Left ventricular size, chamber function, and mass

M-mode echocardiography (echo) measurements of end-diastolic and end-systolic LV minor diameters and end-diastolic posterior and septal wall thicknesses permit direct calculation of LV fractional shortening and relative wall thickness (RWT), and by assuming spherical ventricular geometry, LV volumes, ejection fraction, and mass ( Table 170.1 ). Concentric hypertrophy is defined as increased LV mass (> 95 g/m ² for females, > 115 g/m ² for males) and a RWT greater than 0.42, whereas concentric remodeling is defined as an increased RWT with a normal LV mass index. Increased LV mass with a normal RWT characterizes eccentric hypertrophy, which may be seen later in the course of hypertensive heart disease. Although temporal and spatial resolutions are excellent, M-mode is limited in that a one-dimensional “ice pick” view of the heart is produced, which is suitable only for ventricles with uniform geometry and wall motion; moreover, unrealistic spherical geometry is assumed when either the Teichholz or cubed formula is used, and coupled with the potential for tangential imaging, overestimations of volume and mass result. Two-dimensional (2D) echocardiography overcomes many of these limitations but increases measurement complexity, requires epicardial definition, and is not free of the need for geometric assumptions or errors owing to foreshortened apical views (see Table 170.1 ). Thus, although accuracy is increased, volumes and mass are underestimated and reproducibility remains problematic. In contrast, real-time three-dimensional (3D) echocardiography (RT3DE) accurately and reproducibly measures LV volumes, ejection fraction, and mass when compared to the reference standard, cardiac magnetic resonance imaging. However, the relatively low temporal and spatial resolution and limited sector size remain barriers to the implementation of RT3DE in daily clinical practice.

Ultrasound tissue characterization using videodensitometry or integrated backscatter detects ultrastructural changes in the hypertrophied left ventricle and is a marker of increased fibrosis, altered collagen architecture, and early myocardial dysfunction. LV hypertrophy in hypertensive patients is associated with reduced cyclic variation of integrated backscatter, and regression of LV mass with blockade of the renin-angiotensin system may normalize the abnormal ultrasonic backscatter parameters.

LV hypertrophy is also accompanied by abnormal coronary flow reserve. Reduced coronary flow reserve in hypertensive patients may be detected using either transthoracic Doppler assessment of the left anterior descending (LAD) coronary or intramyocardial velocity before and after hyperemic stimulation with adenosine or dipyridamole. Although LAD flow can be reliably obtained, high-frequency transducers (4 to 8 MHz) with dynamic pulse repetition frequency and adequate time-spatial resolution are needed to adequately visualize the intramyocardial arterioles. However, the procedure is time consuming and requires expertise, and measurements are restricted to the LAD territory. Coronary flow reserve has also been measured with quantitative myocardial contrast echo by analysis of microbubble refilling curves in an intramyocardial region of interest, but this technique has not found application in the clinic.

Cardiac mechanics

Left ventricular systolic function as assessed by LV fractional shortening or ejection fraction is often normal or increased in patients with hypertension. However, these indices measure endocardial motion and therefore assess chamber mechanics, not myocardial mechanics. In contrast, LV midwall shortening, which more accurately reflects sarcomeric shortening, is reduced in hypertensive hypertrophy and/or concentric remodeling ( Table 170.2 ). Similarly, systolic annular tissue Doppler velocity (Sm) and deformational indices (i.e., strain, strain rate) are often reduced in hypertensive patients with normal or increased LV ejection fraction.

Abnormalities of LV longitudinal systolic deformation are seen both in pre-hypertension and early in the course of hypertension, whereas circumferential and radial strains are similar to hearts of both athletes with physiological hypertrophy and control subjects. Reduced global area, longitudinal, and radial (but not circumferential) strains measured with RT3DE are reported in hypertension and are independently correlated with blood pressure and LV mass index. However, rotational indices (twist, rotation, torsion) during systole remain normal or are increased in hypertensive patients with normal to increased LV ejection fraction and may represent a compensatory mechanism for the reduced longitudinal myocardial shortening associated with hypertension. Although hypertensive patients with concentric hypertrophy and concentric remodeling have increased torsional dynamics, torsion is reduced in the more advanced stage characterized by eccentric hypertrophy.

LV diastolic dysfunction, one of the earliest abnormalities of hypertensive heart disease, may occur in the absence of left ventricular hypertrophy and may help risk stratify patients with hypertension. Doppler waveforms of transmitral and pulmonary venous flows coupled with mitral annular tissue Doppler during early diastole (E′) and left atrial volume measurements are commonly used to describe patterns of impaired relaxation, pseudonormal, and restrictive filling (grades I through III, respectively), reflecting abnormalities in the rate of LV relaxation, LV diastolic passive stiffness, and left atrial pressure. However, these indices are load dependent, and because they measure phenomena after isovolumic LV relaxation (i.e., after mitral valve opening), they are influenced by left atrial pressure. In addition, tissue Doppler of mitral annular velocities assumes that a measurement at a single (or multiple) site accurately represents global LV relaxation. Global strain rate during isovolumic relaxation (SR _IVR ) correlates with hemodynamic indices of LV relaxation, and the ratio of transmitral E velocity to SR _IVR predicts LV filling pressures more accurately than E/E′.

Deformational and torsional indices during diastole have also been described in hypertensive patients. The ratio of early to late diastolic longitudinal segmental strains and strain rates are reduced in symptomatic hypertensive patients (and indeed may predict symptomatic status) with diastolic dysfunction and are correlated with relative wall thickness and LV mass index. A promising measure involves torsional dynamics during early diastole. Untwisting (or recoil) represents the release of restoring forces that develop during systole and provides an accurate estimate of LV isovolumic relaxation. The time to peak negative twist velocity is prolonged, and early diastolic untwisting and untwisting rate are reduced pari passu with LV mass index.

Arterial dynamics

Hypertension accelerates age-related arterial stiffness, an important predictor of cardiovascular morbidity and mortality. Arterial stiffening requires the LV to generate greater forces and, by ventricular-vascular (V-V) coupling (i.e., the matching of LV ejection with the systemic vasculature), increases LV end-systolic stiffness and reduces contractile efficiency. Arterial stiffening results in an increase in the speed and magnitude of reflected waves, which amplifies late systolic aortic pressure (i.e., LV afterload); the pulse pressure widens and pulsatile shear increases, contributing to structural changes in the arteries, LV hypertrophy, diastolic dysfunction, subendocardial ischemia, and reduced cardiac reserve. Echocardiographic assessment of arterial dynamics has been validated against and complements the techniques of pulsed wave velocity and analysis of augmented central pulse pressure using tonometry, arguably the gold standard methods used to measure arterial mechanics.

M-mode measurement of aortic diameters and tissue Doppler strain imaging (tissue velocity and radial strain) of the thoracic aorta have been used to analyze aortic stiffness (reduced velocity and strain denote increased stiffness), and 2D and 3D echo have been used to analyze arterial elastance (a measure of the arterial input impedance) and ventricular-vascular coupling ( Table 170.3 ). Using these techniques, increased arterial stiffness and reduced aortic wall strain in hypertensive patients have been shown to be associated with LV hypertrophy, diastolic dysfunction, and increased pulse pressure. Progressive vascular stiffening in hypertensive patients measured with brachial-ankle pulse wave velocity is associated with impairment of speckle-tracking echo-determined systolic (reduced global LV longitudinal strain) and diastolic (reduced early LV diastolic strain rate) myocardial function and attenuation of compensatory (i.e., increased) torsion. M-mode echo-determined arterial stiffness (aortic strain and distensibility) was shown to correlate well with pulsed wave velocity and to be associated with resistant, but not controlled hypertension. 2D echo coupled with radial artery applanation tonometry has been used to demonstrate changes in arterial elastance (Ea, end-systolic pressure/stroke volume), ventricular end-systolic elastance (Ees, end-systolic pressure/end-systolic volume), and V-V coupling (Ea/Ees) after chronic antihypertensive therapy from a coupling ratio that maximized cardiac output to one that optimized mechanical work efficiency. Finally, measurement of Ea, Ees, ventricular-vascular coupling, and systemic arterial compliance (stroke volume/pulse pressure) were shown to be feasible with RT3D echo, but measurement accuracy, reproducibility, and the ability to predict sequelae of hypertension remain to be determined.

