Outline
Valvular Heart Disease as a Treatable Cause of Heart Failure, 347
Etiologies, Epidemiology, and Demographics of Valvular Heart Disease, 347
Pathophysiology of Valvular Heart Disease, 348
Mechanisms Involved in Producing Stenotic and Regurgitant Heart Valves, 348
Genetics Aspects of Valvular Heart Disease, 348
Quantification of Valve Lesion Severity, 348
Impact on Chamber Size, Function, and Myocardial Hypertrophy, 348
Systemic and Pulmonary Arterial Systems in Valvular Heart Disease, 352
Reverse Remodeling after Correction of Valvular Heart Disease, 353
Clinical Manifesations of Valvular Heart Disease, 353
Specific Valve Lesions, 355
Aortic Stenosis, 355
Aortic Regurgitation, 355
Mitral Regurgitation, 355
Mitral Stenosis, 357
Tricuspid Regurgitation, 357
Changing Manifestations of Valvular Heart Disease Related to Comorbid Conditions and Aging, 358
Isolated Valve Lesions versus Multivalvular Heart Disease, 359
Clinical Evaluation of Patients with Valvular Heart Disease, 359
Stages of Valvular Heart Disease and Stages of Heart Failure, 360
Treatment of Valvular Heart Disease, 360
Timing of Interventions, 361
Current State of Transcatheter Therapies for Valvular Heart Disease, 362
Current State of Surgical Therapies for Valvular Heart Disease, 362
Treatment of Valvular Heart Disease The Heart Team and Shared Decision Making, 362
Treatment of Valvular Heart Disease Patients After Interventions, 362
Valvular heart disease (VHD) is not simply a disease of the valve. 1,2 Cardiac valves are the major determinants of the direction of blood flow in the circulation that consists of a system of vessels that distribute and collect blood, and cardiac chambers that create the propelling force for blood movement. VHD causes a disruption of the entire circulatory system. In addition, there is a complex interplay between VHD and comorbid diseases, along with systemic changes seen with aging.
VHD therapy has recently experienced a transformation by changes in its principal etiology in many countries, the medical complexities of many of the patients with VHD, and the introduction of the disruptive technologies of transcatheter treatments. Management of VHD had few major changes for several decades, other than refinements in the techniques for surgical correction of various valve lesions and the replacement of invasive characterization of valve lesions by echocardiography. In the 2006 Guidelines for Management of VHD, there was only one class 1a indication for VHD therapies; mitral balloon commissurotomy for rheumatic mitral stenosis (MS) had positive evidence from multiple randomized trials comparing this first transcatheter VHD treatment to various surgical techniques.
In the past, new knowledge in VHD was primarily driven by single-center studies. Currently a robust multicenter and multinational clinical trial network has been activated in VHD. A learning health care system has also been created with the gathering of comprehensive patient-level data including long-term outcomes and patient-reported health status for all patients in the United States undergoing transcatheter valve therapies (TVTs) in the Society of Thoracic Surgeons (STS) and American College of Cardiology TVT Registry. The national coverage decision for TVTs by Centers for Medicare and Medicaid Services (CMS) requires entry of patient data into an approved national registry as a condition of coverge.
Finally, the process of evaluation and treatment of VHD patients using the heart team approach has also followed the lead of the multidisciplinary teams used in advanced heart failure for decision-making for transplantation and mechanical support. Shared decision-making and decision-aids have also emerged in VHD.
Valvular Heart Disease as a Treatable Cause of Heart Failure
VHD can be definitively treated, in terms of the valve abnormality, with surgery or transcatheter valve repair and replacement, but this often does not occur until patients become symptomatic, as recommended in major guidelines. As a result of this interventional timing late in the natural history of VHD, many patients have persistent issues requiring ongoing management, as will be described.
Etiologies, Epidemiology, and Demographics of Valvular Heart Disease
Age-associated VHD has replaced rheumatic heart disease (RHD) as the dominant etiology of VHD in countries with medium to high personal income levels. Aortic valve sclerosis is an age-associated valve abnormality in which the valve cusps are thickened or calcified but not hemodynamically impactful. In a study with a mean patient age of 81 years, the prevalence of aortic valve sclerosis had reached 42%. Degenerative changes in the aortic and mitral valve resulting in a moderate to severe hemodynamic impact emerge in 14% of the population by the age of 75. Hemodynamically significant mitral regurgitation has a prevalence of 9.3% in the United States for individuals older than the age of 75 years. Functional mitral regurgitation, typically in the setting of left ventricular dysfunction, is the dominant form. VHD in the elderly may be complicated by cardiac amyloidosis, recently reported to occur in 14% of patients with severe aortic stenosis, with a mean age of 86 years.
