Heart Valve Disease: State of the Art

This book provides a state-of-the-art description of the pathophysiology, diagnosis and management of valvular heart disease (VHD). With an aging population, the incidence and complexity of VHD has markedly increased and the introduction of transcatheter valve therapies have revolutionized the management of these frequent and serious cardiovascular diseases. The development of percutaneous valve interventions has revolutionized the management of VHD (or has dramatically changed its management)

Heart Valve Disease: State of the Art is dedicated to provide up-to-date knowledge to clinical and interventional cardiologists, cardiovascular imagers and cardiac surgeons. It provides state-of-the-art information for the health-care professional working in heart valve clinics, heart teams, and centers of excellence that specialize in managing patients with heart valve disease.

• Language: English
• Publisher: Springer
• Release date: Nov 12, 2019
• ISBN: 9783030231040

Book preview

© Springer Nature Switzerland AG 2020

J. Zamorano et al. (eds.)Heart Valve Diseasehttps://doi.org/10.1007/978-3-030-23104-0_1

1. Introduction to Valve Heart Disease

Jose Zamorano¹   and Álvaro Marco del Castillo¹  

(1)

Servicio de Cardiología, Hospital Universitario Ramón y Cajal, Madrid, Spain

Jose Zamorano (Corresponding author)

Email: [e-mail]

Álvaro Marco del Castillo

Keywords

Valve heart diseaseRheumatic feverStenosisRegurgitation

Etiology of Valve Heart Disease

The etiology of valve heart diseases has slightly changed during the last half of the twentieth century, as rheumatic fever’s incidence has declined in developed countries [1]. However, it is still the most common cause of valve disease in the young and in developing countries including Africa, Middle East, Indochina, South America and some parts of Australia. The decline in the prevalence of rheumatic fever is related to sociosanitary evolution, which has led to an improvement in living conditions and in the access to health care.

It is also due to the improvement of life expectancy that valve diseases tend to be much more prevalent in the elderly [2]: an U.S. registry showed how global prevalence is around 2.5%; however, the prevalence amongst patients older than 75 years increased to 13%. Between elderly patients, the most common diseases are calcific aortic stenosis, aortic regurgitation due to aortic root dilation and secondary mitral regurgitation.

Nevertheless, an unknown but probably significant percentage of patients with valve disease remains undiagnosed [3].

Rheumatic Fever

Rheumatic fever is the consequence of an impaired immune response against group A beta-hemolytic Streptococcus (also known as Streptococcus Pyogenes). After the initial infection, which usually takes place during childhood [4], patients can develop acute rheumatic fever after the first 3 weeks post infection. Albeit it is uncommon after a first pharyngitis episode, up to 75% develop rheumatic fever is recurrent episodes occur. Approximately, around 50% of patients with acute rheumatic fever suffer from heart involvement materialized as valve endocardial inflammation [5–7], and, again, the incidence increases with recurrent episodes [8]. Although the initial damage can cause severe valve lesions, rheumatic valve disease is more often based on cumulative damage due to either recurrent episodes of acute rheumatic fever or chronic degeneration cause by an impaired valve function.

The mechanism of the immune response relies on molecular mimicries between several streptococcal and human proteins. Although the exact pathophysiology remains obscure, some advances have been made in this field. The abnormal immune response is based on the streptococcal strain, the presence of genetic susceptibility and an aberrant host-bacteria interaction.

Some bacterial strains are more likely to cause disease than others [9]. S. Pyogenes is adhered to throat epithelial cells thanks to a variety of surface proteins: M, T and R. One of the proposed molecular mimicry associations is the one between streptococcal protein M and several cardiac proteins (myosin, tropomyosin, laminin, vimentin), and it is hypothesized that protein M from several serotypes is keener to the disease, probably because of a higher proximity to human proteins [10, 11]. In addition, some complex carbohydrate structures present in both streptococcus and valve tissue have been implicated in molecular mimicry mechanisms.

