PRE AND POST OPERATIVE ECHO IN HEART TRANSPLANT

CONTRAST FOR CHAMBER OPACIFICATIONWhy Don’t We Give It To Everyone?

Don’t Burst My Bubbles

DR.G.ABISHEK

OUTLINE

• INTRODUCTION• DONOR SELECTION• PRE TRANSPLANT• POST TRANSPLANT• ALLOGRAFT VASCULOPATHY• SERIAL FOLLOW UP• BASICS OF CONTRAST AGENTS• CLINICAL APPLICATIONS• SAFETY ISSUES• CONCLUSION

INTRODUCTION

• Cardiac transplantation remains the treatment of choice for appropriate candidates with end-stage heart failure.

• More than 3000 cardiac transplants are performed worldwide annually.

• mortality rate is greatest in the first 6 months after transplantation; the 1-year survival rate after cardiac transplantation is about 85%, with a 3% to 4% linear decrease annually thereafter and a median survival rate of 10.4

• first year after transplantation-----Graft failure and infections

• 5 years------cardiac allograft vasculopathy (transplant coronary disease), late graft failure (likely a result of allograft vasculopathy), and malignancy disease are more common causes of death.

PRE TRANSPLANT ECHO

EVALUATION BEFORE CARDIAC TRANSPLANTATION

• In the context of evaluation before possible cardiac transplantation, right heart function and presence of pulmonary hypertension are of particular interest.

• Preoperative pulmonary hypertension, particularly if not medically reversible with vasodilators or if reversible at the expense of systemic hypotension, is associated with very high risk of short-term mortality, frequently as a result of right heart failure.

• Although direct measurement of central hemodynamics with a pulmonary artery catheter is currently the gold standard, echocardiography has the advantage of being noninvasive and more widely available.

PVR =[(PEP)/AcT/TT] PEP is preejection period AcT is acceleration time TT is total systolic time

EVALUATION OF THE DONOR HEART

• For regional and global wall motion abnormalities, and valvular or congenital abnormalities.

• Although regional or global wall motion abnormalities may be present on initial assessment, in some cases, contractile function can be improved with medical therapy, particularly if the dysfunction is related to brain death or is catecholamine induced.

• Serial echocardiograms can often confirm improvement in contractile function in the setting of hemodynamic and metabolic correction.

• Lower the initial ejection fraction, the less likely the heart is able to be optimized for use for transplantation because this likely reflects intrinsic and irreversible causes for contractile dysfunction.

INTRAOPERATIVE TEE EVALUATION OF HEART TRANSPLANTATION

• Structural ProblemsInferior vena cava (IVC) stenosis Pulmonary artery (PA) stenosisIntracardiac air

• Functional ProblemsTricuspid regurgitation (TR) Mitral regurgitation (MR)Pulmonary vein obstructionRight ventricular dysfunction Left ventricular dysfunction HypovolemiaVolume overload

POST TRANSPLANT ECHO

PHYSIOLOGY OF THE CARDIAC ALLOGRAFT • Hemodynamics immediately after cardiac transplantation are characterized by elevated filling

pressures associated with impaired relaxation.

• Restrictive physiology early after transplantation may be the result of a combination of ischemic myocardial injury, recipient pulmonary hypertension, and volume overload.

• Persistent restrictive physiology may be attributed to donor-recipient size mismatch, ischemic fibrosis, increased afterload from systemic hypertension, or rejection.

• Denervated, the cardiac allograft has an altered response to exercise, characterized by a slower early rise in heart rate and an overall blunted chronotropic response, with increases in cardiac output primarily the result of increases in stroke volume rather than heart rate.

• Sympathetic reinnervation occurs over time and is associated with improved exercise capacity, including heart rate and ventricular contractile response to exercise.

• Exercise capacity improves in the initial few years after transplantation but may never reach normal nontransplant levels.

TRANSPLANT TECHNIQUE

Early postoperative complications •Early post- operative problems that may be diagnosed and evaluated with echocardiography include pericardial effusion or tamponade, right ventricular dysfunction, tricuspid valve regurgitation, and acute allograft failure.