Pathophysiology

Death and disability due to cardiac dysfunction are perhaps the most common complications of diabetes mellitus (DM). DM can cause pathophysiologic changes in the heart both directly, through its effects on the myocardium, such as through deposition of glycosylation products, and secondarily, through its effects on the coronary circulation and on the cardiac autonomic nerves. In addition, DM can exacerbate these myocardial and coronary processes through its well-known association with lipid disorders and hypertension, often as part of the metabolic syndrome . DM can produce and also exacerbates cardiac changes that accompany the aging process—for example, loss of cardiac myocytes with resultant swelling or hypertrophy in remaining myocytes, resulting in left ventricular (LV) remodeling, characterized by hypertrophy and increased wall thickness (concentric LV remodeling or hypertrophy). In addition, collagen deposition, a repair mechanism, causes further derangement of the myocardium, contributing to reduced LV function. Metabolic disturbances that are characteristic of DM directly and indirectly result in myocyte loss, myocyte hypertrophy, collagen deposition, and fibrosis. A DM-associated microangiopathy also contributes to this decline in cardiac muscle function, or diabetic cardiomyopathy. This microangiopathy is associated with endothelial changes and oxidative stress, accompanied by a depletion of endothelial progenitor cells.

Time course of diabetes mellitus: anatomic and echocardiographic overview

Table 171.1 summarizes the progressive abnormalities of LV anatomy and systolic and diastolic function that occur during the early, intermediate, and late stages of diabetic cardiomyopathy. In the early stages of DM, the cardiac tissue appears to be relatively normal without fibrosis or hypertrophy of the myocytes. In the intermediate stage of DM, advanced glycosylation products, fibrosis, and hypertrophy of the myocytes all cause a decrease in LV relaxation and possibly compliance as well as resting LV diastolic function. In the later stage of DM, cardiac remodeling has occurred, leading to increased cardiac mass, concentric LV hypertrophy, increased volume, and decreased LV compliance. Echocardiographically, in the early stages of DM, although the heart may appear anatomically normal, changes reflecting mild systolic and diastolic dysfunction are apparent when examined via exercise tissue Doppler imaging (TDI) and resting speckle tracking echocardiographic (STE) assessment of strain and strain rate. In the intermediate stage, early LV and LA anatomic changes, a decrease in systolic function with exercise and abnormalities in resting diastolic function (Grade 1 and possibly Grade 2) become evident. In the late stages of DM, cardiac anatomic remodeling is evident and is accompanied by more advanced LV diastolic function and possibly decreased resting LV ejection fraction (EF).

Left ventricular systolic function

The earliest manifestations of LV systolic dysfunction in DM (see Table 171.1 ) are generally decreases in peak global longitudinal strain (GLS) and strain rate as well as in peak LV systolic annular tissue-Doppler velocity (with exercise and possibly at rest). Each of these measures may be reduced before any traditional echocardiographic (echo) measurements, including measures of LV diastolic function. The advent of STE has afforded clinicians the ability to determine whether latent cardiac dysfunction is present using either exercise or dobutamine stress. This preclinical dysfunction can, through the use of STE, be assessed before more advanced diabetic cardiac dysfunction becomes apparent ( Fig. 171.1 ). It has been suggested that abnormal GLS and strain rate may precede abnormalities in circumferential strain and strain rate. The decrease in longitudinal strain has been reported to correlate with the duration of the DM. Furthermore, as DM progresses to its later stages, there is a progression to reduced exercise-induced and, finally, resting LV ejection fraction.

Examples of longitudinal systolic strain and diastolic functional assessment in three male patients with diabetes mellitus with normal longitudinal systolic and diastolic function ( A ), longitudinal systolic dysfunction and normal diastolic function ( B ), and longitudinal systolic dysfunction and grade II diastolic dysfunction ( C ). LS, Longitudinal strain.

(From Ernande L, Bergerot C, Rietzschel ER, et al. Diastolic dysfunction in patients with type 2 diabetes mellitus: is it really the first marker of diabetic cardiomyopathy? J Am Soc Echocardiogr 2011;24:1268-1275.e1.)

Left ventricular diastolic function

The earliest changes in diastolic function detected in DM (see Table 171.1 ) are decreases in exercise-induced mitral annular E′, in E′/A′ ratio, and in peak global early diastolic strain rate. Grade 1 diastolic dysfunction is characterized by delayed relaxation of the myocardium, that is, an increased isovolumic relaxation time (IVRT), accompanied by decreased peak transmitral E wave velocity and a reduced E/A ratio. Atrial strain has also been shown to be decreased in patients with DM compared to control patients and represents another marker in the diagnosis of subclinical DM as well as in the determination of disease progression ( Fig. 171.2 ).

Left atrial strain curves obtained from the apical four-chamber view in four example patients representative of the control, hypertensive, diabetic, and hypertensive plus diabetic study groups.

(From Mondillo S, Cameli M, Caputo ML, et al. Early detection of left atrial strain abnormalities by speckle-tracking in hypertensive and diabetic patients with normal left atrial size. J Am Soc Echocardiogr 2011;24:898-908.)

Right ventricular function

DM is associated with subclinical right ventricular (RV) systolic and diastolic dysfunction—including reduced peak systolic strain rate and peak early diastolic strain rate—in the basal and apical segments of the RV free wall. Furthermore, diabetic patients manifest impaired diastolic function, and particularly impaired relaxation, in both ventricles before the development of systolic dysfunction. These changes in RV function have been attributed to the effects of DM on myocardial function in addition to ventricular interdependence.

Aortic valve and aortic elasticity

In addition to the anatomic changes noted, DM is a risk factor for aortic stenosis (AS). In patients with moderate calcific AS over a 2.5-year follow-up period, a greater mean decrease in aortic valve area in diabetics (0.25 cm ² /year) compared with nondiabetics (0.14 cm ² /year, P = 0.0016) has been reported. In patients with AS, DM exacerbates hypertrophic remodeling produced by pressure overload—that is, increased LV mass, concentric LV wall thickening, and larger cavity dimensions, along with reduced systolic strain. Furthermore, the elasticity of the aorta may be diminished and stiffness increased in DM, serving to diminish organ perfusion.

Can echocardiography be used to determine efficacy of therapy?

Echocardiography can be an important tool in the assessment of disease progression and the effects of therapy in DM. Various DM treatment strategies have been evaluated using echocardiography. For example, metformin and rosiglitazone have been demonstrated to have positive effects on cardiac remodeling. Pioglitazone, however, has not been demonstrated to have an effect on cardiac function.

Novel measures of cardiac function in diabetes: twist and torsion

There is early work that suggests the utility of STE in evaluating twist and torsion as measures of disease progression in DM. Reduced twist and untwisting have been previously identified as a consequence of LV hypertrophy, which is seen in the intermediate-to-later stages of DM. LV systolic twist is defined as the difference between apical and basal rotations, and LV torsion is twist normalized to the distance between apex and base. Peak LV torsion measured by echo has been reported to be significantly greater in patients with mild LV diastolic dysfunction (n = 45; 29.7 ± 9.0 degrees) compared with controls (n = 32; 15.6 ± 4.0 degrees), with normalization in moderate (n = 49; 19.3 ± 4.8 degrees) and severe diastolic dysfunction (n = 22; 17.3 ± 9.3 degrees). Normal rotation measured by magnetic resonance imaging (MRI) has been reported to be 10 ± 2.3 degrees at the apex and 4.4 ± 0.4 degrees at the base. In DM, torsion is reportedly increased while axial strain is reduced in patients with LV diastolic dysfunction. Importantly, changes in twist and torsion (reported using MRI) often precede a decrease in global systolic strain rate or exercise-related change in strain rate.

Epidemiology

Chronic renal disease is a major public health problem. The end-stage renal disease (ESRD) population is increasing in size. More than 26 million people (13%) in the United States have chronic kidney disease (CKD), and most are undiagnosed. Another 20 million are at increased risk of the disease. Cardiovascular disease is the leading cause of death in ESRD patients. Cardiovascular mortality is 5 to 30 times higher in dialysis patients than in individuals from the general population who are the same age, sex, and race. The total annual cost of treating ESRD in the United States was $26.8 billion in 2008. Chronic renal failure (CRF) patients have significant cardiovascular morbidities, including hypertension, left ventricular hypertension (LVH), congestive heart failure (CHF), calcification, and pericarditis. These conditions can be readily assessed and evaluated by echocardiography ( Tables 172.1 and 172.2 ).

Hypertension and/or Left Ventricular Hypertension

Hypertension is prevalent in CRF patients, reaching up to 90% in some published series. LVH is also a common finding among CRF patients. LVH has a prevalence of approximately 32% in patients with chronic renal insufficiency, and rises to approximately 75% at the time of initiation of dialysis therapy.

