Sunday, April 4, 2021

Advanced Heart Failure and Transplantation Case File

Posted By: Medical Group - 4/04/2021 Post Author : Medical Group Post Date : Sunday, April 4, 2021 Post Time : 4/04/2021
Advanced Heart Failure and Transplantation Case File
Eugene C. Toy, Md, Michael d . Faulx, Md

Case 17
A 50-year-old woman asks to see her cardiologist 3 months prior to her scheduled clinic appointment because she “isn’t doing well.” Three years earlier she was diagnosed with an idiopathic non ischemic cardiomyopathy [ejection fraction (EF) 15%]. Since then her medication regimen has evolved to include a beta-blocker, an ACE inhibitor, an aldosterone antagonist, and a diuretic. Two years ago she received an implantable cardioverter defibrillator and cardiac resynchronization therapy defibrillator (CRT-D). Initially she felt better and returned to her job as a cashier, which required her to stand and take the stairs on occasion. However, 3 months ago she reported frequent lightheadedness and was noted to have a low blood pressure of 90/ 60 mmHg with a heart rate of 70 bpm during a regular scheduled visit. Her ACE inhibitor dose was reduced, but despite the change in medication, she continued to feel unwell. The patient now experiences shortness of breath and fatigue on most days. She no longer had the energy to perform the regular activities of daily living such as showering and dressing without needing to rest. Because of these symptoms, she quit her job as a cashier and over the past month has spent most days lying on the couch. In the cardiologists’ office she is noted again to have a blood pressure of 90/60 mmHg and a heart rate of 110 bpm. Her jugular venous pressure (JVP) is elevated to the angle of the jaw. Her peripheral extremities are cool to the touch.
  • What is the most likely diagnosis?
  • What is the best next diagnostic step?
  • What is the best next step in therapy?
Answer to Case 17
Advanced Heart Failure and Transplantation

Summary: A 50-year-old woman with a 3-year history of nonischemic cardiomyopathy (EF 15%) has received appropriate guideline-based therapy for advanced heart failure. Her functional status has recently deteriorated, and she is no longer able to carry out her activities of daily living without symptoms of fatigue, shortness of breath, and presyncope. On physical examination she is noted to have low blood pressure, an elevated JVP, and cool extremities in keeping with low cardiac output (cardiogenic shock). On the basis of her symptom chronology, her low-output state has likely been subacute to chronic.
  • Most likely diagnosis: Advanced cardiomyopathy, end-stage heart failure.
  • Next diagnostic step: Hemodynamic evaluation–right-heart catheterization.
  • Next step in therapy: Initiate evaluation for advanced therapies, including cardiac transplant and/or mechanical circulatory support.

  1. Recognize the spectrum of patients with chronic heart failure and apply the American College of Cardiology (ACC) staging classification to identify patients with advanced or end-stage heart failure.
  2. Understand the definition of cardiogenic shock and the physical exam findings consistent with this clinical state.
  3. Understand the importance of medical therapy in the treatment of chronic heart failure and know the criteria for ICD and CRT implantation.
  4. Become familiar with the process involved in an advanced therapy workup when a patient is considered for cardiac transplant and/or mechanical circulatory support.
This is a 50-year-old woman with a 3-year history of nonischemic cardiomyopathy. She has a persistent low EF (15%) despite optimal medical and pacing therapy, and now presents with deterioration in her functional status over a 3-month period. The first priority should be to recognize the “red flags” associated with her clinical presentation as a sign of end-stage heart failure. These include symptomatic low blood pressure, medication intolerance, and most importantly a functional decline from NYHA II symptoms to NYHA class III/IV symptoms (Table17-1). It is important to highlight the fact that her low EF of 15% is less relevant here than her clinical symptoms. It is a common misconception that if symptoms worsen, the EF must also deteriorate; however, this is not always true. Her EF has not changed in 3 years and cannot explain the whole picture. The syndrome of

classification and staging of heart failure

Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; NyHA, New york Heart Association. (Data from American College of Cardiology.)

advanced heart failure is far more complex than what is reflected in a single variable of ejection fraction.

The patient is noted to have a low systemic blood pressure, resting tachycardia, raised JVP, and cool peripheries, in keeping with a clinical picture of cardiogenic shock. There are four hemodynamic profiles of heart failure pertaining to the cardiac physical examination. This patient’s physical examination is consistent with an elevated filling pressure (WET) and low cardiac output (COLD) (Figure 17-1).

