|GUEST LECTURES IN FULL
|Year : 2003 | Volume
| Issue : 4 | Page : 2
New Horizons in the Management of Cardiovascular Disease
A Jamil Tajik, Thomas J Watson
Professor of Medicine & Pediatrics, Mayo Clinic College of Medicine Chairman Emeritus Cardiovascular Division, Director, Mayo Cardiovascular International, Mayo Clinic, Rochester, Minnesota, USA
|Date of Web Publication||22-Jun-2010|
A Jamil Tajik
Professor of Medicine & Pediatrics, Mayo Clinic College of Medicine Chairman Emeritus Cardiovascular Division, Director, Mayo Cardiovascular International, Mayo Clinic, Rochester, Minnesota
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Tajik A J, Watson TJ. New Horizons in the Management of Cardiovascular Disease. Heart Views 2003;4:2
| Introduction|| |
"I look through a half-opened door into the future, full of interest, intriguing beyond my power to describe . . ."wrote Dr. William J Mayo (in 1931), one of the two founding physician brothers of the Mayo Clinic. Indeed, at the dawn of the 21st century, medicine is full of promise. In the field of cardiovascular disease, the practice of cardiology is being transformed by new technology and medical insights at the molecular level. At the same time, these new discoveries raise important ethical considerations. Hypertrophic cardiomyopathy, a paradigm of cardiovascular molecular genetics, illustrates the progress and the dilemma. The first gene responsible for the disease was identified in 1990. By 2003, ten genes with over 200 mutations have been recognized, and consequently, screening and risk stratification have become problematic.
| Emerging Epidemics|| |
Despite great strides in diagnosis and therapy of cardiovascular diseases in the past four decades, new and emerging epidemics plague us. These epidemics are [Figure 1]: heart failure, atrial fibrillation, obesity metabolic syndrome, and degenerative valvular heart disease such as aortic stenosis and mitral regurgitation. These diseases are not new; rather they are the product of increased longevity, an aging population, and unhealthy life style.
| Diastolic Heart Failure|| |
Diastolic heart failure (DHF) defined as heart failure with normal ejection fraction (EF > 50%) increases with age. In population-based studies , , the prevalence of DHF is as high as 50% and is more prevalent in women. Asymptomatic diastolic dysfunction is much more common than symptomatic disease. This was illustrated in a community-based survey from the Mayo Clinic, which evaluated 2042 subjects > 45 years of age. 20.8% had grade I or mild diastolic dysfunction (DD), 5.6% had grade II or moderate DD, and 0.7% had grade III-IV or severe DD  .
The major etiology is systemic hypertension, followed by ischemic heart disease, diabetic heart disease, and metabolic syndrome with or without sleep apnea. Other less common causes include restrictive cardiomyopathy, constrictive pericardidtis, hypertrophic cardiomyopathy, infiltrative disorders (Amyloidosis), storage disorders (Hemochromotosis), Valvular Heart Disease and female gender [Table 1].
Diastolic heart failure is clinically indistinguishable from systolic heart failure. The diagnosis of diastolic dysfunction is often made or presumed in patients who have signs and symptoms of CHF and a normal LVEF by echocardiography. The plasma concentration of brain natriuretic peptide (BNP) is increased in asymptomatic and symptomatic left ventricular systolic dysfunction and can be used for both diagnosis and prognosis. However, plasma BNP is also elevated in patients with diastolic dysfunction. Hence, BNP cannot be used to distinguish diastolic from systolic dysfunction.
For an objective diagnosis of diastolic heart failure, abnormal relaxation, reduced compliance and abnormal filling must be demonstrated. In clinical practice, the presence of diastolic dysfunction is diagnosed by 2-D/Doppler methodology by assessment of mitral valve inflow velocity by Doppler echocarcardiography. In patients with impaired relaxation, (mild grade 1 dysfunction), the mitral E/A ratio is less than one as well as the E wave deceleration time is prolonged (> 240msec). In contrast, patients with reduced LV compliance (advanced grade 3 dysfunction) have a "restrictive" pattern manifested by increased E/A ratio and short mitral E wave deceleration time (< 150 msec) [Figure 2].
An intermediate (moderate, grade 2) dysfunction is characterized by normal E/A ratio and normal deceleration time hence, also sometimes referred to as "pseudonormal". Distinction from normal can be readily made by utilizing Valsalva maneuver and by observing associated LA enlargement. Furthermore, Doppler Tissue imaging (DTI) and measurement of pulmonary vein flow velocity are also very helpful in diagnosis and grading the severity of diastolic dysfunction. The ratio of mitral E velocity to mitral annulus E' velocity (DTI) has proven to be very useful in clinical practice. With worsening diastolic function and increasing filling pressures, mitral E velocity progressively increases while the annulus E' velocity progressively decreases, hence, the progressive increase in the ratio of E/E' velocities. If the ratio is 3 15, it indicates mean LA pressure of 320 mmHg while an E/E' ratio of <10 indicates normal mean LA pressure.