Major risk factors for the development of LVH include hypertension, increasing age, anemia, and chronic volume overload. Left atrial dilatation is increasingly recognized as an adverse prognostic factor in CKD patients. The etiology of left atrial dilation in CRF patients is multifactorial; these patients have diastolic dysfunction (which occurs in approximately 75% of those with stages 3–5 CKD), volume overload, and inflammation as etiologies.

Kidney transplantation has been shown to cause regression of LVH. In one study, 24 patients followed for 1 year after transplantation with serial echocardiograms had a reduction from 75% to 52.1% in the incidence of LVH ( Fig. 172.1 ).

Hypertensive heart disease. Ao , Aorta; LA , left atrium; LV , left ventricle; MAC , mitral annular calcification.

(From Otto C. Cardiomyopathies, hypertensive and pulmonary heart disease. In: Otto CM, ed. Textbook of clinical echocardiography , 5th ed, St. Louis: Saunders, 2013;245.)

Congestive Heart Failure

The incidence of CHF increases with declining renal function. The diagnosis of CHF in CKD patients is challenging because volume-overloaded CKD patients can have clinical signs, such as effort intolerance, fatigue, and edema. These signs are also present in non-CKD patients with CHF. Thus, echocardiography plays a key role in the evaluation of these patients, because LVH, diastolic and systolic dysfunction, and valvular and pericardial disease can be readily assessed using echocardiography. LV diastolic function is a frequent finding in CKD patients. Diastolic dysfunction is associated with the development of CHF and increased mortality. Myocardial fibrosis is one of the etiologies for the development of diastolic dysfunction. CKD patients are exposed to several factors that help facilitate the development of CHF. Volume overload is related to excess fluid accumulation due to reduced renal function. Pressure overload develops because of hypertension and vascular stiffness. The heart is subjected to increased LV wall stress from these factors. The myocardium is exposed to various factors that lead to dysfunction and subsequent cardiac abnormalities. Hemodialysis can result in progressive LV systolic dysfunction.

CKD patients develop CHF and other cardiovascular disorders because of the cardiorenal syndrome. Cardiorenal syndromes are disorders of the heart and kidneys, in which acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other ( Fig. 172.2 and Box 172.1 ).

The cardiorenal syndrome. BMI , Body mass index; Ca , calcium; CKD , chronic kidney disease; EPO , erythropoietin; H ₂ O , water; LDL , low-density lipoprotein; Na , sodium; Phos , phosphorus.

(From Ronco C, et al: Cardiorenal syndrome. J Am Coll Cardiol 2008;19:1527–1539.)

Box 172.1

Definition and Classification of the Cardiorenal Syndromes

Chronic Cardiorenal Syndrome (Type 2)

• 
  

  Chronic abnormalities in cardiac function leading to renal dysfunction

Acute Reno-Cardiac Syndrome (Type 3)

• 
  

  Acute worsening of renal function causing cardiac dysfunction

Chronic Reno-Cardiac Syndrome (Type 4)

• 
  

  Chronic abnormalities in renal function leading to cardiac disease

Secondary Cardio-Renal Syndromes (Type 5)

• 
  

  Systemic conditions causing simultaneous dysfunction of the heart and kidney

From Ronco C, et al: Cardiorenal syndrome. J Am Coll Cardiol 2008;19:1527-1539.)

Pericarditis

Renal failure is associated with pericardial effusions, pericarditis, and (rarely) chronic constrictive pericarditis. Up to 20% of renal failure patients can develop pericardial disease. Echocardiography is the diagnostic test of choice to diagnose pericardial effusions. There are two major types of CRF-related pericardial disease. Uremic pericarditis occurs in 6% to 10% of patients with renal failure before dialysis begins or afterwards. The etiology is inflammation of the pericardium, which is correlated with the degree of azotemia. Dialysis-associated pericarditis has been reported in up to 13% of patients who are on maintenance dialysis. The etiologies of dialysis-associated pericarditis include inadequate dialysis and/or fluid overload. Treatment includes intensive hemodialysis. Serial echocardiograms are recommended to follow-up on the size of the effusion ( Fig. 172.3 ).

Pericardial effusion on echocardiography. Ao , Aorta; DA , descending aorta; LA , left atrium; LV , left ventricle; PE , pulmonary embolism; RV , right ventricle.

(From Otto C, Pericardial disease. In Otto CM, ed. Textbook of clinical echocardiography , 5th ed, St Louis: Saunders, 2013; 256.)

Mobile Calcific Calcinosis of the Heart

Calcinosis is a known complication of ESRD. The heart is subjected to abnormal calcification in ESRD, including extensive calcification of the valves and the mitral valve annulus. Arterial calcification is another cardiac manifestation of ESRD. Mobile cardiac calcinosis has been identified by echocardiography as another cardiac syndrome associated with ESRD. Calcinosis has been associated with strokes and peripheral emboli ( Fig. 172.4 ).

A and B, Mobile cardiac calcific calcinosis.

(Modified from Kubota H, Fujioka Y, Yoshino H, et al. Cardiac swinging calcified amorphous tumors in end-stage renal disease patients. Ann Thorac Surg 2010;90:1692-1694.)

Guidelines

Pathophysiology

Far from being a passive storage site for energy, adipose tissue synthesizes and releases proinflammatory markers into the bloodstream, instigating a low-level, chronic inflammatory state, which in turn may induce insulin resistance and endothelial dysfunction ( Fig. 173.1 ). Extensive capillary networks surrounding adipose tissue require extra blood flow that can ultimately add to the total circulatory volume. An increase in skeletal muscle mass also accompanies obesity to support the resulting increase in body weight. Except during the fasting state, skeletal muscle, with its higher metabolic activity, has significantly higher resting blood flow than the adipose tissue. This extra blood flow, or preload, adds further to the total circulatory blood volume, resulting in higher left ventricular (LV) volume and higher cardiac output primarily through increase in stroke volume. Ensuing increase in left ventricular mass (LVM), eccentric and concentric, is also an independent predictor of CV risk with a 1.3-fold risk for death or CV events for each mild, moderate, and severe category of LVM. Increasing adipose tissue in the epicardium and myocardium leads to myocyte degeneration, pressure-induced atrophy, and conduction defects and also contributes to a higher LVM. The frequent association of hypertension with obesity adds to LV dilatation and hypertrophy.

Summary of potential pathways by which obesity can influence cardiac and vascular structure and function. The broken lines indicate a significant association.

Lean body mass, primarily composed of organs and skeletal muscle, is the foremost determinant of energy requirements and correlates strongly with LVM. Conversely, increased adipose tissue is primarily responsible for adverse metabolic and energy-related changes that may alter myocardial function. Accumulation of adipose tissue in and around (epicardial) the heart may add to diastolic and systolic ventricular dysfunction. Although congestive heart failure in obese individuals may occur as a result of either diastolic or systolic dysfunction, systolic dysfunction, when measured only by left ventricular ejection fractions (obesity cardiomyopathy), is rare with obesity alone. Diastolic dysfunction linked to obesity is seen independent of LVM. The active myocardial relaxation is a result of calcium homeostasis and myocardial energetics. A lower cardiac energetics, as measured by phosphocreatine-to-ATP ratio, at rest and during dobutamine stress, may help explain the lower LV peak filling rates associated with obesity.

Cardiac assessment by echocardiography

Echocardiographic assessment in obesity begins with an assessment of the subject’s age, gender, weight, height, and blood pressure, as these factors may affect measured parameters associated with obesity. Clinical information including history and physical examination helps to ascertain the etiology of abnormalities seen on imaging and to differentiate individuals with associated comorbidities, aortic stenosis, and hypertrophic cardiomyopathy. Obese subjects will often present with technical challenges including poor acoustic windows that limit the ability to obtain acceptable studies. The inferior vena cava is often compressed. To ensure the accuracy of measurements, contrast-enhanced studies, particularly in the severely obese, may help better delineate LV endocardial and LA borders ( Fig. 173.2 ).

Apical image of the left ventricle (LV) in an obese patient. A, Standard two-dimensional imaging. B, Contrast-enhanced image in the same patient shows improved LV endocardial delineation.

When indexing the chamber sizes, it should be implicit that LA and LV growth may not be linear to the body surface area (BSA). Therefore, LA and LV sizes and LVM when not indexed may be higher as compared to nonobese controls, whereas with indexing these same measurements to BSA, the chamber sizes may appear normal or even be underestimated in severely obese individuals. Furthermore, if indexed measurements are made after significant weight loss, the chamber sizes are often overestimated when corrected for the (new) BSA, giving a false impression of increasing chamber size, particularly after bariatric surgery or liposuction. Similarly, exercise intervention that may have the consequence of improving LV filling properties may accompany an increase in skeletal muscle with little or no change in weight or BMI, resulting in confounding results if indexed measurements are used.