These facts on VHD associated with aging need to be coupled with the profound demographic change of rapid population aging in the United States and other countries predominantly as a result of increases in life expectancy. As a consequence, and on a very practical level, the number of patients potentially needing a valve intervention, such as aortic valve replacement for severe aortic stenosis, is expected to see a major surge in the next decade. Therefore heart failure as a consequence of VHD is demographically programed to increase.
RHD has not disappeared; its global impact remains enormous. RHD was present in 2010 in an estimated 34 million people worldwide and is disproportionately felt in many countries with limited health care budgets and in individuals with low personal income levels. Acute rheumatic fever in the United States has disappeared, and chronic rheumatic VHD, such as MS, in the United States is predominantly found in recent immigrants from countries with a persistent pool of individuals who had rheumatic fever in childhood. Bicuspid aortic valve, the most common congenital heart defect, continues to occur in approximately 0.9% to 1.36% of live births throughout the world and often leads to clinical manifestations from valve malfunction in all age groups. Nearly all patients with bicuspid aortic valves will require valve intervention during their lifetimes. A congenital etiology is the leading cause for pulmonic valve abnormalities and has received much attention in the adult congenital heart disease community with the development and widespread use of transcatheter pulmonary valve replacement.
Pathophysiology of Valvular Heart Disease
This section will review broad pathophysiologic concepts and findings applicable to most forms of VHD.
Mechanisms Involved in Producing Stenotic and Regurgitant Heart Valves
In primary VHD the pathologic process from which a valve becomes stenotic or regurgitant is multifactorial and differs with the specific causes, including congenital, rheumatic, infectious, and degenerative. As shown in Fig. 26.1 , leaflet calcification is pronounced in aortic stenosis and follows a process of inflammation and fibrosis. The pathology also includes lipid deposition and an inflammatory process leading to bulky leaflets not capable of opening fully and increasingly require a higher ventricular pressure to open. The renin-angiotensin-aldosterone system (RAAS) is activated in this process ( see also Chapter 5 ) and contributes to pathologic alterations of the leaflet structure and function. Myxomatous degeneration occurs in mitral valve prolapse leading to leaflet redundancy and malcoaptation which produces valve insufficiency. New insights into disease progression, genetics, and molecular alterations have occurred to enhance our understanding of its pathophysiology.
Primary VHD typically is a progressive disease process of the valve, with the hemodynamic burden of pressure or volume overload increasing over time. This process may be gradual, as with aortic stenosis, for which the rate of progression has been studied. It may also be rapid as in some patients with degenerative mitral regurgitation, in which chordal rupture can cause a sudden increase in the degree of mitral regurgitation.
Genetics Aspects of Valvular Heart Disease
There are four congenital abnormalities of cardiac valves that have a defined genetic basis and are currently being investigated for candidate mutations. Bicuspid aortic valve, myxomatous mitral valve regurgitation, pulmonic valve stenosis, and Ebstein anomaly of the tricuspid valve are the focus of linking these congenital valvulopathies to human genetics. Some evidence has emerged linking adult-onset VHD to genetic influences on the process of valvular calcification and production of aortic stenosis.
Quantification of Valve Lesion Severity
The quantification of valvular stenosis and regurgitation is now routinely performed noninvasively, with echocardiography playing the major role because of availability, accuracy, information about mechanism, assessment of changes in chamber size and function, semiquantitative metrics of pulmonary hypertension, and well-defined metrics of lesions severity ( see also Chapter 32 ). Noninvasive evaluation of native valve regurgitation now has guidelines and standards for both echocardiography and cardiovascular magnetic resonance (CMR). Currently there is a trend to use CMR to assess not only the severity of mitral regurgitation but understand pathophysiology in terms of chamber sizes and interstitial fibrosis.
Quantification of the degree valve stenosis is also a first step in characterizing these forms of VHD and understanding subsequent remodeling of anatomy and function of affected structures and is a major component of determining the timing of interventions. Problematic areas in stenosis quantification often involve low flow states that require means of augmenting flow, such as with exercise and intravenous agents that are either positive inotropic or vasodilating agents to determine if Doppler gradients reach thresholds of lesion severity. There has also been renewed interest in better understanding the severity of aortic stenosis by studying individual patient’s pressure versus flow curves while undergoing dobutamine infusion. The heterogeneity of the responses indicated that the fixed orifice model initially proposed by Gorlin often breaks down.