Pericardial effusion •Moderate to large-sized pericardial effusions in the postoperative period (9% to 35%).

•These effusions do not appear to negatively impact survival, and there does not appear to be a correlation with occurrence of rejection.

•Pericardial effusion that occurs more than 1 month after transplantation associated with less favorable implications.

•Association between late-onset persistent or increasing pericardial effusion with occurrence and severity of rejection.

Ventricular Systolic Function

• Early after transplantation, LV mass and end-diastolic volume increase; these changes may or may not persist for years, without adverse consequences to ejection fraction, although subtle dec- rements in systolic contractility may manifest early.

• In the absence of complications that cause graft dysfunction, allograft ventricular systolic function generally remains normal as many as 10 to 15 years after transplant.

• LV hypertrophy is a common finding, as is postoperative septal motion.

• Systolic ventricular function remains largely normal

Diastolic Function• Diastolic function is abnormal early after transplantation, the effects of which are frequently

compounded by postoperative volume overload.

• A restrictive filling pattern may persist to some degree chronically in some patients or may reemerge during episodes of acute rejection.

• Early after transplantation, a restrictive filling pattern is present, characterized by shorter isovolumic relaxation time and E wave deceleration time and an increased E/A ratio , with gradual evolution to a nonrestrictive pattern by 6 weeks after transplantation.

• Clinical factors, such as preoperative pulmonary systolic pressures or pulmonary vascular resistance, duration of cardiopulmonary bypass, total ischemia time, or age of donor heart, did not significantly correlate with parameters of restrictive filling early after transplantation.

Pre transplant Post transplant

• The incidence of diastolic dysfunction decreases over time, but diastolic abnormalities persist beyond the early postoperative period in a small proportion of patients.

• Right ventricular diastolic dysfunction (elevated right atrial pressure to stroke volume ratio) was associated with increased mortality.

• In general, transplant recipients with constrictive-restrictive hemodynamics had higher right-sided and left-sided filling pressures, shorter LV isovolumic relaxation times and E wave deceleration times, and higher mitral and tricuspid E/A ratios.

• Persistence of restrictive filling pattern up to 6 months after cardiac transplantation may be associated with reduced long-term survival.

• The etiology of persistent diastolic dysfunction after transplantation is not fully defined but likely includes cumulative immune-mediated injury, fibrosis related to immune or nonimmune damage, and allograft vasculopathy.

RIGHT VENTRICULAR STRUCTURE AND FUNCTION

• A significant proportion of patients with severe heart failure have pulmonary hypertension as a result of longstanding elevated left-sided filling pressures.

• Pulmonary hypertension frequently improves to normal or near-normal levels in the weeks to months after cardiac transplantation.

• The evolution of right sided structure and function after transplantation parallels the resolution of pulmonary hypertension and volume overload , although some right ventricular enlargement may persist long term.

TRICUSPID REGURGITATION • Tricuspid regurgitation occurs early and late after cardiac transplantation.

• Early tricuspid regurgitation is more related to preoperative and postoperative pulmonary hypertension and right ventricular failure,

• Valve injury from endomyocardial biopsies is often responsible for late tricuspid regurgitation

• Severity of tricuspid regurgitation on intraoperative transesophageal echocardiogram may be a marker for right ventricular dysfunction and appears to correlate with poor late survival..

• These patients are at increased risk for heart failure and may need tricuspid valve replacement

Echocardiographic Abnormalities Of The Cardiac Allograft During Rejection

• Changes in systolic and diastolic function.

• Increases in LV wall thickness or mass.

•Gold standard for diagnosis of rejection is with endomyocardial biopsy

Structure And Function Of The Cardiac Allograft During Acute Rejection

• Acute cardiac allograft rejection is usually characterized by lymphocytic infiltration with or without myocyte necrosis, termed “cellular rejection.”

• Endothelial cell activation and complement deposition that primarily involves the allograft vasculature termed “antibody-mediated rejection” (also called vascular or humoral rejection)

• Classification• grades 0• 1R, mild rejection • 2R, moderate rejection • 3R, severe rejection

CHANGES IN SYSTOLIC AND DIASTOLIC FUNCTION

• New-onset systolic dysfunction in the setting of acute rejection is generally a late finding and indicates higher grade rejection, which is associated with hemodynamic compromise and clinical symptoms and with poorer prognosis.