Indexing of LVM to body size by weight, height, or BSA had limited success because of the nonlinear relationship between body size and LVM. Allometric approaches, such as LVM/height ^2.7 , were found to be more sensitive indicators for future CV events, although there was an inverse relationship with height during the first 10 years of life. LVM/height ^2.7 tends to overcorrect for height by artificially increasing LVM index in short subjects and by lowering LVM index in tall subjects. Indexing with height ^1.7 may be superior in predicting CV outcomes and may also be a reliable indicator of obesity-associated LV hypertrophy in children.

Most obese individuals have mild LA and LV enlargement. Although obese subjects have higher blood volume, enlargement of the LA invariably signifies higher LV filling pressures. Both eccentric hypertrophy and concentric hypertrophy are reported. Generally, obese individuals have normal LV ejection fractions. A lower LV ejection fraction with obesity, or obesity cardiomyopathy, is extremely rare and invariably signifies a long-standing morbid obesity with associated comorbidities. The role of obstructive sleep apnea associated with obesity, if any, in the reported mild right ventricular enlargement and hypertrophy is unclear.

Doppler echocardiography

Increased preload that tends to increase the early diastolic filling at the mitral valve (E) may not manifest itself because of altered LV filling pressure in the setting of the higher LVM often seen in obesity. This would tend to lower the E wave velocity while significantly increasing the late diastolic transmitral blood flow (A) during atrial contraction, resulting in an overall lower E/A ratio. Thus diastolic function measurements based on the transmitral flow alone may be equivocal in certain obese subjects. In such instances, tissue Doppler diastolic velocity may be better.

At early stages of increasing weight gain and increasing stroke volume, alterations are seen in the myocardial velocities: a lower mitral annulus early diastolic velocity (e′) and a higher mitral annulus late diastolic velocity (a′). A lower e′ results in higher E/e′, reflecting higher LV filling pressures ( Fig. 173.3 ). Estimations of LV filling pressures by E/e′ and grading for diastolic dysfunctions are described in another chapter. Isovolumic relaxation time is frequently prolonged in obese individuals.

A, Transmitral inflow Doppler showing mild increase in “A” wave velocity, but normal E/A ratio preserved. B, Mitral annulus tissue Doppler from the same obese patient showing lower mitral annulus early diastolic velocity (e′) and a higher mitral annulus late diastolic velocity (a′).

Despite reported normal LV ejection fractions, LV systolic function, when measured by more sensitive methods such as tissue Doppler imaging, strain and strain rate, and calibrated integrated backscatter parameters, shows subclinical systolic dysfunction even in overweight (BMI 25 to 29.9) or mildly obese (BMI 30 to 35) individuals despite the fact that these individuals have a higher preload ( Fig. 173.4 ). BMI correlates significantly with average LV strain, e′ waves, and systolic myocardial velocities. Overweight and mildly obese individuals show reduced myocardial systolic and e′ velocity, reduced LV basal septal strain, and increased reflectivity by calibrated integrated backscatter, suggesting the presence of underlying myocardial fibrosis. In severely obese individuals (BMI > 35), additional reduction in the myocardial velocities is noted in the LV basal inferior and average LV strain. These indices may prove to be more useful in assessing cardiac changes with weight loss. As myocardial velocities change with increasing age, an awareness of the patient’s age is warranted during the proper interpretation of lower e′ and higher a′ waves.

Abnormal peak systolic strain in a patient with morbid obesity.

Although epicardial adipose tissue, a measure of visceral fat, can be measured by echocardiography, computed tomography may be a more sensitive modality as it provides higher spatial resolution. The use of dobutamine stress echocardiography in detecting coronary artery disease in a select group of obese patients can be safe and useful. Significant weight loss in obese subjects results in the lowering of LV volume, LVM, and LA volume. The reversal of diastolic dysfunction with weight loss, however, remains controversial.

Epidemiology

Currently, ARF and RHD are not commonly encountered in the United States and all first-world countries. When cases are encountered, they are usually found among immigrants. In contrast, the incidence of ARF in children ages 5 to 14 years worldwide is estimated to range from 300,000 to 350,000 per year. The majority of these cases are found in sub-Saharan Africa, but due to the paucity of epidemiological studies, accurate estimates of ARF are lacking. The highest documented rates of ARF and RHD in the world are in indigenous Australians.

Pathogenesis

ARF occurs following a GAS infection. In the absence of previous ARF and/or RHD, a small minority of individuals (0.3%–3%) with a GAS throat infection will develop ARF and/or RHD. The pathogenesis of ARF is complex and may be multifactorial. The general consensus is that the development of ARF requires a few key factors—a susceptible host, GAS infection with specific strains that are thought to be rheumatogenic (M subtypes 1, 3, 5, 6, or 18), an abnormal immune response, and environmental factors (e.g., poverty and overcrowding)—that contribute to this interaction ( Fig. 174.1 ).

Pathogenesis of acute rheumatic fever (ARF). GAS , Group A β-hemolytic streptococcus infection.

Acute rheumatic fever

Diagnosis

The modified Jones criteria offer an integrated clinical approach to improve the diagnosis of ARF and allow differentiation from other disorders that may mimic it ( Box 174.1 ). In recent years, it has been proposed that echocardiography should become the standard for diagnosing carditis. This has been debated for several years; currently, the diagnosis of carditis is still made by clinical assessment.

Box 174.1

Modified Jones Criteria *

* Data taken from Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. JAMA 1992;268:2069-2073.

for the Diagnosis of Acute Rheumatic Fever (updated 1992)

• •
  

  Evidence of a preceding streptococcal infection (throat culture or serology) with either two major criteria or one major and two minor criteria

  
  
• •
  

  Major criteria: Carditis, polyarthritis, subcutaneous nodules, erythema marginatum, chorea

  
  
• •
  

  Minor criteria: Prolonged PR interval on the electrocardiogram, arthralgia, fever, acute phase reactants (raised erythrocyte sedimentation rate or raised C-reactive protein levels).

There are several advantages of echocardiography, which include the identification of valvular regurgitation that is not detectable with clinical examination, detection of concomitant subclinical pericardial effusions and left ventricular dysfunction, and the differentiation of physiological murmurs from the pathology, especially in febrile or hyperdynamic states. The latter scenario can often lead to an incorrect conclusion that ARF may be present, as was the case in a study by Abernathy et al. The most important advantage of echocardiography is that it can identify an alternative diagnosis, such as mitral valve prolapse or congenital heart disease.

There are two major limitations to echocardiography being used as a diagnostic criterion. First, it is a relatively expensive examination that is not widely available in poorer communities where the prevalence of ARF is high. Second, unless end users of echocardiography have adequate training, misdiagnosis may easily occur, especially because adequately trained cardiologists or sonographers are unlikely to be working in rural and/or semirural areas.

The aim of echocardiography in assessing valvulitis in ARF is to integrate the anatomic abnormalities of the entire mitral valve apparatus with detection of pathological regurgitation ( Table 174.1 ). This is important, because pathological regurgitation needs to be distinguished from physiological regurgitation. The latter is usually not pansystolic; the color jet is often localized and extends less than 1 cm in dimension. To fully evaluate these two key features, the color jet needs to be evaluated in multiple views at standard technical settings, whereas color M-mode and continuous-wave Doppler of the regurgitant jet will aid in timing the duration of the regurgitant jet. This diminishes the likelihood of misdiagnosing physiological regurgitation as valvulitis.

Table 174.1

Echocardiographic Correlates of Pathological Abnormality in Acute Rheumatic Fever

Abnormality	Echocardiographic Features
Annulitis	Annular dilatation
Chorditis	Chordal lengthening/thickening
Valvulitis	Leaflet thickening, anterior mitral leaflet prolapse, nodules Pathological regurgitation: Pansystolic/pandiastolic regurgitation Jet area extending > 1 cm
Myocarditis	Left ventricular dysfunction out of keeping with the degree of valvular regurgitation
Pericarditis	Pericardial effusion

 

Morphological valve thickening may represent valvulitis, and may be focal or involve the entire leaflet tips. Vasan et al. reported nodules detected on the body or the tips of the leaflets in almost 25% of patients with ARF. They postulated that these nodules represent the echocardiographic equivalents of the verrucae seen either at surgery or in autopsy specimens. It is essential that the echocardiographer integrate the morphological abnormalities with Doppler evaluation of regurgitation ( Figs. 174.2 and 174.3 ; Video 174.1) within the correct clinical context to avoid several pitfalls in the diagnosis of ARF ( Box 174.2 ).