Impact on Chamber Size, Function, and Myocardial Hypertrophy
The traditional approach to pathophysiology of VHD focused on the hemodynamic principles of pressure and volume overload produced by stenotic and regurgitant valve lesions. These abnormalities of valve function do lead to changes in chamber size, myocardial hypertrophy, and modifications of systolic and diastolic function. Most recently there has been a renewed interest in understanding changes in left ventricular pressure–volume relationships after the reduction of mitral regurgitation using the most widely used transcatheter reparative technique, MitraClip, that reduces the regurgitant orifice by holding together the edge of the posterior and anterior mitral leaflets where the regurgitation originates. These acute changes in left ventricular preload, unchanged contractility, and reduced regurgitant volume are free of the confounding impact of cardiopulmonary bypass used in surgical mitral interventions.
Myocardial hypertrophy, whether eccentric or concentric, remains as a central feature in the pathophysiology of VHD because it represents a response to the increased work load imposed by stenotic and regurgitant valves. The degree of hypertrophy can be assessed with echocardiography and CMR. The relationship of the degree of hypertrophy to valve lesion severity is variable, and other factors modifying the hypertrophic response include age, gender, obesity, polymorphisms of the ACE 1/D gene, and other hemodynamic loads such as system hypertension. In aortic stenosis there is a sex dimorphism of left ventricular adaption to aortic stenosis, first described using echocardiographic techniques and recently studied in depth with cardiac magnetic resonance imaging (MRI), shown in Fig. 26.2 . Gender differences in left ventricular fractional shortening and wall stress are illustrated in Fig. 26.3 .
Since VHD in the elderly has become the dominant etiology in many countries, it is not surprising to see emerging reports on transthyretin cardiac amyloid ( see also Chapter 22 ) occurring in approximately one in seven patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis. Amyloid infiltrative cardiomyopathy will alter diastolic and systolic left ventricular properties but, in contrast to those alterations due to valvular disfunction, will not regress after relief of stenosis.
Chronic pressure and volume overload of cardiac chambers as seen in VHD also has quantifiable effects on the underlying myocardial molecular and cellular structure and function. These fundamental molecular alterations translate over time to directly observable macroscopic changes in cardiac chamber structure and function. As illustrated in Fig. 26.4 , these transitions have become most apparent and widely studied in aortic stenosis, where it has been demonstrated that chronic pressure overload of the left ventricle leads to both reversible and irreversible alterations in myocardial structure and function. These changes include increases in myocardial cellular hypertrophy, increases in extracellular matrix volume, and both diffuse and focal interstitial fibrosis. Later changes include declines in ventricular myocardial function, including reduction in left ventricular ejection fraction (LVEF) along with ventricular dilation. Myocardial cellular hypertrophy and diffuse fibrosis and increased extracellular matrix volume regress after aortic valve replacement, whereas left atrial enlargement and areas of focal fibrosis appear to be unimpacted.
This chapter identifies heart failure as a consequence of VHD, but it is also true that primary myocardial disease and coronary artery disease (CAD) with ventricular dysfunction can result in secondary or functional valvular regurgitation. Left ventricular dysfunction leading to alterations in valvular and subvalvular geometry leads to functional mitral regurgitation ( Fig. 26.5 ). In addition, tricuspid regurgitation is often functional in nature (i.e., with a normal tricuspid valve apparatus) and is caused by disorders producing right ventricular dysfunction whether isolated or in the context of pulmonary vascular disease.
The binary approach to mitral regurgitation as either being primarily a valve function issue versus valvular regurgitation secondary to ventricular dysfunction is convenient in organizing pathophysiology and has therapeutic implications. However, it also can be misleading as it becomes apparent that VHD needs to be understood from a pathophysiologic perspective of the complex interplay between the valve abnormality, the associated vascular properties that determine preload and afterload, and left ventricular structure and function. Changes in both the arterial system (i.e., increased resistance and decreased compliance) and left ventricle (various forms of hypertrophy, increasing interstitial fibrosis, and myocyte dysfunction) may precede and impact on the patient’s response to the development of a severe valve abnormality.
Systemic and Pulmonary Arterial Systems in Valvular Heart Disease
The arterial properties of both the pulmonary and the systemic arterial system are underappreciated aspects of hemodynamic load in VHD. These arterial properties impact on the remodeling associated with VHD. The traditional metric of arterial properties has been the resistance component, but the compliance of larger arteries also produces a hemodynamic load, modifies pressure waveforms, and may mitigate the reverse remodeling after correction of the valve abnormality. The vascular resistance component is most commonly quantified as the pressure gradient across both the pulmonary and systemic vascular bed divided by the flow.
Quantification of large arterial hemodynamic properties requires novel methodologies. These include measurement of pulse wave velocity and pulse pressure and various approaches to quantifying large artery compliance including aortic input impedance and arterial elastance.