• The vast majority of rejection episodes are not associated with systolic impairment, and significant changes in echocardiographic systolic function parameters are generally lacking.

• Abnormalities of diastolic filling are the earliest alterations to manifest in acute rejection.

• Rejection of increasing severity has been associated with a progressive shortening of isovolumic relaxation time and pressure half-time and with an increase in peak early mitral flow velocity,

• Measures of diastolic dysfunction generally return to baseline values after treatment of acute rejection.

TISSUE- DOPPLER IMAGING

• Late diastolic mitral annular velocity (a′) and mitral annular systolic velocity (s′) appear to be sensitive markers of acute severe rejection, they are not particularly specific.

• The combined peak systolic and peak diastolic velocity (peak-to-peak amplitude) of the tissue-doppler mitral annular waveforms was significantly lower in patients experiencing any rejection and may be helpful in excluding presence of significant rejection.

CHANGES IN LEFT VENTRICULAR MASS OR WALL THICKNESS

• Although older reports have suggested LV mass increases in the setting of acute cellular rejection, this has not been a consistent finding and change in LV wall thickness alone has not proven to be a sensitive enough marker for diagnosis of cellular rejection.

• Increased LV mass in the setting of rejection may be the result of increased interstitial edema or vascular leakage of fibrin due to “antibody-mediated rejection” (also called vascular or humoral rejection)

• In a series of 41 cardiac transplant patients, LV mass increased from a baseline of 109 ± 17 g to 151 ± 17 g during vascular rejection, although it did not signicantly change during cellular rejection.

• Concurrently, LV wall thickness increased by nearly 20% during vascular rejection (1.3 ± 0.1 cm at baseline versus 1.6 ± 0.1 cm).

Echocardiographic Guidance For Endomyocardial Biopsy

• Endomyocardial biopsy remains the gold standard for diagnosing allograft rejection and following response to immunosuppressive treatment for rejection.

• Echocardiography has been successfully used to guide endomyocardial biopsies with the benefits of lack of radiation exposure, portability, and provision of information on cardiac structure and function.

• Complication rates with echocardiography for biopsies are extremely low and comparable with those for fluoroscopic guided biopsies

• One disadvantage is that initial insertion and advancement of the bioptome from the superior vena cava until entry into the right atrium is not directly visualized with echocardiography.

• The development of severe tricuspid regurgitation in the cardiac allograft is correlated with the total number of biopsies performed.

Post transplant MonitoringRoutine Follow-up Echocardiography is primarily used for

1.routine monitoring of cardiac allograft structure and function, 2.valvular abnormalities such as tricuspid regurgitation; 3.as part of stress imaging for cardiac allograft vasculopathy surveillance4.as an adjunct to endomyocardial biopsy in the diagnosis of acute rejection.

•For patients with suspected acute rejection, an echocardiogram should be obtained with particular attention paid to identification of changes in measures of systolic and diastolic function.

•Comparison with prior echocardiograms obtained when no rejection was present may be helpful.

DIAGNOSIS OF CARDIAC ALLOGRAFT VASCULOPATHY

• Primary factors limiting the long-term functioning and life span of the allograft.

• Allograft vasculopathy is an accelerated form of intimal hyperplasia that likely results from both immune and nonimmune mechanisms.

• A classic finding is diffuse “pruning” of the smaller distal coronary vasculature, although discrete stenoses characteristic of native coronary disease may develop as well.

• In addition to transplant specific immunologic risk factors, typical risk factors for native coronary disease, such as dyslipidemia and hypertension, also impact the development of cardiac allograft vasculopathy.

• As a result of cardiac denervation, clinical symptoms from cardiac allograft vasculopathy are frequently late and atypical, if at all

Coronary Angiography with Intravascular Ultrasound

• Coronary angiography is relatively insensitive in detection of early transplant vasculopathy; up to three quarters of patients with intimal thickening with intravascular ultrasound (IVUS) have normal coronary angiograms.