Left atrial (LA) volume [Figure 3] has a strong indicator correlation with diastolic filling abnormalities and is an important predictor of cardiovascular events. In a clinical and echocardiographic model, indexed LA volume was strongly associated with diastolic function grade [Figure 4] independent of LV ejection fraction, age, gender, and cardiovascular risk score. In patients without a history of atrial arrhythmias or valvular heart disease, LA volume expressed the severity of diastolic dysfunction and provided an index of cardiovascular risk and disease burden  .
| Atrial Fibrillation and Diastolic Dysfunction|| |
The prevalence of atrial fibrillation (AF) increases with age and with an increasing older population, AF is a growing epidemic. AF is associated with increased morbidity, mortality, and socioeconomic burden. Studies have shown that AF is one of the most powerful independent risk factors for stroke , .
The decline in rheumatic heart disease in the developed world has shifted the etiology toward a preponderance of nonvalvular AF (NVAF)  . A Mayo clinic study  published in 2002 highlighted the importance of diastolic function as a predictor for the development of NVAF. The clinical and echocardiographic characteristics of patients age 3 65 years who had an echocardiogram performed between 1990 and 1998 were reviewed. Of 840 patients who had no prior AF, 9.8% developed NVAF over a mean follow-up of four years. The presence and severity of diastolic dysfunction were independently predictive of first documented NVAF in the elderly [Figure 5]. In this study of older adults, even a milder form of diastolic dysfunction, namely abnormal relaxation, significantly increased the propensity for NVAF. The incidence increased further with worsening grades of diastolic dysfunction. On the other hand, in patients with normal diastolic function and normal LA volume inspite of older age, the incident AF was practically absent during the study period. It can, therefore, be surmised that the rising epidemic of diastolic dysfunction and DHF is responsible for the increasing epidemic of atrial fibrillation.
Thromboembolism and stroke are serious complications of AF hence, treatment continues to be a challenge. The mechanisms leading to an increased risk of stroke, thrombus, and embolism in AF are multiple, complex, and closely interact with each other. For patients with NVAF, the vast majority of thrombi are located within or involve the left atrial appendage (LAA) [Figure 6]. The LAA is a cul-de-sac that creates an appropriate milieu for blood stasis, which may be due to its shape and the presence of trabeculations and reduced contractility.
The LAA is the source of the large majority of emboli associated with AF. For this reason, percutaneous LAA occlusion has been developed so that a special device can be implanted in the cardiac catheterization laboratory to seal the LAA in patients with chronic AF who are not candidates for long-term anticoagulation. The devices are PLAATO , and the Watchman; Filter System [Figure 7]. Early clinical experience with these devices appears promising but larger trials are needed to assess their safety and effectiveness in preventing embolic events  .
| Prognosis of Diastolic Dysfunction|| |
The presence or absence of symptoms affects the prognosis in diastolic dysfunction.
In symptomatic heart failure patients with normal left ventricular ejection fraction, data from the Framingham Heart Study, the V-HeFT trials, and a community-based survey of elderly subjects from the Cardiovascular Health Study (CHS) revealed similar findings: diastolic dysfunction was associated with a better prognosis than heart failure due to systolic dysfunction ,, . However, a more recent and larger study than Framingham and CHS found that the comparative mortality for diastolic versus systolic dysfunction was similar, 25% versus 42% at five years  .
A prospective study of patients hospitalized for congestive heart failure found higher mortality rates at 6 months but lower risk of death in those with preserved EF, 13% versus 21%. However, there was no difference in the risk of readmission or the odds of functional decline or death  . Thus, diastolic heart failure with preserved EF confers a considerable burden on patients, with the risk of readmission, disability, and symptoms subsequent to hospital discharge, comparable to that of CHF patients with depressed EF.