A dominant influence on large arterial compliance in the systemic circulation is the impact of aging and the additive effects of common disease processes such as systemic hypertension and atherosclerosis. The changes in arterial stiffness due to aging modify the response to vasodilator therapy in heart failure. These aging-related changes in arterial properties add to age-related myocardial changes to modify the manifestations of a variety of cardiovascular diseases, including VHD. Systolic hypertension and widened pulse pressure are associated with aging and relate to increases in aortic stiffness. Large artery stiffness is due to increased collagen and decreased elastin produced by variations in activity of various elastases, including matrix metalloproteinases. The major increase in aortic pulse wave velocity associated with aging can be observed in those with degenerative aortic stenosis. After aortic valve replacement that relieves obstruction at the valvular level, the left ventricle then faces an increase in arterial load as reflected by augmented forward and backward compression waves with frequent unmasking of systemic hypertension and a reduction in stroke volume in the majority of the elderly patients undergoing TAVR ( Fig. 26.6 ).
Pulmonary hypertension ( see also Chapter 43 ) is a common pathophysiologic consequence of left-sided VHD ( Fig. 26.7 ). The increase in venous pressure produces a postcapillary form of pulmonary hypertension. With chronicity and severity of left-sided VHD there may be both alveolar-capillary stress failure and the development of precapillary pulmonary hypertension. The major pathophysiologic components of pulmonary hypertension in VHD are illustrated in Fig. 26.8 . Pulmonary hypertension can also lead to right ventricular dilatation, failure, and functional tricuspid regurgitation. These various manifestations for pulmonary hypertension from left-sided VHD can become irreversible and may significantly limit recovery following left-sided valve repair or replacement.
Reverse Remodeling After Correction of Valvular Heart Disease
Postoperative studies after surgical valve replacement and repair have provided an extensive understanding of the reverse remodeling process. More recent studies have shown how TAVR and MitraClip transcatheter therapies have reversed the heart failure syndrome. In aortic stenosis treated with valve replacement, the irreversible and reversible elements of interstitial fibrosis have been identified using cardiac MRI. Further insights into postoperative diastolic dysfunction in patients with VHD have been produced by echocardiographic studies showing typical abnormalities of diastolic dysfunction persisting after valve replacement and requiring medical therapy.
Clinical Manifesations of Valvular Heart Disease
The major etiologies, clinical manifestations, prognosis, therapeutic issues, and emerging markers of disease severity of the major isolated valve lesions are presented subsequently.
Specific Valve Lesions
Aortic Stenosis
Aortic stenosis ( Table 26.1 ) is generally a chronic and slowly progressive valvulopathy which leads to pressure overload on the left ventricle. In aortic stenosis, there is progressive narrowing of the outflow of the left ventricle such that higher left ventricular pressure is required to overcome this obstruction to maintain normal systemic aortic pressure leading to a pressure gradient through the narrowed aortic valve. In the early stages of the disease, mild narrowing of the left ventricular outflow carries few apparent consequences and patients are asymptomatic. As the degree of narrowing progresses, compensatory mechanisms become more active to maintain cardiac output and systemic blood pressure. The main compensatory mechanism is that of left ventricular hypertrophy (LVH). As left ventricular myocyte hypertrophy progresses, there is an increase in left ventricular wall thickness and left ventricular mass. These alterations lead to increased left ventricular stiffness and need for higher filling pressures (preload) to achieve adequate filling of the left ventricle, leading to diastolic dysfunction. Diastolic dysfunction alone may lead to symptoms in patients with AS even with normal systolic function. The issue of systolic dysfunction and the mechanisms which lead to it are still incompletely understood. As LVH progresses, along with increases in left ventricular diastolic pressure, coronary perfusion to the subendocardium decreases (coronary perfusion pressure = aortic diastolic pressure − left-ventricular end-diastolic pressure [LVEDP]). One component of progressive left ventricular systolic dysfunction can be attributed to chronic subendocardial ischemia leading to decreases in fractional shortening and global left ventricular systolic function (LVSF).
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Aortic Regurgitation
Aortic regurgitation or insufficiency ( Table 26.2 ) can broadly be characterized into acute and chronic because the manifestations of this lesion are generally related to the severity, abruptness of onset, and duration of the regurgitation. During diastole, the aortic valve prevents backflow of aortic blood into the left ventricle. In aortic insufficiency, there is leakage of blood through the incompletely closed aortic valve and into the left ventricle. Aortic insufficiency leads to increase ventricular preload (usual filling plus regurgitant volume), which results in volume overload of the ventricle. Chronic aortic insufficiency generally begins with mild leakage through the incompetent aortic valve, such that there is progressive increase in left ventricular preload. Over time, this leads to increases in left ventricular mass due to eccentric hypertrophy and left ventricular dilation. The increase in LV mass leads to increases in wall tension and myocardial oxygen demand, which contributes to symptoms and may ultimately lead to alterations in systolic function.
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| Assessments of disease at stage C (presymptomatic) |
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