In 1889, it was noted that the probability of an acute rheumatic fever episode is significantly higher in patients with familiar history of rheumatic fever [12]. Although no single HLA haplotype has been consistently linked to the development of rheumatic fever, it is generally accepted that HLA class II molecules seem to be more closely associated with an increased risk of the disease [13]. Also, some genetically determined immune markers alter the risk of acute infection and chronic rheumatic disease, such as Mannose-binding lectin (MBL) [14]. Nevertheless, the exact mechanism is unknown.

Although improved living conditions, universalization of medical care and increase in the use of penicillin have substantially changed the epidemiology of rheumatic fever [15], it still prevails in developing nations and indigenous populations. However, the real prevalence is difficult to estimate, as almost all the information comes from passive survey systems, and a underreporting of acute and chronic cases is still an unaddressed issue [16].

The global incidence of acuterheumatic fever per year in children (5–14 years) is somewhere around 300,000–350,000 cases, taking into account significant regional deviations [1, 9, 15, 17]. Modifiable factors are related to socioeconomic situations: poverty, overcrowding, malnutrition and employment [6]. The yearly incidence of an acute episode ranges from 5 per 100,000 population in richer communities up to more than 350 per 100,000 population in indigenous Australian communities [18, 19]. Approximately 200,000–250,000 deaths per year are caused by rheumatic fever, and is the major cause of cardiovascular death in developing countries in children and young adults [15].

By using Jones diagnostic criteria, 15–19 million people worldwide have rheumatic heart disease [15]. However, global distribution is markedly unequal, being sub-Saharan countries and indigenous communities in Australia those with the highest numbers. Those regions reach 8 per 1000 population cases, whether the estimate prevalence in developed countries is below 0.3 per 1000 population [1]. However, if echocardiography rather than clinical criteria is used as screening tool, prevalence increases significantly [3].

Calcific Valve Disease

This term gathers all those valve diseases caused by calcific degeneration of either the leaflets or the annulus, being aortic stenosis (AS) the main entity of this group. Mitral annulus calcification is also a frequent condition, but rarely causes enough valve dysfunction as to require surgery or specific therapeutics.

The incidence of AS is markedly related to age, as valve degeneration is part of the normal process of ageing. However, the whole degenerative course is definitely not a passive one [20], as it involves active calcification, atherosclerotic lipid deposition, angiogenesis and an impaired local immune response.

It has come to light that the real prevalence of AS is higher than what was previously known [21]. Amongst a 30,000-people sample composed of patients who underwent a transthoracic echocardiography examination, 7.2% had any grade of AS. Even so, 2.8% had severe AS. This data is, to best of the knowledge of the authors, the largest registry ever carried out at the time of the writing of this book, and is in contrast with previous registries [2, 22] in which AS prevalence was found to be lower. As AS is markedly related to age, probably the increase in life expectancy is accountable for the rise in this disease’s prevalence.

Aortic sclerosis (ASc), which is the first stage of aortic degeneration, is a highly frequent entity. Defined as valve thickening and calcification in the absence of significant transvalvular gradient (peak velocity < 2.5 m/s) [23]. Depending on the mean age of the population of the available studies, ASc prevalence varies from 9 to 42% [23–38], and is clearly associated with myocardial infarction, especially in population who would otherwise be at low cardiovascular risk, such as women o <55 year-old patients [31, 36, 37, 39–43].

Mitral annulus calcification (MAC) is a common finding during echocardiographic examination in elderly patients, with a reported prevalence of 8–15% [44–48] depending on the consulted series. It is also an age-related process [49], although a lot more factors play a significant role (cardiovascular risk factors [50], hemodynamic stress, calcium-phosphorus metabolism alterations [32]), in a similar fashion as occurred in aortic calcification.

Usually, MAC is diagnosed as an incidental asymptomatic finding as significant valve dysfunction is not frequently associated [45]. This is probably because, unlike in rheumatic mitral disease, leaflet commissures have a mild degree of calcification which preserves the valve’s natural movement [51]. Nevertheless, it has been proposed as a marker of increased cardiovascular risk as is associated with cardiovascular events and mortality [52].

Endomyocardial Fibrosis

After rheumatic disease, endomyocardial fibrosis (EMF) is the second cause of acquired heart disease in children and young adults in equatorial Africa [53]. Structured information about prevalence and incidence is scarce and diffuse, but an echocardiographic study carried out in Mozambique estimated a prevalence of 20% (CI 17.4–22.2%) [54]. In any case, high frequency areas for EMF include Africa, Asia and South America [55, 56].