A, Left parasternal view demonstrating prolapse of the anterior leaflet of the mitral valve, with failure of coaptation of the anterior and posterior leaflet tips. B, Left parasternal view demonstrating an eccentric jet of mitral regurgitation due to prolapse of the anterior leaflet.

Left parasternal view demonstrating the prolapse of the anterior leaflet with prominent thickened chordae attached to both leaflets.

Box 174.2

Avoiding Pitfalls in the Diagnosis and Assessment of Acute Rheumatic Fever

Detecting Regurgitation

• •
  

  Differentiate physiological from pathological regurgitation.

  
  
• •
  

  Ensure all technical settings are correct

  
  
• •
  

  Evaluation must be performed using multiple views

  
  
• •
  

  Interpret findings judiciously when high-output states such as anemia and fever are present

  
  
• •
  

  Caution should be exercised when only Doppler regurgitation is found in the absence of other clinical features of acute rheumatic fever

  
  
• •
  

  Diagnosing isolated tricuspid or pulmonary regurgitation as evidence of carditis in the absence of left-sided involvement

Morphological Assessment and Measurements

• •
  

  Ensure correct gain settings and avoid harmonic imaging

  
  
• •
  

  Use high-frequency imaging, such as zoom mode to evaluate nodules

  
  
• •
  

  Differentiate true prolapse from leaflet malcoaptation, ideally avoiding sole assessment using an apical 4-chamber view

  
  
• •
  

  The presence of restricted leaflet motion may point to previous rheumatic involvement and is not a feature of de novo acute carditis

  
  
• •
  

  Diagnosing myocarditis as the cause of left ventricular dysfunction in the presence of hemodynamically significant valvular regurgitation

  
  
• •
  

  Detecting myocardial abnormality or pericardial effusion in the absence of valvular abnormality should be viewed with caution as evidence of rheumatic carditis

ARF most commonly affects the mitral and aortic valves; involvement of the tricuspid and pulmonary valves is uncommon. Mitral regurgitation (MR) is the most common lesion encountered in ARF; its mechanisms are multifactorial and should be carefully evaluated using echocardiography to identify the mechanisms at play, particularly in patients who may require surgery ( Fig. 174.4 ). Currently, the assessment and quantification of valvular regurgitation should be based on the American Society of Echocardiography guidelines on valvular regurgitation, despite the lack of modern studies on ARF that determine long-term outcomes based on using this approach.

Mechanisms of mitral regurgitation in acute rheumatic fever.

Identifying the severity of MR is of paramount importance, as is identifying the degree of left ventricular remodeling and ejection fraction. The impact of valvular regurgitation is usually commensurate with the degree of ventricular remodeling and dysfunction. Although myocarditis may occur, the major dysfunction is most often valvular related and can be reversed with surgery. Although the ejection fraction is a less reliable marker of contractile dysfunction in MR, identification of an abnormality using echocardiography may warrant surgery in some patients with worsening New York Heart Association functional class despite the absence of clinical heart failure. A second clinical scenario in which an integrated approach using echocardiography is effective is to determine if the degree of symptoms are commensurate with the degree of valvular and ventricular dysfunction. This is particularly important when concomitant fever and anemia may be present in young children or adults and may alter the hemodynamics. Assessment of the tricuspid valve and the degree of regurgitation is very important in patients undergoing left-sided valvular surgery because this may mandate a concomitant tricuspid annuloplasty.

Recurrent Acute Rheumatic Fever

The incidence of recurrent ARF following a strep throat infection is 50% in patients with a history of ARF compared with 0.3% to 3% in those who have never had ARF. The recurrence rate is highest in the first 5 years after the first episode of ARF and can be decreased by secondary prevention with penicillin. The 2004 World Health Organization report suggests that the presence of only two minor Jones criteria in combination with evidence of streptococcal infection are adequate for the diagnosis of ARF in this clinical context. These patients may have features of chronic rheumatic disease, such as diastolic doming of the anterior leaflet and shortened posterior leaflets with diminished leaflet motion, which are not found in ARF (Videos 174.2 and 174.3).

Rheumatic heart disease

Chronic RHD is chronic valvular dysfunction that may manifest as either purely stenotic, purely regurgitant, or as mixed lesions. The detection of clinically overt disease is not difficult; however, the identification of subclinical RHD and its milder forms in children and young adults can be challenging. The last decade has witnessed numerous echocardiographic studies on screening for RHD in various parts of the world. These studies have attempted to document the prevalence of RHD, but they have also been problematic due to the lack of standardized criteria for diagnosing RHD. Different definitions of RHD can result in dramatically different burdens of diseases in the same cohort. Recently, the World Heart Federation proposed guidelines for the diagnosis of RHD that were based on expert consensus in an attempt to standardize disease definitions. The details of these criteria should be consulted because they represent the minimum criteria to diagnose RHD.

Therapy

Conclusions

An understanding of the various spectrums of ARF and chronic RHD is essential to allow for correct diagnosis and intervention in these clinical scenarios. Echocardiography is an additive tool that, if used in a responsible and judicious manner, is additive to the clinical assessment of both ARF and RHD.

Etiology and pathophysiology

The etiology of SLE is unknown and is likely related to genetic, immunologic, environmental, and hormonal factors. Genetic factors play a role, with the most common predisposition occurring at the major histocompatibility complex in which genes that encode for antigen-presenting cells are affected. The derangement in adaptive immunity that forms the pathologic hallmark of SLE involves polyclonal B-cell activation, hypergammaglobulinemia, and autoantibody production that results in immune-complex formation with self-antigens. The production of these autoantibodies likely plays an important role in the pathogenesis of SLE, and their presence can be used in detecting the disease and in monitoring disease activity.

The classic Libman-Sacks valvular and mural lesions can either be active or healed. Active lesions more commonly seen in patients with recent disease onset may demonstrate focal necrosis, fibrinous clumps, and inflammatory mononuclear infiltrates, whereas healed lesions are often associated with calcification of the valves involved. Multiple mechanisms of valvular dysfunction may be operative in SLE ( Table 175.1 ), and the prevalence of cardiac involvement does not appear to be correlated with the severity of disease activity. The presence of antiphospholipid antibodies is associated with cardiac involvement according to a recent meta-analysis of echocardiographic studies in SLE patients. The importance of immune-complex deposition is highlighted by the deposition of C3 and immunoglobulin on direct immunofluorescence. Pericardial involvement is predominantly fibrinous in the acute phase and may become fibrous in the chronic phase. Myocardial involvement is nonspecific, and mononuclear invasion into the perivascular and interstitial space in addition to myocyte injury and associated fibrosis has been described. The myocardial dysfunction may be a consequence of the disease process, but it can also be caused by hydroxychloroquine therapy, which can be part of the treatment ; cardiac myocyte cytoplasmic vacuolization, interstitial fibrous connective tissue on light microscopy, and lamellar lysosomal structures on electron microscopy are the typical pathological findings. Coronary artery disease can result from intimal narrowing due to coronary arteritis or atherosclerosis.

Prevalence and outcome

The estimated incidence of SLE using data from Olmstead county, Minnesota, from 1980 to 1992, after adjusting for age and sex to the 1970 U.S. white population, was 5.56 per 100,000 individuals (95% confidence interval 3.93-7.19), which was more than triple the incidence in the 1950 to 1979 cohort. The overall prevalence of SLE using California and Pennsylvania hospital administrative databases is 107 to 150 per 100,000 individuals and approximately 1.8 to 2.5 per 1,000 women. In terms of cardiovascular morbidity and mortality, a large Toronto cohort from 1997 to 2005, with a 9-year follow-up, reported a standardized mortality ratio of 3.46 for patients with SLE. Cardiovascular morbidity in SLE consists of a two- to tenfold increase in risk of nonfatal myocardial infarction that is associated with prolonged hospitalization and increased in-hospital mortality. SLE patients have accelerated atherosclerosis, but they do not demonstrate a specific pattern of coronary involvement. Young women with SLE have a 2.5-fold increased risk of congestive heart failure (CHF) hospitalization and a 3.5-fold increase in CHF-associated mortality compared with CHF patients without SLE. It is prudent to aggressively manage the traditional risk factors of atherosclerosis in these patients.

