Additional Heart Failure Topics

Additional Heart Failure Topics


I. Arrhythmia-induced cardiomyopathy

The 3 forms of arrhythmia-induced cardiomyopathy are reversible within 2-12 weeks of arrhythmia control and are not usually associated with significant LV scar. The arrhythmia may be the sole cause of the cardiomyopathy or, in a patient with underlying cardiomyopathy, it aggravates it and further reduces EF.

A. Tachycardia-induced cardiomyopathy

Biventricular dilatation then failure may develop with any uncontrolled tachyarrhythmia that persists for over 2 weeks (range: 3 days to 6 months). This ventricular failure results from depletion of energy stores; in a way, it is a form of ischemic hibernation. Both LV and RV dilate with mild thinning and no hypertrophy. While faster rates increase the risk and speed of its occurrence, this cardiomyopathy may be observed with chronic rates of only 105–110 bpm, rates that are usually well tolerated chronically and do not come to medical attention until the patient develops HF. It is seen with uncontrolled AF, atrial flutter, atrial tachycardia, or the slow and incessant form of AVRT (PJRT).1 Interestingly, the tachyarrhythmia may not be persistent; tachycardia that occurs over 10–15% of the day may cause a cardiomyopathy.2

A newly diagnosed tachyarrhythmia at a rate >105-110 bpm, coinciding with HF exacerbation, suggests the possibility of tachycardia-mediated cardiomyopathy.3,4 This is the case in 25–50% of new-onset AFs or atrial arrhythmias coinciding with a new HF presentation.2,4,5 Also, the persistence of the fast heart rate after diuresis and HF improvement suggests this diagnosis.

After HF is treated (diuresis) and compensated, the tachyarrhythmia is targeted with a heart rate goal < 100 bpm (as good as a goal <80 bpm based on RACE-II HF substudy, substudies of β-blockers in HF, and Swedish HF registry).6 In addition, rhythm control is attempted (e.g., ablation for atrial flutter and atrial tachycardia, DC cardioversion and antiarrhythmics for AF). This cardiomyopathy usually reverses several weeks after rhythm control, typically between 2-12 weeks (initial improvement of LV contractility, followed by LV size reduction).1,4 Rate control only achieves marginal improvement. Residual ultrastructural abnormalities persist, explaining a fast recurrence of LV dysfunction with recurrence of the arrhythmia.

B. PVC-induced cardiomyopathy

Frequent PVCs, with a burden of > 10% of the patient’s total rhythm on a Holter monitor, may lead to LV dilatation followed by reduced EF. About 7-30% of patients with a PVC burden >10% develop cardiomyopathy, particularly when the PVC burden is >24%.3,7 In a canine model, half the canines with an induced PVC burden of 33% developed cardiomyopathy. This cardiomyopathy generally develops slowly, over months or years, and resolves 2-12 weeks after ablation.

PVC-induced cardiomyopathy is partly explained by calcium mishandling. Normally, calcium is pumped into the cytosol in systole, triggering actin-myosin cross-bridging; it is then actively pumped out in diastole. When 2 close systolic cycles occur, as is the case with PVC, calcium is not pumped out effectively and cytosolic calcium overload occurs. Post-PVC contraction initially increases, but calcium channels are eventually downregulated leading to an eventual reduction in contraction; also, the pause initiates a harmful catecholamine activation. However, this cannot be the sole mechanism, as frequent PACs with similar heart rate irregularity do not induce cardiomyopathy.3,8,9 In fact, the degree of LV dyssynchrony induced by the PVC is a major predictor of LV dysfunction, explaining why PVCs with QRS>150 ms (or PVCs originating from the epicardium) more readily induce cardiomyopathy, mimicking RV pacing.3,9 Also, AV dyssynchrony in PVC, i.e. atrial contraction against a closed valve, further reduces cardiac output and EF and causes a cannon A wave, and is more prevalent with shorter coupling intervals of <450 ms.10

Conversely, the more extreme irregularity of AF may induce cardiomyopathy solely through a more sustained calcium mishandling. Also, the sustained tachycardia of tachycardia-induced cardiomyopathy results in a more pronounced calcium overload than PVC-cardiomyopathy.11

Of note, fibrosis and apoptosis do not usually occur with PVC-cardiomyopathy, and only functional and electrical remodeling occurs;3,7 mild fibrosis may be seen with tachycardia-induced cardiomyopathy (ischemic process) and more questionably, AF-induced cardiomyopathy.

