failure and post-myocardial infarction.

Delaying disease progression should delay the occurrence of morbid events. This intuitive concept remains to be proven. The delay of morbid events should improve quality of life and delay health care costs. Society then might have to make some decision about age-related health care responsibility, because while interventions slow progression they do not necessarily halt progression, so disease may occur at a later age. The cost-benefit-risk ratio in specific population groups must be evaluated to mount the effort to identify disease early.

The Rasmussen Center at the University of Minnesota is evaluating the effect of earlier intervention. Screening tests for early detection of disease are performed in healthy persons who are self-referred to learn whether they are at risk for cardiovascular events. Testing that provides markers for early blood vessel disease, early heart disease, and risk contributors for intervention is performed. A two-hour screening procedure, nearly all non-invasive, includes a vascular evaluation with the measurement of arterial elasticity of both the small and large arteries. Blood pressure is measured at rest and during a three-minute treadmill exercise test at five METS workload. A digital photograph of the retina to evaluate the vasculature directly is taken. A urine test for the microalbumin-creatinine ratio is conducted and a Doppler measurement of the ankle brachial index.

The cardiac evaluation includes an electrocardiogram, an ultrasound of the left ventricle for measurement of chamber dimension and wall thickness (hand-held ultrasound evaluation), measurement of the plasma BNP level as a further index to left ventricular remodeling, and a forced vital capacity for ventilatory function. A series of modifiable disease contributors is also measured: fasting lipid levels, LDL, HDL, triglyceride, fasting blood sugar, HS-CRP, homocysteine and PAI-1. Other markers of cardiovascular disease are: normal, borderline, and abnormal blood pressures at rest and exercise; the vasculature in the optic fundus; the presence of microalbumin; the ankle brachial index; the electrocardiogram; the ultrasound, measurement of the left ventricular dimension and LV mass; body surface area ratio; and BNP levels.

The measurement of elasticity is an important component of the screening process, using a technique developed at the University of Minnesota. A transducer is placed on the wrist and records the waveform from the radial artery. The waveform is analyzed statistically to solve a third order equation dividing the diastolic decay recorded into two components, an exponential decay (largely dependent on the large artery elasticity or compliance) and an oscillatory wave form (largely dependent on the reflected waves or oscillations, formed in the more distal, small arteries). This technique allows evaluation separately of large and small artery elasticity. Elasticity is reduced progressively with age, and is lower in females than in males.

The results from the first 333 persons screened indicate that those already on the cardiovascular continuum were identified. Elevated blood pressure was present in many and surprising number had an abnormal exercise treadmill test. Borderline abnormalities were seen in many. The ankle brachial index was not very discriminating. A remarkable number of people without diabetes and without known disease had microalbuminuria, indicating mall artery disease in the kidney. Abnormal LV dimension or wall thickness was identified.

The benefits to early screening for disease are: identification of undetected and untreated advanced disease; evidence to support efforts at lifestyle modification, if indicated; provide data for establishing the rate of progression in an asymptomatic population; the potential to improve quality and duration of organ system disease-free life.