Diagnostic approach

Patients with SLE often have multiple constitutional symptoms, including musculoskeletal and cutaneous manifestations, many of which are criteria for the diagnosis of SLE. Because much of the cardiac involvement in SLE is clinically silent, there should be a low threshold to initiate cardiac investigations in patients with suspected or proven SLE, irrespective of cardiac symptomatology. Echocardiography should be performed in SLE patients because of its ability to provide a comprehensive cardiac assessment.

Initial investigations include routine hematology and biochemistry to assess for cytopenias and renal function. Urinalysis and urine protein quantification should be performed when renal involvement is documented. Serology includes the use of the sensitive antinuclear antibody assay in addition to specific markers, such as the Smith antigen and double-stranded DNA. Inflammatory markers, such as the erythrocyte sedimentation rate or C-reactive protein may also be used to monitor disease activity.

Cardiac manifestations

The prevalence of cardiac abnormalities varies widely depending on the type of involvement ( Table 175.2 ). The pericardium is most frequently affected and pericarditis is usually present at the onset or during relapse of the disease. Pericardial effusion may be seen as a consequence of the serositis and is rarely symptomatic. In contrast, symptomatic effusion is associated with reduced survival. A recent study of 85 Chinese SLE patients found pericardial effusion in 22 (25.9%) patients and pericardial thickening in 5 (5.9%) patients. Therapy consists of nonsteroidal anti-inflammatory drugs for mild disease, whereas symptomatic effusion may require higher steroid doses in addition to pericardiocentesis.

There is a spectrum of SLE-associated myocardial involvement that ranges from increased left ventricular (LV) mass and excess hypertrophy to myocarditis. Longer disease duration and higher disease activity are associated with diastolic abnormalities and LV systolic dysfunction. Myocardial involvement can be clinically overt or silent, but this involvement needs to be recognized immediately because urgent therapy is indicated. Independent of the disease activity, myocardial dysfunction can occur as a result of the treatment with hydroxychloroquine; this dysfunction is potentially reversible with cessation of the drug. Hydroxychloroquine-associated cardiomyopathy is rare, but it typically manifests as restrictive cardiomyopathy with bi-atrial enlargement, a restrictive filling pattern, and thickened atrioventricular valves. Cardiac magnetic resonance imaging may show thickened LV walls with patchy late gadolinium enhancement.

Valvular heart disease from SLE can range from mild valvular thickening with normal function to overt valvulopathy with vegetations and severe regurgitation or stenosis ( Fig. 175.2 ). Galve et al prospectively followed 74 SLE patients for almost 5 years with echocardiography and demonstrated a prevalence of 18% of valvular abnormalities that consisted of two types of involvement, with vegetation in seven patients and valvular thickening with associated stenosis or regurgitation in six patients. The patients with vegetations were younger and had a shorter duration of disease activity.

A, Parasternal long-axis view showing the thickened mitral leaflets (6 mm in thickness) and restricted posterior mitral leaflet motion in a patient with lupus-associated valve disease. B, Short-axis view of the mitral valve showing a restricted posterior mitral valve leaflet with no commissural fusion. C, Apical 4-chamber view demonstrating mixed mitral valve disease with moderate mitral stenosis and regurgitation. D, Continuous wave Doppler of mitral inflow demonstrating increased transvalvular mitral gradients (see accompanying Video 175.2, A-C ).

Transthoracic echocardiography (TTE) is able to detect SLE-associated vegetations (Libman-Sacks endocarditis) with a sensitivity of 63% and a specificity of 58%. Transesophageal echocardiography (TEE) is superior to TTE in assessing SLE-associated valve disease. In a prospective study of 69 patients, TEE detected valve thickening in 51% of patients at baseline and 52% of patients during follow-up ; valve thickening was defined as more than 3 mm for the mitral or tricuspid valves and more than 2 mm for the aortic valve with involvement of at least two cusps or with associated regurgitation or vegetation. The diffuse thickening of leaflets and the lack of commissural fusion distinguish SLE-valve disease from rheumatic valvular disease. The potential incremental diagnostic value of real time three-dimensional TEE in this disease remains to be defined, because there are only case reports of its use in this entity. Early detection of SLE-related vegetations may prompt the early and aggressive use of corticosteroids and immune-suppressive therapy, because a recent study showed a strong association of this finding with cerebral microemboli and neuropsychiatric events. Surgical intervention, including valve repair or mechanical valve replacement, may be considered in patients with severe valvulopathy.

Patients with SLE have premature and accelerated atherosclerosis, which correlates with disease duration and activity, and coronary artery disease may arise through a number of mechanisms, including atherosclerosis and vasculitis, which have important therapeutic implications but are difficult to determine clinically. In addition, the pattern of cardiac involvement may be influenced by the effect of corticosteroid therapy. Increased aortic stiffness predates atherosclerosis in SLE patients and appears to be ameliorated with cyclophosphamide therapy, which suggests a role for aggressive immunosuppression. The prevalence of SLE-associated pulmonary hypertension is low; thus, screening echocardiography is not currently recommended for asymptomatic patients. The presence of high SLE disease activity, Raynaud phenomenon, anticardiolipin antibodies, serositis, and anti-ribonucleoprotein antibodies are predictors of pulmonary hypertension in SLE patients. These features can be used to identify high-risk patients who should be screened for pulmonary hypertension.

In summary, SLE affects all aspects of the cardiovascular system. Echocardiography plays an integral role in the diagnosis, monitoring, and management of SLE-associated cardiac disease.

Demographics and presenting symptoms

As mentioned previously, it may not be appropriate to categorize APS into primary and secondary forms, and the association of APS with SLE is well-recognized. In patients presenting with thrombotic events, 5% to 20% of them have APLAs , whereas the prevalence of APLAs is 1% to 10% in the general population and higher in patients with autoimmune diseases such as rheumatoid arthritis and SLE, which are 16% and 30% to 40%, respectively. The risk of thrombosis in patients with APLAs is variable and may be related to the type and magnitude of circulating autoantibodies. Asymptomatic patients with APLAs have a low annual rate of thrombotic events (0%-4%), and many of these patients can remain free of symptoms for years. Lupus patients with APLAs are at the high end of the range. Valvular heart disease occurs in approximately one third of the patients with APS, but it appears to be more frequent when associated with SLE.

The spectrum of clinical presentation can also be quite variable, ranging from asymptomatic APLA carrier to catastrophic APS with multiple small vessel thrombosis involving different organs and a mortality rate of 50% ( Fig. 176.1 ). Thrombosis is the hallmark of primary APS, with deep venous thrombosis and stroke or transient ischemic attack representing the most common venous and arterial events. Additional non-APS manifestations include cutaneous findings such as livedo reticularis, nephropathy, and cardiac abnormalities.

Clinical manifestations of antiphospholipid syndrome (APS). APLA , antiphospholipid antibody.

(Modified from George D, Erkan D. Prog Cardiovasc Dis 2009;52(2):115-125.)

Pathophysiology

APS is an autoimmune systemic disease characterized by the presence of APLAs, which are a family of heterogeneous autoantibodies directed against phospholipid-binding plasma proteins. Binding of APLAs to endothelial cells, which leads to thrombosis through the expression of tissue factor by monocytes and endothelial cells, as well as activation of the complement system, has been demonstrated. The inflammatory response may be a key component of APS. Platelets also play a role in the pathogenesis of APS through expression of glycoprotein IIb/IIIa and synthesis of thromboxane A2, which is a procoagulant. Because there are many carriers of APLA without clinical thrombotic events, a “two-hit hypothesis” has been proposed. An incident, such as minor injury, pregnancy, malignancy, or infection, is believed to be the required trigger to initiate the thrombotic process in susceptible carriers of APLAs.

Cardiac manifestations

Cardiac involvement in APS is diverse and includes ventricular dysfunction, ventricular hypertrophy, coronary thrombosis, premature atherosclerosis, intracardiac thrombi, valvular abnormalities, and pulmonary hypertension. Although none of the cardiac manifestations are specific enough to be included in the classification criteria (see Table 176.1 ), valvular disease can be the most striking feature in APS patients who have involvement of the left-sided valves, particularly the mitral valve ( Fig. 176.2 /Video 176.2, A-D ). Large, mobile valvular masses or vegetations can be seen in 10% to 40% of patients and may be difficult to differentiate from infective vegetations. In addition to valvular vegetations, focal or diffuse thickening of valve leaflets has been observed. In contrast to rheumatic valvular disease, significant valvular stenosis is uncommon, despite diffuse thickening of the valve leaflets, and valvular regurgitation is far more common due to improper coaptation that results from leaflet thickening or interference by vegetations. Destruction of the valve leaflets or annulus is absent, and this is a clear distinction from infective endocarditis. The morphologic features of valvular disease in APS are summarized in Box 176.1 .