The impact of severity of diastolic dysfunction on prognosis was evaluated in the Mayo Clinic cross-sectional community survey of 2042 adults 3 45 years of age 3. After controlling for age, sex, and the presence of systolic dysfunction, all-cause mortality was 8-fold increased in patients with even mild (grade 1) diastolic dysfunction, 95% of whom were asymptomatic. Mortality was further significantly increased in those with moderate to severe (grade 2-3) diastolic dysfunction, 90% of whom were asymptomatic [Figure 8].
| Management|| |
It should be remembered that heart failure does not represent a specific disease entity, rather it is a constellation of findings - "syndrome" - which is a common manifestation of advanced form of diverse cardiovascular disorders. It, therefore, presents the final common pathway. When a patient presents with heart failure, he/she is akin to a patient presenting with fever. The management strategies for treatment of fever include general measures such as use of various antipyretics, but effective treatment of fever is possible only if the therapy is specifically directed at the etiology of the fever. Similar to the fever analogy, it is critically important that a concerted effort be directed to comprehensively define the etiology of diastolic heart failure as shown in [Table 1], and then to target etiologically specific treatment strategies. Short of this approach, one cannot hope to effectively treat and manage the morbidity and mortality of DHF.
General measures for management of DHF include the judicial use of diuretics, ACE inhibitors, ARB agents, Aldosterone receptive blockers, and beta blockers. Statins may also play an important role in select groups of patients. Furthermore, it is equally important to treat the specific underlying pathophysiology:
- Adequate control of hypertension
- Regression of hypertrophy
- Reduce/eliminate ischemia
- Decrease myocardial fibrosis
- Decrease intracellular calcium
Numerous trials have illustrated the importance of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of ventricular dysfunction (systolic as well as diastolic). The beneficial effect of ACE inhibition has been documented in many large randomized trials for the treatment of hypertension, after myocardial infarction, and in heart failure. The Heart Outcomes Prevention Evaluation (HOPE) study confirmed that ACE inhibitors are vasoprotective, independent of their effects on blood pressure and remodeling  .
Lowering the systemic blood pressure is the mainstay of therapy in patients with LVH due to hypertension. Regression of LVH is an important therapeutic goal, since it may improve diastolic function. The decrease in left ventricular mass index was significantly higher with angiotensin II receptor blockers (13%), calcium channel blockers (11%), and angiotensin converting enzyme inhibitors (10%) compared to beta blockers (6%)  .
Myocardial fibrosis, which is a result of both increased collagen (type 1) synthesis and decreased collagen degradation, is responsible for an increase in intrinsic myocardial stiffness in the hypertensive heart. Furthermore, alterations of diastolic function are more pronounced in patients with severe fibrosis than in patients with nonsevere fibrosis  . Thus, there appear to be an association between altered collagen metabolism, myocardial fibrosis, and increased LV stiffness. Treatment with Losartan (ARB agent) demonstrated regression of myocardial fibrosis with associated reduction of left ventricular chamber stiffness in hypertensive patients  . Thus, the ability of losartan to improve LV diastolic properties in hypertensive patients appears to be linked to its capacity to repair myocardial fibrosis as the result of normalization of type I collagen metabolism. Recent CHARM-Preserved Trial also demonstrated that the use of candesartan, another ARB agent, was effective in reducing hospitalizations for CHF among patients with diastolic heart failure  .
The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is the major enzymatic pathway for degradation of natriuretic peptides, which are endogenous inhibitors of the renin angiotensin system. Thus, inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) as well as bradykinin and adrenomedullin. The combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure  .
Of interest, new research has demonstrated that brain natriuretic peptide is produced in cardiac fibroblasts and induces matrix metalloproteinases (MMPs). Cardiac fibroblasts produce extracellular matrix proteins and participate in the remodeling of the heart. The study found that BNP decreased collagen synthesis and increased MMPs. These findings support a role for BNP as a regulator of myocardial structure via control of cardiac fibroblast function  .
A recent study administering intravenous BNP (nesiritide) in acutely decompensated patients with systolic CHF improved cardiovascular dynamics underscoring the therapeutic potential of BNP in the treatment of acute heart failure  . Likewise, a recent study from Mayo Clinic administered low dose SQ BNP (nesiritide) in conjunction with acute vasopeptidase inhibition (omapatrilat) produced a synergistic effect  . This approach is a novel and promising strategy in the treatment of systolic CHF. Its role in isolated DHF has not been investigated.
Glycated Collagen Cross-Link Breakers: Novel Approach
Advanced glycated end-products (AGEs) are implicated in the production of myocardial and arterial stiffness, which is seen with aging and also in patients with diabetes mellitus and insulin resistance syndromes. AGEs result in strong cross-linkages between collagen fibers resulting in increased stiffness of the myocardium, responsible for diastolic heart failure. A novel strategy directed at breaking the collagen cross-linkages appears promising. This approach, if validated in prospective studies, could be an important strategy in the management of diastolic dysfunction and diastolic heart failure , .
| Metabolic Syndrome: A Rising Epidemic|| |
The combined prevalence of overweight and obesity among adults in the USA now exceeds 60%24. The body mass index (BMI) is the most practical way to evaluate the degree of excess weight. Overweight is defined as a BMI between 25 and 29.9 and obesity is defined as a BMI of 3 30. Abdominal obesity is defined as a waist circumference in men > 102 cm (40 in) and in women > 88 cm (35 in)  . The obesity epidemic [Figure 9] is mainly responsible for the rising prevalence of metabolic syndrome  .