• Coronary angiography, which defines the luminal silhouette of the coronary artery, is not able to detect the often diffuse and concentric intimal hyperplasia that characterizes allograft vasculopathy.

• Because IVUS images vascular wall morphology, it has emerged as the gold standard for detection of transplant vasculopathy, particularly in its early stages.

• Extent of vasculopathy can be quantified according to intimal thickness and circumferential extent and also by change in measures of plaque burden over time.

Dobutamine stress echocardiography• Highly sensitive and specific in detection of cardiac allograft vasculopathy. • Positive dobutamine stress echocardiography is associated with increased risk of cardiac events, including

myocardial infarction and heart failure, and risk for death.

• Dobutamine stress echocardiography appears to agree better with IVUS–diagnosed disease• Performs better than nuclear medicine myocardial perfusion scans• Sensitivity of stress echocardiography with exercise is somewhat limited by the blunted heart rate response to

exercise that occurs from cardiac denervation; sensitivity 15% to 20%.

• Worsening on serial dobutamine stress echocardiogram studies is variably accurate in diagnosis of angiographic/IVUS cardiac allograft vasculopathy,

• The addition of quantitative M-mode analysis or strain rate imaging to standard dobutamine stress echocardiography may also improve its diagnostic accuracy.

CORONARY FLOW VELOCITY RESERVE MEASUREMENT

CONTRAST FOR CHAMBER OPACIFICATION

Ideal contrast agent

1. Non-toxic2. Intravenously injectable3. Has to behave similarly to blood4. Crosses pulmonary filter5. Resistant to intravascular and intra-cardiac pressures6. Stable throughout during the exam7. Improve the Doppler signal-to-noise ratio

MICROBUBBLE FORMULATIONS

Name Size (µm) Shell composition Gas content indication

AI-700 2.9 SYNTHETIC POLYMER PERFLUORO CARBON Myocardial perfusion

CARDIOspere 4.0 POLYMER BILAYER NITROGEN Myocardial perfusion

DEFINITY(USA)

1.1-3.3 Lipid encapsulated PERFLUOROPROPANE LV opacification

OPTISON7(USA)

2.0-4.5 DENATURED ALBUMIN PERFLUOROPROPANE LV opacification

SONOVUE(EUROPE, ASIA)

2.5 PHOSPHOLIPIDS SULPHUR HEXAFLUORIDE

Myocardial perfusion, LV opacification

LOW–MECHANICAL-INDEX IMAGING SCHEMES

Fundamental Harmonic

Low Mechanical Index High Mechanical Index

CLINICAL APPLICATIONS

Assessment Of Cardiac Structure And Function

• The use of echocardiographic contrast agents for LVO is particularly helpful when standard resting echocardiographic imaging is unyielding, which often occurs in patients who are obese, have lung disease, are critically ill, or are receiving ventilator care.

Quantification of LV volumes and LVEF

• The accurate determination of LVEF is critically important for managing patients with cardiovascular disease, and it has prognostic value for predicting adverse outcomes in patients with congestive heart failure, after myocardial infarction, and after revascularization.

• Contrast-enhanced echocardiography defines the endocardial border better than unenhanced echocardiography.

• Compared with unenhanced echocardiography shows better agreement and reduction in intraobserver and interobserver variabilities in measured lv volumes and lvef.

• The underestimation of cardiac volumes by echocardiography is nearly resolved when contrast agents are used.

Cardiac anatomyEchocardiographic contrast agents also have been of value in the structural assessment of the left and right ventricles, the atria, and the great vessels.

1.LV apical abnormalities2.LV apical hypertrophy3.LV noncompaction4.LV apicalthrombus 5.LV apical aneurysm 6.Complications of myocardial infarction:-LV pseudoaneurysm, free- wall rupture, and post–myocardial infarction ventricular septal defects

LV Apical Hypertrophic Cardiomyopathy

LV Noncompaction

LV Apical Thrombus

Perfusion Imaging With Real-time PerfusionEchocardiography

Intracardiac masses.

• Most malignancies have abnormal neovascularization that supplies rapidly growing tumor cells, often in the form of highly concentrated, dilated vessels.