The pathogenesis of EMF remains obscure, and it is thought to be a result of an interaction of several pathogenic factors: autoimmunity, environment and genetic susceptibility [57]. It predominantly affects impoverished young adults of low socioeconomic status in a bimodal fashion, peaking at 10 and 30 years of age [58], and the natural history is clearly divided in three phases: inflammation, transition and chronification.

EMF usually starts with a febrile disorder along with dyspnea, itching, periorbital swelling and eosinophilia [59]. Acute inflammation of the heart results in myocardial edema, with subendocardial necrosis and vasculitis, leading to a subsequent interstitial fibrosis and myocyte hypertrophy [60, 61]. An unknown percentage of patients evolve to heart failure and death during the acute phase, while others develop a subacute burnout phase [59]. Mural thrombi are commonly observed during the acute inflammation stage, being thromboembolic events highly frequent.

After the acute inflammation resolution, patients who survive can develop a progressive restrictive cardiomyopathy. During this phase, a tricuspid and mitral encasement occurs, causing significant regurgitations [57].

Infectious Endocarditis

The incidence of infectious endocarditis (IE) is hard to ascertain, as definitions have varied over time and there is significant regional variability. Approximately, there are 15 per 100,000 population cases a year in the United States [62, 63], and global incidence varies from 3 to 18–20 per 100,000 population.

In fully developed countries compared to underdeveloped, patients are older and IE is increasingly associated with intracardiac device implantation and replacement or intravascular techniques, such as dialysis or port-a-cath systems [64–66]. A significant percentage of the reported endocarditis cases occurs in patients with prosthetic valves, which have an estimated 50-fold risk of endocarditis. However, endocarditis related to IV drug use is much rarer than it used to be during previous decades, as the use of parenteral administration is significantly less used.

In underdeveloped countries, on the counterpart, most of the patients have rheumatic heart disease and streptococci are the main responsible organisms [67].

Valve Fibrous Structure Dilation

One of the most frequent causes of aortic regurgitation (AR), specially in developed countries, is aortic root dilation [68], which can also be associated to a primary cause of regurgitation such as bicuspid aortic valve of calcific valve disease. Although aortic root dilation can be seen in the context of inheritable collagenous diseases such as Marfan syndrome or Ehlers-Danlos, or inflammatory disease such as vasculitis, the vast majority of patients have hypertensive/atherosclerotic root dilation or aneurisms [69].

Chronic Systemic Inflammatory Disorders

Ankylosing spondylitis is associated with aortic root dilation and left heart valve’s endocardial damage. The incidence of cardiovascular involvement in patients with this inflammatory disorder ranges from 10 to 30%, being rhythm abnormalities the most common manifestation. However, some series have reported aortic regurgitation in up to 24% of patients [70]. The hypothesized underlying mechanism is the fibrosis of subaortic tissues and the leaflet, which experience cusp thickening and retraction. Sometimes, an aortic root downward displacement can be seen, leading to mitral regurgitation due to anterior mitral leaflet retraction [71].

Rheumatoid arthritis can also have valve involvement. However, it is not well characterized in the literature and the available information is scarce. In the largest series [72], patients with rheumatoid arthritis presented mostly left-sided valve disease, with the specific presence of nodules in the 32% of the studied population. Also, valve thickening was present in 53% of patients. However, no correlation was found between the severity of the systemic disease and the valve affectation.

Patients with systemic lupus erythematous (SLE), especially if antiphospholipid antibodies are present, can have valve lesions being leaflet thickening the most frequent manifestation. Libman-sacks vegetations, although rare, are a very specific lesion: they are most common seen on the atrial side of the mitral leaflets, with a maximum diameter of 10 mm, and tend to occur by the commissural edges [73].

Congenital Diseases

Bicuspid aortic valve is the most common congenital cardiac malformation, affecting up to 0.7–0.8% of the population in some large population registries [74, 75]. Males tend to present this malformation in a 2:1 ratio against female, with significant familiar clustering: first-degree relatives have a 10% risk for bicuspid aortic valve [76]. The most common malformation consists on a failure of right-left separation, and it is usually associated with aortic root disease.