Acute coronary syndrome can occur, but is far less common than cerebrovascular disease. Patients with APS have an increased risk of myocardial infarction, and APS should be considered in young patients with acute coronary syndrome with normal coronary arteries and no conventional atherosclerotic risk factors. Other important features of cardiac APS are intracardiac thrombi and biopsy evidence of myocardial microthrombosis without vasculitis. Dense spontaneous contrast, a precursor of thrombosis, in the left atrium has been demonstrated by transesophageal echocardiography (TEE) in 10% of APS patients with no apparent reason for stasis. Finally, pulmonary hypertension can occur as a result of recurrent pulmonary embolism from deep vein thrombosis or less commonly from in situ right ventricular thrombosis. Left untreated, right ventricular dysfunction and tricuspid regurgitation will invariably develop.

Management

Management of patients with APS depends on the clinical scenario, bearing in mind the wide spectrum of presentation. Asymptomatic carriers of APLAs without a previous obstetric mishap or thrombotic event require no therapy or probably aspirin only. Patients with a first venous thrombotic event with definite APS warrant anticoagulation with a target INR of 2.0 to 3.0, whereas patients with arterial events may require a higher target INR of 3.0 to 4.0, although there are no data that show the superiority of the higher anticoagulation target. Recurrent thrombotic events, despite therapeutic anticoagulation, are a treatment dilemma. A higher anticoagulation target (INR 3.0-4.0), concomitant use of an antiplatelet agent, low-molecular-weight heparin, or the new oral antithrombotic agents can be tried, but there are no trial data to support any of these strategies. The management of APS-associated valve disease is also uncertain. Espínola-Zavaleta et al reported a 1-year follow-up TEE study in which the antithrombotic therapy failed to modify the valvular lesions in 22 of 29 APS patients. New lesions occurred in seven patients despite the treatment. In a 5-year follow-up study by Turiel et al, the lack of efficacy of antiplatelet and antithrombotic agents on the APS-associated valvular disease was again demonstrated, although higher intensity anticoagulation appeared to reduce the incidence of new valve lesions. The role of antiinflammatory or immunosuppressive therapy with corticosteroids or cyclophosphamide in the treatment of valvular thickening or vegetations has not been properly evaluated. Valve replacement or valve repair with excision of valvular vegetations is associated with high perioperative mortality and morbidity, as well as a high rate of recurrence. A conservative approach with medical treatment is generally preferred, and lifelong anticoagulation is recommended in patients following valve surgery.

Carcinoid heart disease

Carcinoid heart disease is poorly understood, but it is believed to be due to the release of vasoactive substances from hepatic metastases into the systemic circulation. Plasma serotonin and urine (5-hydroxyindoleacetic acid) (5-HIAA) levels are higher in patients with carcinoid syndrome with carcinoid heart disease, and urine 5-HIAA greater than or equal to 300 μmol/24 hours is an independent predictor of the development or progression of carcinoid heart disease. Typical cardiac lesions are described as fibrous, plaque-like areas of endocardial thickening that lead to retraction of the valve leaflets, which causes a combination of stenosis and regurgitation. The tricuspid valve is the most commonly affected valve, followed by the pulmonic valve. The left side of heart is affected less commonly and usually in the setting of right-to-left shunts or bronchial involvement. Isolated left heart involvement may occur with primary bronchial carcinoid tumors. Carcinoid tumors metastasize to the heart rarely, in approximately 4% of patients, and may occur without valvular involvement. Patients with carcinoid heart disease often present with a murmur or symptoms of right heart failure. The onset of carcinoid heart disease is a marker for increased mortality in patients with carcinoid tumors, who have a median survival of 14 months.

Echocardiographic findings of tricuspid valve involvement

There is thickening of the ventricular aspect of the tricuspid valve that leads to shortening or fusion of the chordae. This leads to retraction and impaired coaptation of the valve leaflets, and results in regurgitation, and to a lesser extent, stenosis ( Figs. 177.1 and 177.2 /Videos 177.1 and 177.2). The leaflets may be affected asymmetrically, which results in an eccentric regurgitant jet. Right atrial and ventricular enlargement may also be present. Doppler examination reveals a “dagger-wave form” with early peak pressure and rapid decline ( Fig. 177.3 ), and may also demonstrate a prolonged pressure half-time consistent with tricuspid stenosis. Tricuspid stenosis and regurgitation severity are graded the same as in all other etiologies.

“Dagger-wave form” in the spectral Doppler signal of severe tricuspid regurgitation.

Tricuspid valve replacement

The development of symptomatic tricuspid regurgitation, moderate to severe right ventricular dilation, and right ventricular failure are associated with worse outcomes and are currently indications for tricuspid valve replacement. Recent data suggest that survival has improved over the past decades for patients with carcinoid heart disease who undergo earlier tricuspid valve replacement surgery.

Echocardiographic Findings of Pulmonic Valve Involvement

Involvement of the pulmonic valve is characterized by diffuse thickening of the arterial aspect of the valve leaflets, which results in reduced leaflet excursion and pulmonic stenosis, although pulmonic regurgitation may also be present ( Figs. 177.4 /Video 177.4, A and B , and 177.5 ). The use of Doppler enhances the detection of pulmonic valve involvement, especially if the valve is poorly visualized. Pulmonic stenosis and regurgitation are graded the same as in all other etiologies.

Spectral Doppler signal demonstrating severe pulmonic stenosis.

Pulmonic balloon valvuloplasty

Balloon valvuloplasty may be an option for patients with symptoms of pulmonic stenosis and elevated right-sided heart pressures to palliate symptoms and decrease the severity of tricuspid regurgitation and right-sided pressures. Balloon valvuloplasty has been reported to be successful in a handful of cases.

Introduction

The term amyloidosis (from Greek ἄμυλον: amylon , starch) was popularized in the nineteenth century by the German pathologist Rudolf Virchow, because of amyloid’s affinity for staining dyes with starch. It is clearly a misnomer because amyloid deposits are made of protein and not starch. In general, amyloidosis entails typically extracellular infiltration by one of a variety of misfolded proteins, which all share the same β-pleated sheet configuration. This misfolded protein configuration is visualized as apple-green birefringence under polarized light when tissue specimens are stained with Congo red. At least 27 proteins have been shown to be amyloidogenic. Amyloidosis is a multiorgan disorder; the degree of myocardial involvement varies because amyloidogenic proteins are not equally cardiotropic.

Amyloid light-chain (AL) amyloidosis is the most common form of amyloidosis. It results from accumulation of clonal immunoglobulin light chain deposits in multiple myeloma and from similar disorders. Only 10% to 15% of patients with multiple myeloma develop AL amyloidosis. Cardiac involvement occurs in up to one half of the patients with AL amyloidosis, and half of these patients will develop restrictive, nondilated cardiomyopathy. Only 5% of patients with AL amyloidosis present with isolated cardiac disease without other signs of systemic involvement.

Amyloid A (AA) amyloidosis is the result of deposition of serum amyloid A protein in patients with chronic inflammatory disorders, such as rheumatoid arthritis or inflammatory bowel disease. It primarily affects the kidneys, and rarely, the heart.

Amyloidosis related to transthyretin (TTR) deposits takes two forms: hereditary familial systemic amyloidosis and senile systemic amyloidosis.

Hereditary familial systemic amyloidosis is caused by autosomal dominant mutations in the TTR gene. Predominant features are peripheral neuropathy and autonomic dysfunction; cardiac involvement is less aggressive than that in AL disease. Isolated cardiac involvement of familial amyloidosis is associated with a mutation in the isoleucine 122 location.

Senile systemic amyloidosis is an age-related, slowly progressive form caused by deposition of amyloid derived from wild-type TTR. It primarily manifests as cardiac amyloidosis, but can also occur in multiple organ systems, including the brain, lung, liver, and kidney. It is less aggressive than AL amyloid.

Other amyloidogenic proteins

Other forms of cardiac amyloidosis include isolated atrial amyloidosis, which is caused by endocardial deposition of atrial natriuretic peptide, and hemodialysis-related amyloidosis, which is caused by the accumulation of β2-microglobulin in the setting of chronic uremia.

Clinical presentation

Clinically, cardiac amyloidosis is often first suspected as a discordant combination of a markedly increased left ventricular wall thickness on cardiac imaging (such as echocardiography) and the absence of electrocardiographic voltage criteria for left ventricular hypertrophy ( Fig. 178.1 ). In advanced amyloidosis, the electrocardiogram may even demonstrate low QRS voltage (≤ 0.5 mV in limb leads and ≤ 1.0 mV in precordial leads).