The constellation of abdominal obesity, hypertension, diabetes, and dyslipidemia has been called the metabolic syndrome, syndrome X, the insulin resistance syndrome, and the obesity dyslipidemia syndrome , .
Individuals with metabolic syndrome are at increased risk for coronary artery disease  . In Framingham, the metabolic syndrome alone predicted 25% of all new-onset cardiovascular disease (CVD). Overweight or obese individuals experience greatly elevated morbidity and mortality from stroke, coronary heart disease, congestive heart failure, cardiomyopathy, and possibly arrhythmia/sudden death. There is also an alarming increase in overweight and obese children and adolescents with corresponding increased rates of dysplipidemia, hypertension, type 2 diabetes mellitus (DM) and hepatic damage.
Genetic predisposition, lack of exercise, diet and lifestyle are major factors that contribute to the development of obesity, and consequently, the metabolic syndrome. The metabolic syndrome seems to have 3 potential etiological categories: obesity and disorders of adipose tissue; insulin resistance; and a constellation of independent factors (eg, hepatic, vascular, and immunologic origin) that mediate specific components of the metabolic syndrome. Other factors such as aging, proinflammatory state, and hormonal changes have been implicated as contributors as well  .
Insulin resistance results in hyperinsulinemia, which directly causes other metabolic risk factors. Insulin resistance generally rises with increasing body fat content. Obesity, particularly abdominal obesity, is associated with resistance to the effects of insulin on peripheral glucose utilization, often leading to type 2 DM. The hyperinsulinemia may then lead to hypertension and an abnormal lipid profile, both of which promote the development of atherosclerosis. Individuals with the metabolic syndrome or even insulin resistance alone have an increased risk of coronary artery disease , . Individuals with metabolic syndrome also appear to be susceptible to other conditions such as polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disordered breathing, and some forms of cancer.
| Therapeutic Targets|| |
Since obesity contributes significantly to the development of the metabolic syndrome in the general population, first line therapy is directed towards lifestyle changes: weight reduction and increased exercise. Weight loss lowers serum cholesterol and triglycerides, raises HDL cholesterol, lowers blood pressure and glucose, and reduces insulin resistance. Recent data further show that weight reduction can decrease proinflammatory and prothrombotic states.
Weight reduction and increased physical activity will reduce insulin resistance. Insulin resistance, whether primary or secondary to obesity, is in the chain of causation of metabolic syndrome, and therefore, is an attractive target.
Two classes of drugs are currently available that reduce insulin resistance: metformin and insulin sensitizers such as thiazolidinediones (TZDs). Metformin has long been used for treatment of type 2 diabetes. TZDs reduce insulin resistance, favorably modify several metabolic risk factors, and reverse abnormal arterial responses. Although both are approved for the treatment of type 2 DM, no clinical trial data exist to document their benefit in CVD risk reduction. TZDs, although promising, can not be recommended at present for preventing CVD in patients with metabolic syndrome or DM  . Currently, pioglitazone and rosiglitazone are the only approved TZDs. Troglitazone was withdrawn because of liver toxicity.
| Degenerative Valvular Disease|| |
Over the past 50 years, there has been a dramatic shift in the etiology of valvular heart disease, from rheumatic heart disease to degenerative disease in the developed countries. This is due mainly to a remarkable increase in life expectancy. Aortic stenosis and organic (degenerative, myxomatous) mitral regurgitation are the most common valvular disorders in the elderly and their incidence is rapidly rising.
| Aortic Stenosis: Newer Insights|| |
Calcific or degenerative aortic valve disease is considered the most common valvular lesion encountered among elderly patients  . Up to 90 percent of aortic valve replacements in patients over age 75 are performed for calcific aortic stenosis  .