• Contrast hyperenhancement of the tumor (compared with the surrounding myocardium) suggests a highly vascular or malignant tumor.

• Conversely, stromal tumors (such as myxomas) have a poor blood supply and appear hypoenhanced.

• Thrombi are generally avascular and show no enhancement.

Intracardiac Mass vs. Thrombus

Kirkpatrick JN, et al. JACC 2004.

Extracardiac anatomy(Vascular imaging)

Aortic dissection:

•In patients with aortic dissection or great-vessel dissection, or both, contrast enhancement helps delineate the true and false lumens.•entry or exit point of the dissection may be identified, and extension of the dissection plane into major aortic branches (brachiocephalic, subclavian, celiac, or renal) may also be visualized.

•Femoral arterial pseudoaneurysms:

Doppler enhancement

• Contrast enhancement of the doppler signal has been shown to be of value when the signal is weak or technically suboptimal.

• Peak velocity measurement in patients with aortic stenosis may be enhanced with echocardiographic contrast agents.

• Transmitral, pulmonary venous flow velocities regurgitant velocities (for assessing pulmonary artery systolic pressure) can be enhanced by either agitated bacteriostatic saline contrast or commercially available echocardiographic contrast agents.

Contrast Enhancement Of Aortic Stenosis Signal

Shunt Detection

• Right-to-left shunts (agitated saline - agent of choice)

• Atrial septal defects of all types

• Patent foramen ovale

• Pulmonary arteriovenous malformations

• Larger ventricular septal defects during diastole

• Left SVC

• Left-to-right shunt

• Negative contrast effect

Right-to-left shunt Negative contrast effect

Persistent Left SVC

Echocardiography in the Emergency Department

• Contrast echocardiography can also assess myocardial perfusion, provides incremental diagnostic and prognostic utility.

• The combination of abnormal myocardial function and perfusion had an odds ratio of for the development of an early event.

• Echocardiography in the emergency department can play a substantial role in the triage of patients with chest pain through the accurate diagnosis or exclusion of acute ischemic syndromes and the prediction of early and late cardiac events.

Contrast Agent Use In The ICU • In ICU hyperinflated lungs due to mechanical ventilation, lung disease, subcutaneous emphysema,

surgical incisions, chest tubes and bandages, crowded quarters, and poor lighting, endocardial resolution is frequently suboptimal

• The use of contrast echocardiography overcomes several of the disadvantages associated with standard echocardiographic imaging in the ICU and can be beneficial for assessment of global and regional ventricular function.

• Several studies have demonstrated their safety and allowed a more accurate estimation of wall motion and global function, with results similar to those achieved with TEE.

• contrast enhancement can be helpful in characterizing or confirming pericardial effusion with associated cardiac tamponade and aortic dissection.

Contrast Agent Use in Cardiac Interventional Therapy

• Direct intracoronary injection of contrast agents into suspected culprit septal perforator arteries during transthoracic echocardiographic monitoring has been used to identify the septal artery in patients with hypertrophic cardiomyopathy who are undergoing alcohol ablation for chemical myectomy.

• According to FDA sthe intracoronary use of contrast agents is contraindicated.

Transcatheter alcohol septal ablation

Use of Contrast Agents in Pediatric Echocardiography • Ultrasound contrast is not approved by the FDA for use in pediatric patients because the safety and efficacy of

contrast agents have not been established definitively in children.

• Stress echocardiography role in kawasaki disease , arterial switch operation.

• Functional evaluation of the right ventricle in patients after repair tetralogy of fallot and senning and mustard procedures.

• With significant intracardiac shunts, microspheres may bypass filtering by the pulmonary capillary bed and directly enter the arterial circulation, potentially resulting in microvascular obstruction.

• Contrast use in pediatric patients has not been associated with adverse effects when used in patients without significant intracardiac shunts or severely increased pulmonary vascular resistance.

Contrast Enhancement in Stress Echocardiography

• Detection of CAD with stress echocardiography is based on the observation of contractile dysfunction in any myocardial segment at rest or with stress, complete visualization of all LV endocardial borders is necessary to document or exclude abnormalities of regional myocardial wall thickening confidently.