Echocardiographic and electrocardiographic appearance of amyloidosis. Note the apparent discordance between marked thickening of the left ventricular (LV) walls on transthoracic echocardiogram in the parasternal long-axis view (A) and the low QRS voltage on the electrocardiogram ( B ) (see accompanying Video 178.1, A ). LA , left atrium; RV, right ventricle.

Cardiac magnetic resonance imaging demonstrates characteristic diffuse, predominantly subendocardial enhancement on delayed images. This late enhancement may reflect fibrosis rather than amyloid deposition per se. The diagnosis of amyloidosis is confirmed by tissue biopsy, which is typically fat pad or endomyocardial biopsy ( Fig. 178.2 ).

Histopathology and magnetic resonance imaging of amyloidosis. Congo red stained tissue samples demonstrating amyloid deposits (arrow) in a fat pad biopsy specimen ( A ) and the myocardium ( B ). Note in ( B ) the extracellur location of amyloid deposits between myofibrils. C, Cardiac magnetic resonance–delayed images demonstrate diffuse late gadolinium enhancement throughout the left and right ventricles consistent with amyloidosis. The deposits are predominantly subendocardial (arrow) . LA , left atrium; LV , left ventricle; RA , right atrium; RV , right ventricle.

(Courtesy of Dr. Robert Donnino, New York University Division of Cardiology and Veterans Administration New York Harbor Healthcare System.)

Echocardiographic features

Functional Changes

Cardiac amyloidosis typically presents as heart failure with a preserved left ventricular ejection fraction (LVEF). Left ventricular diastolic dysfunction is the predominant feature and eventually progresses to restrictive cardiomyopathy ( Fig. 178.3 ). Although LVEF is preserved until terminal stages of the disease, subtle systolic dysfunction is detectable early on by strain imaging ( Fig. 178.4 ).

Diastolic dysfunction in amyloidosis. A , Tissue Doppler imaging at both the lateral and medial (septal) annulus demonstrates very low e′ velocities (< 5 cm/sec). B , Mitral inflow demonstrates a restrictive filling pattern: E/A greater than 2 and rapid E-wave deceleration (< 150 msec; dashed line ). C , Pulmonary vein flow velocity pattern demonstrates an S/D less than 1 pattern, which is indicative of elevated left atrial pressure. D , In this patient, mitral flow propagation velocity recording demonstrates paradoxically normal slope of the first aliasing velocity (dashed line) of 55 cm/sec. A normal slope of the first aliasing velocity does not exclude the diagnosis of amyloidosis.

Two-dimensional echocardiography and strain imaging of amyloidosis. A, Transthoracic echocardiogram in the apical 4-chamber view demonstrates typical features of amyloidosis: increased left ventricular (LV) and right ventricular (RV) wall thickness, biatrial enlargement, thickened valves (arrow) , pericardial effusion (asterisk) , and pleural effusions. B and C, Speckle-based longitudinal strain imaging demonstrates the phenomenon of apical sparing (relative preservation of apical longitudinal strain in the setting of otherwise decreased LV longitudinal strain). Global longitudinal strain in this patient was diminished to − 10% (see corresponding Video 178.4, A and B ). LA, left atrium; LPE , left pleural effusion; RA , right atrium; RPE, right pleural effusion.

Mitral tissue doppler

Pulsed wave tissue Doppler velocity measured at the septal annulus and lateral mitral annulus in the apical views reflects the longitudinal excursion of the mitral annulus in systole and diastole, and can provide evidence of systolic and diastolic impairment in the presence of a preserved ejection fraction. Normal values of tissue Doppler velocity at the septal and lateral mitral annulus typically decrease with age. For instance, at 60 years of age or older, normal early diastolic (e′) wave values are 10.4 ± 2.1 cm/sec at the septal annulus and 12.9 ± 3.5 cm/sec at the lateral annulus. In cardiac amyloidosis, very low e′ velocities are frequently seen; these velocities are typically less than 8 cm/sec (see Fig. 178.3 , A ). Furthermore, the ratio of early diastolic (e′) to late diastolic (a′) mitral annular tissue Doppler velocity (e′/a′ ratio) progressively diminishes as cardiac amyloidosis advances.

Mitral inflow pattern

With disease progression, the mitral inflow filling pattern progresses from impaired relaxation early on to the pseudonormal and restrictive filling pattern seen in advanced disease. Initially, isovolumic relaxation is impaired with an increased dependence on atrial contraction, which results in an impaired relaxation pattern with a decreased early diastolic flow across the mitral valve (E wave) relative to the atrial (A) wave (E/A ratio < 1 and e′/a′ < 1).

As myocardial infiltration progresses, left ventricular wall compliance decreases and left atrial pressures increases; this initially leads to a pseudonormal inflow pattern (1 < E/A < 2 with e′/a′ < 1) and then to a restrictive inflow pattern with E/A greater than 2, E-wave deceleration time less than 150 msec, and a very low e′ (see Fig. 178.3 , B ). Elevated mid-diastolic flow (> 20 cm/sec) can also be indicative of elevated left atrial pressure and advanced diastolic dysfunction. In contrast to constrictive pericarditis, there are no marked respiratory variations in peak mitral E-wave velocities in patients with cardiac amyloidosis.

Pulmonary vein pattern

In a patient with sinus rhythm, pulmonary venous flow demonstrates two anterograde (systolic [S] and diastolic [D]) and 1 retrograde (atrial reversal [AR]) waves. In general, the peak velocity of the S wave is influenced by changes in left atrial pressure, contraction, and relaxation, whereas the D wave is influenced by changes in left ventricular compliance; D wave changes occur in parallel with the mitral E wave. As filling pressures rise with progression of cardiac amyloidosis, the S velocity decreases and the D velocity increases, which results in a S/D ratio less than 1 (see Fig. 178.3 , C ). As left ventricular diastolic pressure increases, peak velocity and duration of the AR wave tend to increase. Left ventricular diastolic pressure is likely elevated whenever the AR wave outlasts the mitral A wave by at least 30 msec. In atrial fibrillation, which frequently accompanies cardiac amyloidosis, there is a loss of the AR wave, and the peak velocity of the S wave diminishes even if the left atrial pressure is normal.

Left ventricular strain imaging

On strain imaging, amyloidosis is characterized by diminished longitudinal strain in basal and mid-left ventricular segments with characteristic apical sparing (see Fig. 178.4 ). The loss of global longitudinal function occurs because amyloid fibrils deposit predominantly in the subendocardial region, which is primarily responsible for longitudinal deformation. The normal range of global longitudinal peak systolic strain is greater than − 18 ± 2%; patients with amyloidosis typically have peak longitudinal strain values less than − 12%. The loss of longitudinal function occurs early in the course of amyloidosis and reflects systolic dysfunction despite preserved LVEF and fractional shortening.

The exact mechanism for apical sparing is yet to be fully elucidated. Nonetheless, apical sparing has been shown to be both sensitive (93%) and specific (82%) for the diagnosis of amyloidosis compared with other disorders with increased left ventricular wall thickness, such as hypertrophic cardiomyopathy and aortic stenosis.

Echocardiographic findings of cardiac sarcoidosis

Despite the increased utilization of imaging modalities such as CMR and PET, echocardiography remains central to the evaluation and management of individuals with suspected or known CS, because it is widely available and relatively inexpensive. In addition, it can be readily performed and helpful in patients with cardiac devices. Echocardiography is typically thought to have a high specificity for the detection of CS (as high as 95% in one series ), but some have recently suggested that the specificity may be as low as 29%. In patients who are highly suspected of having CS or who have known CS, the prevalence of LV systolic dysfunction (ejection fraction [EF] < 50%) as detected on echocardiography may be high, with estimates ranging from 54% to 87%. However, with the increased utilization of more sensitive tests, such as CMR and PET for the detection of CS, it is becoming increasingly evident that the prevalence of LV systolic dysfunction in patients with CS may be significantly lower. Similarly, others have shown that individuals with symptomatic CS (i.e., those with congestive heart failure or palpitations) often have abnormalities evident on echocardiography. However, it must be recognized that one of the limitations of echocardiography for the assessment of CS is its low sensitivity (25%-62%). In one series of CS patients who presented with significant atrioventricular block or ventricular tachycardia, an echocardiographic abnormality was present in only 10 of 20 patients. Despite its limited sensitivity, echocardiography is an important component of the Japanese Ministry of Health and Welfare Criteria, which are traditionally used to diagnose CS ( Box 179.1 ).

Box 179.1

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