Drugs

Drug-induced disease mainly affect left-sided valves and is highly close to the affectation seen in carcinoid tumors. The principle pathway of endocardial damage is based on fibroblast activation mediated via 5-hidroxitriptophan (5HT) 2B receptors, same as carcinoid tumors. The drugs that have been reported as significant responsible of heart valve damage are:

Pergolide/cabergolide: both medications, used as dopaminergic agonists, have moderate 5HB effects. However, only in the doses used in Parkinson’s Disease has the valve damage been reported [77] consistently, although even in that setting, significant valve disease is rare.

Ergot alkaloids (ergotamine, dihydroergotamine, methysergide).

One of the most sounded cases of drug-induced valve disease was fenfluramine, an anorexic agent related to the family of serotonin antidepressants. Fortunately, it was withdrawn in 2009, after the report of mitral and aortic regurgitation in more than 90% and 75% of the patients respectively [78].

Apart from medical-use drugs, 3, 4-Methylenedioxymethamphetamine (MDMA), used as recreational drug with psychoactive effects, has been related with a high incidence of valvular lesions [79].

Heart Valve Clinic

Patients with valve heart disease are quite different from the rest of the patients seen in cardiology. They require a close follow-up to monitor the ventricular function and dimension, much closer than patients with ischemic heart disease or atrial fibrillation. Also, the diagnosis of this entities is usually challenging, and the interpretation of the echocardiographic results demand a high level of cardiac imaging knowledge to know the ups and lows in order to provide an accurate diagnosis. Again, the complications they can experience during follow up differ from others, having a profile in which both endocarditis and thrombotic complications are especially incident. Finally, the timing of the cardiac surgery is often difficult to decide, particularly in asymptomatic patients, in which a lot of prognostic factors must be integrated. Because of all the previous reasons, in the experience of the authors, these goals are best achieved with the development of interdisciplinary Heart Valve Clinics (HVC). In this line of thought, the European Society of Cardiology released a position paper in 2013, regarding the objectives, requirements, organization and workflow [80].

Models of Heart Valve Clinic

There are several potential models that may be adapted for the structure of HVC. The most common model is based on a consultative physician, which should be a cardiologist with expertise in VHD, and a trained nurse. The services offered should include both inpatient and outpatient management and a support organization with links to a fully equipped cardiac imaging unit, an exercise test infrastructure and a cardiac catheterization laboratory.

In some countries, the responsible cardiologist is used to be an experienced echocardiographer and performs the ultrasound explorations. However, in other places, especially in the US, most studies are performed by technicians.

The nurse’s role is to measure vital signs regularly, record a 12-lead ECG, obtain blood tests if required and schedule the follow-up appointments.

More advanced HVC models are those in which the role of the HVC cardiologist is to help general cardiologist only in the management of patients with a special risk profile or complex comorbidities, where the risk/benefit ratio of the different therapies is harder to estimate. In addition, this more advanced model includes direct connection to cardiac surgery and interventional cardiology departments, being able to provide transcatheter therapies when necessary.

Available Evidence Regarding HVC

The first evidence showing the positive impact of an HVC was published by Rosenhek et al. [81] in 2006, who showed that a watchful waiting strategy in patients with severe asymptomatic primary mitral regurgitation could be implemented without an increased peri-operative morbidity and mortality.

Later, Chambers et al. [82] showed that the patients followed-up in the HVC were significantly closer to what is expected as best-practice guidelines, while the total number of unwarranted echocardiograms performed fell.

Recently, Zilberszac et al. [83] showed how regularly follow-up in a valve clinic program permits an early symptom recognition, granting an optimal surgical timing.