• The documented benefits of using contrast enhancement for LVO with resting echocardiography (ie, improved EBD, assessment of ventricular volumes and ejection fractions, recognition of wall-motion abnormalities, and enhanced reproducibility) clearly translate into benefits for stress echocardiography.

• Contrast echocardiography can convert a technically difficult, nondiagnostic stress echocardiogram into an accurate diagnostic study and avoid either an unachievable or a missed diagnosis.

• This obviates the need for alternative testing and improves efficiency, resulting in cost savings.

Exercise stress echocardiogram

SAFETY OF ECHOCARDIOGRAPHIC CONTRAST AGENTS

FDA “Black Box” Warning

• Issued on October 10, 2007

• Post-marketing reports of 11 deaths 1-12 hours following administration of perflutren-based contrast agents

• 10 patient deaths following Definity injection and 1 death following Optison injection• 4 patient deaths temporally related to contrast injection

Perflutren-based compounds contraindicated for use in patients with:1. Acute coronary syndromes2. Acute myocardial infarction3. Worsening or clinically unstable heart failure

http://www.fda.gov/cder/drug/InfoSheets/HCP/microbubbleHCP.htm

“PSEUDOCOMPLICATION”• Main ML, Goldman JH, and Grayburn PA. Thinking outside the “Box”—the ultrasound contrast

controversy. J Am Coll Cardiol 2007; 50 (25): 2434-2437.

• Complications occurring after a medical procedure may be due to either the procedure itself or due to progression of the underlying disease state

• Major cardiovascular events are more likely to occur in patients who are “ill enough” to require diagnostic testing

• Echocardiography often the test of choice (or the only test available) for critically ill patients (shock, hypotension, tamponade, etc.)

• Association of adverse events following contrast administration does not establish causality

The present FDA documents for both definity and optison state that these products are not to be administered to patients in whom the following conditions are known or suspected:

1.Right-to-left, bidirectional, or transient right-to-left cardiac shunts; 2.Hypersensitivity to perflutren; and 3.Hypersensitivity to blood, blood products, or albumin (applies to optison only).

• The intra-arterial injection of ultrasound contrast agents also is contraindicated.

• Additional monitoring of vital signs, electrocardiography, and cutaneous oxygen saturation (for 30 minutes) is not required in all patients but is now limited to patients with pulmonary hypertension or unstable cardiopulmonary conditions.

Use Of Ultrasound Contrast Agents In PHT

• The FDA had initially considered PHT as a contraindication for IV UCAS.

• unshelled microbubbles administered intravenously could result in progressive drops in arterial saturation, cardiac output, and stroke volume, with increases in pulmonary vascular resistance and pulmonary artery pressure.

• The current UCAS approved by the FDA are composed of high–molecular weight gases and various types of shells that remain relatively stable in circulation and for the most part are <10 mm.

• In patients with PHT by improving the evaluation of regional right ventricular wall.

• Doppler image quality, especially the tricuspid regurgitant jet that is used to estimate pulmonary artery systolic pressure.

Short-and long-term outcomes after both IV Optison and Definity injections inpatients with varying severity of PHT

.

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Abdelmoneim et al

INDICATIONS

Agitated saline contrast echocardiography•Evaluation for right-to-left intracardiac shunt (enlarged right heart, ASD/PFO).•Diagnosis of persistent left-sided SVC.•Evaluate for PFO as a potential source of cerebral embolic phenomena (stroke, TIA).

Transpulmonary contrast echocardiography•Poor left heart endocardial border visualization•Diagnosis of left ventricular apical thrombus

CONTRAINDICATIONS

Saline and transpulmonary contrast echocardiography:•Known large intracardiac shunt•Pregnancy

Transpulmonary contrast echocardiography:•Hypersensitivity to perflutren•Severe pulmonary hypertension (relative contraindication)

FUTURE PERSPECTIVE

• SonoVue is a lipid-encapsulated sulfur hexaflu- oride–containing microbubble that also is administered as an infusion or as small boluses during real-time very low MI imaging.

• 3D contrast echo

Thank you