Before this patient’s heart failure progressed toward an end stage, she received appropriate guideline-based medical therapy. One can refer to the original landmark

Advanced Heart Failure and Transplantation

Figure 17-1. Characterization of heart failure based on physical examination; patients may be classified according to their volume status (wet or dry) and perfusion status (warm or cold) using examination findings and other clinical tools (JVP, jugular venous pressure; PCWP, pulmonary capillary wedge pressure). The patient presented in this chapter falls into the cold and wet category.

medical therapy in heart failure

*Examples of some original landmark clinical trials supporting the use of beta blockade, ACE inhibition, angiotensin receptor blockers, and aldosterone antagonists in heart failure are reported in the following literature sources; this list is not intended to be comprehensive:

Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344(22):1651–1658.

Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334(21): 1349–1355.

The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353(9146): 9–13.

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001–2007.

The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian enalapril survival study (CONSENSUS). N Engl J Med. 1987;316:1429–1435.

The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325(5):293–302.

Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349(20):1893–1906.

Cohn JN, Tognoni G for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–1675.

Young JB, Dunlap ME, Pfeffer MA, et al. for the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Investigators and Committees. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction. Results of the CHARM low-left ventricular ejection fraction trials. Circulation. 2004;110:2618–2626.

Pitt B, Zannad F, Remme WJ, Cody R, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709–717.

Zannad F, McMurray JJV, Krum H, for the EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms N Engl J Med. 2011;364:11–21.

trials supporting the use of beta blockade, ACE/ARB inhibition, and aldosterone antagonists in the treatment of heart failure (Table 17-2). The indications for ICD and CRT continue to evolve. Appropriate implantation of an ICD or CRT device requires an integration of data including ejection fraction, functional class, and time elapsed since diagnosis and the presence of guideline-based medical therapy.

She should be referred for an advanced therapy workup, including a transplant and/or left ventricular assist device (LVAD). This workup involves a multidisciplinary team who will assess the patient’s clinical and psychosocial background to assess suitability. In addition, patients and their families require education about the ethical and legal implications of these therapies.

Approach To:
Advanced Heart Failure and Transplantation


NONISCHEMIC CARDIOMYOPATHY: Cardiomyopathy in the presence of normal or minimally narrowed coronary arteries. This term is generally used when a diagnostic coronary angiogram has ruled out the presence of obstructive coronary artery disease.

EJECTION FRACTION: A quantitative measurement of the volume of blood ejected from the left ventricle with each contraction compared to the resting volume of the left ventricle at end diastole. This value can be determined using a number of imaging modalities such as echocardiography, ventriculography, and nuclear imaging.

CARDIOGENIC SHOCK: Inadequate end-organ perfusion due to a failing ventricle (right, left, or both) in the setting of adequate filling pressures.

CARDIAC RESYNCHRONIZATION THERAPY (CRT): A small pacemakerlike device that sends impulses to both ventricles to coordinate biventricular contraction in the presence of asynchronous contraction due to bundle branch block.

MECHANICAL CIRCULATORY SUPPORT: The use of a mechanical/electrical heart pump to provide additional flow to a failing ventricle. Commonly used as a synonym for a long-term VAD (ventricular assist device), but the term is also used in reference to short-term extracorporeal support such as ECMO (extracorporeal membrane oxygenation).

When a patient with chronic heart failure presents to your office or emergency room, the clinical approach involves multiple steps: confirm the diagnosis, look for the etiology, characterize baseline status, identify severity, and determine prognosis and possible need for advanced therapies (Table 17-3).

Chronic heart failure occurs when cardiac output is inadequate to meet the body’s end-organ needs over a sustained period of time. A number of structural abnormalities involving the coronary arteries, valves, pericardium, and myocardium can lead to this persistent abnormal clinical state. Congenital and genetic abnormalities affecting any of these structures can occur and should be sought as a potential etiology in the correct clinical context.

patients with chronic heart failure

Acquired abnormalities due to longstanding hypertension, coronary artery disease, valvular regurgitation or stenosis, infection, inflammation, infiltration, druginduced toxicity (cocaine, chemotherapy, alcohol), and arrhythmias are more common. The syndrome of heart failure can occur in the setting of systolic dysfunction (heart failure with low ejection fraction) or diastolic dysfunction [heart failure with preserved ejection fraction (HFpEF)].