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© Springer Nature Switzerland AG 2020

J. Zamorano et al. (eds.)Heart Valve Diseasehttps://doi.org/10.1007/978-3-030-23104-0_2

2. Evaluation of Patients with Heart Valve Disease

Jose Zamorano¹  , Ciro Santoro¹ and Álvaro Marco del Castillo¹  

(1)

Servicio de Cardiología, Hospital Universitario Ramón y Cajal, Madrid, Spain

Jose Zamorano

Email: [e-mail]

Álvaro Marco del Castillo (Corresponding author)

Keywords

EchocardiographyComputed tomographyMagnetic resonanceCatheterization

Echocardiographic Evaluation of Valvular Heart Disease

In the evaluation of patients with valvular heart disease (VHD) clinical history, physical examination and previous diagnostic studies are pivotal to frame the severity of this disease. Nevertheless, diagnostic imaging represents a necessary approach to a careful evaluation of concomitant valve lesions and to screen other lesions that might be misdiagnosed as VHD such as subaortic membrane, ventricular septal defect or dynamic obstruction. Echocardiography is considered the preferred diagnostic modality to evaluate valve disease, providing information on both structure and function of the valves. Cardiac magnetic resonance (CMR) and computed tomography (CT) may be of great help in selected cases, especially in patients with suboptimal acoustic windows and in those in whom detailed data on anatomy of the valves and its relationship with surrounding structures are needed. Cardiac catheterization played a significant role in the evaluation of patients with VHD during the past decades. However, the global use of catheterization for this purpose has been progressively abandoned in favour of less invasive assessment methods with a comparable reliability. Nevertheless, it is still used in some cases, such as (I) coronary anatomy assessment in patients that are undergoing valve surgery; (II) Patients with suboptimal echocardiographic imaging; (III) Patients in which diagnosis remains uncertain despite non-invasive imaging; (IV) Pulmonary hypertension assessment.

Assessment of Valve Anatomy

Anatomic assessment of all four valve is mandatory in the assessment of patient with this condition [1]. In some cases, the evaluation of valve anatomy must be incorporated in the anatomic evaluation with other clinical information such as age of the patients, concomitant valve and heart structural changes, associated immune-mediated or infective process, to determine etiology of the disease. Typical anatomy features of different disease process are easily assessed by two-dimensional (2D) echocardiography . Using different planes scan it is possible to detect the involved valve and the mechanism of valve disease (Fig. 2.1a, b).

../images/460505_1_En_2_Chapter/460505_1_En_2_Fig1_HTML.png

Fig. 2.1

(a) Mitral valve seen from 4C apical view. (b) Mitral valve seen from PLAX view

When acoustic window is suboptimal evaluation through transesophageal echocardiography (TEE —Fig. 2.2a, b) may help to increase the quality of the imaging avoiding acoustic obstacles of chest wall and lungs, especially when posterior structures must be visualized. Indeed, TEE is fundamental to locate scallops prolapse of the mitral valve, chordal rupture or to exclude presence of thrombus in left atrial and appendage. TEE is also useful to detect paravalvular leak in presence of prosthetic mitral valve, due to the opportunity to see the regurgitant jet without the acoustic interference of the prosthesis itself.

../images/460505_1_En_2_Chapter/460505_1_En_2_Fig2_HTML.jpg

Fig. 2.2

(a) 4C apical view of a patient with a poor acoustic window. (b) TEE of the same patient

In mitral stenosis the presence of commissural fusion, thickening of leaflet tips and sub valvular chordae are considered aspects pathognomonic for rheumatic disease. On the contrary, voluminous calcifications of the mitral annulus that extend to leaflet bases with preserved excursion of the leaflet tips are typical features of degenerative function mitral stenosis especially in elderly patients.

In aortic stenosis identification of specific etiology may be more complicated. Independently from etiology a stenotic aortic valve appears thickened with reduced systolic excursion with a resulting star-shaped orifice. Rheumatic aortic stenosis may result in commissural fusion and constantly associated with mitral involvement. Aortic stenosis due to bicuspid valve , usually seen in young patients, is diagnosed after the deformed aspect in systole with fusion of one of the commissures [2, 3]. Degenerative aortic stenosis is the main cause of aortic stenosis in the elderly population and is characterized by diffuse calcification of the leaflets. In some cases, transesophageal echocardiography is crucial to determine the etiology of aortic stenosis since the transthoracic visualization of the aortic leaflet can be insufficient especially when in presence of extended calcification.