Degenerative aortic valve disease is characterized macroscopically as increased leaflet thickness, stiffening and calcification, and absence of commissural fusion. Although the prevalence of aortic valve disease increases with age, recent findings suggest that degenerative aortic valve disease may not simply be a consequence of aging. 25% to 45% of octogenarians have no evidence of aortic valve calcification  . In addition, several clinical factors associated with degenerative aortic valve disease have been identified, including age, gender, elevated lipoprotein(a) [LP(a)] and cholesterol levels, smoking and hypertension  . These clinical factors are well-known risks for atherosclerosis and support the theory that the same risks factors are responsible for the occurrence of calcific aortic stenosis  . However, since only 50% of patients with severe aortic stenosis have co-existent significant coronary artery disease, other important factors maybe involved in the development of aortic stenosis. An interesting new Mayo Clinic study demonstrated that calcification in human aortic valve leaflets has similar features to that of osteoblastogenesis during skeletal bone formation. The study findings support the concept that aortic valve calcification is not a random and passive process but an active regulated process associated with transformation of cells in the human aortic valve to those of an osteoblast-like phenotype  .
| Does Statin Therapy Stop the Progression of Aortic Stenosis? New Hope|| |
The only established treatment for symptomatic aortic valve stenosis has been valve replacement. As discussed above, new research suggests that the underlying etiology maybe an inflammatory and atheromatous and active calcification process. If so, anti-atherosclerotic drugs may retard its progression and reduce the need for surgery.
There are a number of studies demonstrating that statin therapy maybe effective for stopping the progression of aortic stenosis. A correlation of LDL cholesterol level with progression of aortic valve calcification has been shown, suggesting that lipid-lowering therapy may be effective in decreasing this progression  . Using a rabbit model of hypercholesterolemia, it was found that atorvastatin inhibited a proliferative atherosclerosis-like process in the aortic valve  . Wu and colleagues showed that statins prevent calcification of aortic valve interstitial cells in vitro  , and findings in humans suggest that statins may decrease aortic valve calcium accumulation  . Furthermore, the calcium score as measured by electron beam computerized tomography (EBCT) has been reported to be inversely related to the aortic valve area, i.e., higher calcium scores correspond to smaller valve areas  .
These reports offer insight into the challenging approach of delaying the progression of degenerative aortic valve disease , and suggest that cardiac valve calcification appears to be treatable by medical therapy. However, further prospective studies are warranted to investigate the mechanism and medical therapy of aortic stenosis.
Further understanding of both the cellular and molecular mechanisms involved in the pathogenesis of degenerative aortic and mitral valve disease and the risk factors may lead to interventions that will prevent or delay disease progression. Statins appear to play a key role in combating the growing epidemic of "degenerative" aortic stenosis and perhaps also in "degenerative" mitral regurgitation.
| Prevention is the Key|| |
"The aim of medicine is to prevent disease and prolong life . . ."
Dr. William J. Mayo, 1928
Although CVD is the leading cause of morbidity and mortality in industrialized and developing countries, it is the most preventable of all chronic diseases (with the possible exception of lung cancer prevention through smoking cessation). If the burden of CVD is to be substantially reduced, effective strategies for primary prevention must be put in place. While there is no doubt that genetics, environment, and lifestyle are important factors in the development of coronary heart disease, epidemiological and intervention studies proved that modifiable risk factors in heart disease can be prevented through lifestyle changes. This can be achieved through community based prevention programs, as exemplified by The North Karelia Project (Finland).
The North Karelia Project was launched in 1972 in response to reduce the great burden of exceptionally high coronary heart disease mortality rates in the area. In cooperation with local and national authorities and experts as well as with WHO, the North Karelia Project was formulated and implemented to carry out a comprehensive intervention through the community organizations and the action of the people themselves. By 1995 the annual mortality rate of coronary heart disease in North Karelia in the working age population had fallen approximately 75%, compared with the rate before the Project [Figure 10].
The North Karelian Project has shown that by dealing on a community wide level with the lifestyle issues of diet, tobacco, and exercise, the rate of death by heart disease can be reduced significantly.
Now the World Health Organization is setting up trial versions of the program around the globe, from China to South America to the Middle East. Mayo Clinic has launched a community wide primary prevention program named Cardio Vision 2020 in the Olmsted County in Southeastern Minnesota. The aim is to "prevent disease and prolong healthy and productive life". It is hoped that by the year 2020, Olmsted County will become the most "Heart Healthy" county in the USA while it is projected by WHO that by 2020 heart disease will be the number one killer in the world. Cardio Vision 2020 promotes heart healthy lifestyles and consists of campaigns and program for active involvement of the community residents. These measures will effectively counter the emerging epidemics of obesity, metabolic syndrome, heart failure, atrial fibrillation and aortic stenosis. The goal of Cardio vision 2020 brings to mind the vision of Dr. William J Mayo who said, "The best interest of the patient is the only interest to be considered.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]