Clinical Presentation
Most patients with chronic heart failure present with a number of symptoms that can be elicited from a detailed history and physical exam. Exertional dyspnea and/or exercise intolerance is most common. The functional limitation associated with the dyspnea must be determined to better classify the patient’s symptoms. Keeping the ACC/NYHA classification scheme in mind, focused questions such as “Can you climb a flight of stairs?” or “Do you need to stop to catch your breath while bathing yourself?” can further elucidate this limitation. Advanced heart failure patients often complain of volume retention, which can take the form of peripheral edema or ascites despite high-dose diuretics. Orthopnea and paroxysmal nocturnal dyspnea are symptoms that patients rarely volunteer on their own and should be specifically elicited by the physician. Presyncope, anorexia, unexplained weight loss, persistent nausea, and right upper quadrant tenderness are symptoms of congestion and low cardiac output. These symptoms tend to occur more frequently in advanced heart failure and are markers of poor prognosis. Additional poor prognostic markers include frequent hospitalizations despite aggressive fluid management and close medical follow-up.

Although patients’ symptoms can change over time (particularly if they are experiencing an exacerbation), a patient with advanced disease spends most days in the  functional class III/IV range. To get a sense of chronology and better characterize baseline status (Table 17-3, step 3), questions such as “When was the last time you felt you were at your best?”, “How long have you been experiencing symptom X?”, or “How many days in the week do you experience symptom X?” should be asked. Questions such as these can help the clinician differentiate deterioration due to an acute exacerbation from a more chronic deterioration due to progression of the underlying disease.

The physical examination should focus on the vital signs, volume status, and perfusion status. Many patients with advanced heart failure will have atrial fibrillation. Symptomatic hypotension and tachycardia are worrisome signs, reflecting the body’s attempt to maintain cardiac output in the setting of low stroke volume. The best physical examination surrogate for evaluating intravascular volume status is the jugular venous pressure (JVP). When the JVP is elevated, one can fairly accurately conclude that the patient is congested. Peripheral edema, in addition to an elevated JVP, points to heart failure as an etiology for the edema. Edema due to other causes such as venous insufficiency or lymphedema would have a normal JVP. Unlike the lungs in acute pulmonary edema, the lungs in chronic advanced heart may be clear on auscultation, due to a pulmonary vascular system that has adapted to chronically elevated left-sided filling pressures over time. An S3 may be expected, particularly in a severely dilated ventricle and/or in a decompensated state. An S4 may point to hypertension as the etiology of a stiff ventricle. Accompanied murmurs of mitral regurgitation are common. A pulsatile or tender liver and elevated transaminases can occur as a result of congestion. Laboratory evidence of poor cardiac output includes end-organ dysfunction such as elevated creatinine and lactic acidosis. Chronic hyponatremia is commonly seen in advanced heart failure due to elevation in antidiuretic hormone (ADH) in response to low cardiac output.

Medical and Device Treatment
Beta blockade and ACE inhibition are the mainstay of medical therapy in chronic heart failure. Both classes of medication have been proven in large randomized control trials to increase survival in heart failure. The use of aldosterone antagonists was originally reserved for patients with advanced heart failure only, but is increasingly recommended in mild to moderate heart failure patients.

The guidelines regarding ICD and CRT implantation continue to evolve over time and are quite complex. ICD therapy is recommended for primary prevention of sudden cardiac death in patients who are symptomatic with an EF < 30–35% despite good medical therapy. This recommendation is independent of the etiology of left ventricular systolic dysfunction. CRT is also indicated in these patients if they have a wide LBBB (QRS duration >150 ms) on ECG.

Patient Selection for Advanced Therapies
If a patient continues to experience refractory heart failure symptoms despite optimal medical and CRT therapy (if applicable), advanced therapies such as cardiac transplantation and mechanical circulatory support should be considered. The need for alternative therapies to transplant is increasingly necessary, as the demand for donor hearts has outstripped supply. LVAD technology has become a welcome alternative to bridge patients safely to transplant. LVADs can also offer permanent support for patients who are not eligible for cardiac transplantation because of age, comorbidities, or other contraindications to transplant. Although a definitive age cutoff does not exist, regarding cardiac transplantation age >70 years represents the upper limit of candidacy among most transplant programs worldwide.

The population typically considered for advanced therapies includes individuals with ACC stage D, NYHA class III/IV symptoms. These are patients whose heart failure is refractory to best medical therapy with recurrent hospitalizations and/or in need of inotrope therapy. Objective measurements to guide candidacy for advanced therapies can also include a VO2,max from a cardiopulmonary stress test or direct measurement of cardiac output from a right-heart catheterization. Some absolute contraindications to cardiac transplant include malignancy within the last 5 years, severe pulmonary hypertension, active infection, extreme BMI, and psychosocial contraindications.