Differently from stenotic valve disease , regurgitant lesions may be provoked by different component of the valve apparatus resulting in a wide range of abnormalities. Mitral regurgitation may result as a malfunction of one or more components of the mitral valve apparatus. Echocardiographic evaluation of mitral annulus, leaflets, sub valvular apparatus, papillary muscle, left ventricular dimension and function is crucial to define the etiology of the lesion. Thanks to its position within the heart and its dimension, mitral valve can be easily studied by standard 2D echocardiography limiting the TEE to evaluate complicated lesion such as Barlow’s disease or in case of pre-procedural or intra-procedural assessment for percutaneous intervention.

Similarly, aortic regurgitation may be caused generally by valve leaflets dysfunction or aortic root dilation. 2D echocardiographic evaluation allows the assessment of leaflets abnormalities (aspect and numbers of cusps) and dynamics besides aortic root dimension. Echocardiographic visualization of the leaflets can help to diagnose irregularity of the valve resulting from endocarditic process or commissural thickening following to rheumatic disease. The evaluation of the aortic root could also lead to specific diagnosis such as Marfan syndrome, if un-tapered sino-tubular junction is seen, or autoimmune arteritis disease when in presence of a concomitant systemic immune-mediated signs.

In right side valve disease are usually secondary to left-side valve disease or due to residual congenital disease (e.g. Ebstein anomaly or pulmonic stenosis). Right side valves are not easily visualized by echocardiographic evaluation due to the posterior position of the right heart, so usually clinical features, transesophageal assessment and/or different imaging technique are needed for diagnostic interpretation.

Evaluation of Stenosis Severity

The sizing of the valve area through echocardiographic assessment allows a close esteem of the effective anatomic valve area independently from flow rate. Planimetry of both mitral and aortic valve is obtainable with 2D echocardiographic evaluation from a parasternal long axis view. Aortic valve anatomy is more complex though, due to a non-planar star-shaped orifice associated with superimposed calcification that makes planimetry tricky. 3D measurement of both mitral and aortic planimetry is suggested in selected cases due to its improved reliability and accuracy.

Under normal conditions, an open valve should offer almost no resistance to flow, allowing for an instant equalization of pressures at both sides. However, a diseased valve is often associated with restrictive opening, which implies a gradient across the valve: pressure is higher in the chamber before the valve.

Echocardiographic evaluation of transvalvular flow allows to determine direct assessment of pressure gradient and functional assessment of the stenotic orifice using continuity equation. Transvalvular pressure gradient can be derived using the Bernoulli simplified equation:

$$ \varDelta P=4{{\mathrm{V}}_{\mathrm{max}}}^2 $$

computed by velocity measurement using continuous-wave Doppler (CW) . To avoid underestimation of transvalvular pressure gradient particular care must be payed to orient the CW parallel to the direction of the blood flow. Other limitations that have to be taken into account consist in beat-to-beat variability due to respiratory motion, irregular rhythms and inadequate flow signal due to poor acoustic windows.

Valve area can be calculated by the continuity equation by using the principle of conservation of mass that results in the formula:

$$ {\displaystyle \begin{array}{l}{\mathrm{Area}}_{\mathrm{stenotic}\ \mathrm{orifice}}=\left({\mathrm{LVOT}}_{\mathrm{area}}\times {\mathrm{VTI}}_{\mathrm{proximal}}\right)/\\ {}{\mathrm{VTI}}_{\mathrm{stenotic}\ \mathrm{orifice}}\end{array}} $$

using CW to measure VTIstenotic orifice, LVOT diameter from parasternal long axis to calculate LVOTarea and the pulsed wave (PW) Doppler to calculate VTIproximal.

The velocity ratio is a simplified version of the continuity equation and is represented by the formula:

$$ {\mathrm{V}}_{\max \kern0.375em \mathrm{LVOT}}/{\mathrm{V}}_{\max \kern0.375em \mathrm{aortic}\kern0.375em \mathrm{orifice}} $$

This formula excludes the measurement of cross-sectional area of the left ventricular output tract making this ratio independent from size of the patients and from errors due to cross sectional area measurement.

In case of atrioventricular flow were the emptying is a passive process and depend largely on the area