Patient selection for LVAD continues to be a moving target as the field evolves. The reader is referred to the most recent guidelines published by the International Society of Heart and Lung Transplant (ISHLT) in this regard. LVADs were initially implanted in the sickest patient population such as those in acute refractory cardiogenic shock. However, there has been increasing recognition that implanting the LVAD before that critical period is more favorable.

The decision to pursue advanced therapies is complex and requires an integration of a number of variables. Any transplant or LVAD program is made up of a multidisciplinary committee, including heart failure cardiologists, transplant/VAD surgeons, psychiatrists, psychologists, social workers, and specialized transplant and VAD nurses. The decision to pursue advanced therapies is often reached by consensus after careful evaluation of all of the available data and therapeutic options.

Complications Related to Advanced Therapies
Survival after transplant beyond the perioperative period is dependent on medication compliance to prevent acute and chronic rejection. Cardiac biopsies are completed routinely in the first year to fine-tune immunosuppression to a level that prevents rejection but also does not allow for significant infection. This fine balance between rejection and infection is a consistent challenge in the posttransplant course. Long-term complications such as transplant vascular disease and malignancy can threaten the long-term integrity of the new heart.

Patients with a ventricular assist device require long-term anticoagulation to prevent pump thrombosis and formation of emboli. The need for chronic anticoagulation brings with it a host of complications, including GI bleeding, hemorrhagic stroke, and anemia. Ischemic stroke, chronic hemolysis, risks of device infection, and pump thrombosis remain the drawback of chronic VAD management.

  • See also Case 16 (acute heart failure).


17.1 Match the following hemodynamic profiles with the appropriate heart failure profile:

appropriate heart failure profile

17.2 A 34-year-old patient was diagnosed with a nonischemic cardiomyopathy at age 30 years. His previous cardiologist started him on a low-dose beta-blocker, but the patient never saw him again. He presents to your office with NYHA class II symptoms. Echocardiography confirms an EF of 20%. Your next step in management is to
A. Refer him for ICD implantation and a CRT device if his QRS > 150
B. Perform a right-heart catheterization
C. Increase his beta-blocker dose and plan to initiate an ACE inhibitor
D. Refer him for advanced therapies workup

17.3 A patient presents to your office with a 2-year history of ankle swelling that is worse at night than in the morning. He complains of shortness of breath while walking up a hill. On examination you note that he is morbidly obese and has varicose veins. His JVP is 2 cm above the sternal angle. The most likely etiology of his ankle edema is
A. Alcoholic cirrhosis
B. Lymphedema
C. Venous insufficiency
D. Congestive heart failure


17.1 1B, 2C, 3D, 4A.

17.2 C. This 34-year-old patient has a nonischemic cardiomyopathy. Although it is concerning that his EF remains 20%, he has not been on optimal medical therapy. Before he is referred for more invasive therapies, his medical regimen should be uptitrated. It is possible that on good medical therapy he may experience some left ventricular recovery and/or improvement in his symptoms. This is your first time meeting him, and it is too early to consider advanced therapies. This type of decision should be made over time once you get to know this patient and see how he responds first to medical therapy, and then to device therapy if needed.

17.3 C. This patient’s shortness of breath is likely accounted for by his morbid obesity. Because his swelling (edema) is less in the morning than at night, and as he has varicose veins, venous insufficiency is more likely. The clincher here is the presence of a normal JVP, further solidifying the likelihood that his edema is related to venous insufficiency and not heart failure.

  • Left ventricular ejection fraction is only a minor piece of the chronic heart failure syndrome. Many patients with chronic heart failure have a pre served ejection fraction.
  • The trajectory of heart failure is difficult to predict. Advanced or end stage heart failure can be better recognized with long-term patient follow-up and recognition of poor prognostic symptoms and signs such as frequent hospitalizations and refractory symptoms despite close medical management.
  • Timing and patient selection are a key part of the advanced therapies evaluation. Early referral to an advanced heart failure specialist ensures that this timing is not missed.
  • Determining a patient’s candidacy for advanced therapies (transplant or LVAD) is complex and requires the integration of a number of clinical and historical variables as evaluated by a multidisciplinary advanced therapeutics committee.

Feldman D, Pamboukian S, Teuteberg J. The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: executive summary. J Heart Lung Transplant. 2013;32(2):156–186. 

Mehra MR, Kobashigawa J, Starling R et al: Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates. J Heart Lung Transplant. 2006;25(9);1024–1042. 

Nohria A, Tsang S, Fang JC, et al. Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure. J Am Coll Cardiol. 2003;41(10):1797–1804. 

Tracy CM, Darabr D, Dunbar B, et al: 2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2012 ( available online at 

Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guidelines for the Management of Heart Failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147–e239.


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