In patients with cardiomyopathy and frequent PVCs>10%, PVCs are the cause of the cardiomyopathy or an aggravating factor in ~85% of the cases. Lack of scar on MRI, monomorphic PVC pattern (rather than multifocal), and global hypokinesis favor the role of PVCs. Post-PVC potentiation, with increased SBP and pulse pressure by 10 mmHg after a PVC, strongly predicted LV recovery with ablation in one study.10

Holter monitoring, preferably for 6 days, is performed to quantify PVC burden. Before the development of cardiomyopathy, frequent symptomatic PVCs may be treated with β-blockers or verapamil, keeping in mind a limited efficacy of 10-24%; alternatively, class Ic drugs (flecainide) are highly effective (>70%).3 Spontaneous reduction of PVC burden may occasionally occur (12% in one study). Once cardiomyopathy develops, the options are limited to ablation vs. amiodarone therapy, both of which are highly effective.3

Asymptomatic frequent PVCs with normal LV do not have any indication for therapy. Since cardiomyopathy is reversible, aggressive preventive therapy is not warranted.3 A watch-and-wait approach is adopted, with LV monitoring every 6-12 months.

C. AF-induced cardiomyopathy (see chapter 10, Section VIII)

AF may induce a low EF through a fast ventricular rate, i.e. a form of tachycardia-induced cardiomyopathy. However, even when rate controlled, AF, per se, may induce LV systolic dysfunction. This is partly related to: (a) loss of atrial contribution to LV preload and stroke volume; (b) pronounced irregularity which blunts stroke volume on short R-R intervals: for the same heart rate, an irregular rhythm generates lower cardiac output and creates significantly more calcium mishandling and overload than a regular rhythm.3,11 In fact, in patients with rate-controlled AF and HF, AF ablation improves EF by 10-18% (e.g., CAMERA-MRI trial).12 Patients with AF, no LV scar on MRI, and a persistently low EF despite rate control are suspicious for AF-induced or aggravated cardiomyopathy.

D. LBBB-induced cardiomyopathy

Patients with isolated LBBB and no associated myocardial or coronary disease may develop a dilated cardiomyopathy secondary to LV dyssynchrony. This likely occurs in a minority of patients with LBBB (<5-10%), over years to decades (mean 11.6 years in one study),13 particularly when LBBB is very wide ≥150 ms, and is suggested by several data:

  • Long-term follow-up of middle-age patients with isolated LBBB shows a 2-to-3-fold higher risk of HF (Swedish and Framingham data).14,15
  • About 20-25% of patients with low EF and LBBB are super-responders to CRT, i.e., EF normalizes with CRT, suggesting that dyssynchrony is the primary cause of the cardiomyopathy. This is more likely the case in women with non-ischemic cardiomyopathy and LBBB≥150 ms.13,16
  • In a retrospective analysis of cardiomyopathy with LBBB, standard HF therapy did not improve EF.16

II. Viral myocarditis

There are several forms of viral myocarditis:

  • Subclinical myocarditis signifies asymptomatic myocarditis (no HF). It is usually self-limited, but a minority of patients develop chronic HF and are diagnosed years later with idiopathic dilated cardiomyopathy.
  • Clinical myocarditis implies myocarditis that manifests clinically with HF or with signs of pericarditis. It can take several forms:

    1. Mild acute myocarditis presents with LVEF of 40–50% and sometimes mild HF, along with acute pericarditis signs. It usually recovers, in >90% of the patients, within weeks or months.17
    2. Severe acute myocarditis is a myocarditis that manifests as HF or significant LV dysfunction. It reverses in ~35%, significantly improves in ~40%, and progresses to a more severe HF in ~25% of patients.18 The overall 5-year mortality of patients with persistent HF is similar to idiopathic DCM (~50%).19
    3. Very severe acute myocarditis manifests as severe HF of recent onset (typically 2 weeks) with cardiogenic shock or ventricular arrhythmias, usually with a normal-size LV that has not had time to dilate and with severe thickening of the ventricular walls from edema, sometimes leading to low QRS voltage. There are two forms of very severe myocarditis: (i) fulminant lymphocytic myocarditis, in which the patient is unstable acutely but often fully recovers if appropriately supported with vasopressors or ventricular assist devices, as the process mainly consists of myocardial depression by cytokines rather than necrosis (the long-term prognosis was excellent in old registries, with >90% survival at 10 years, but not as good in a contemporary registry, 80% at 60 days);2022 (ii) giant-cell myocarditis, in which autoimmune myocardial destruction occurs and the illness continues its aggressive downhill course and intractable ventricular arrhythmias occur; multinucleated giant cells are seen (of histiocytic origin). These very severe forms are seen in young patients with aggressive immune systems.

Myocarditis is associated with two types of clinical manifestations:

  • HF, sometimes severe with shock
  • A syndrome mimicking MI may be seen with any acute or hyperacute myocarditis, along with pericarditic chest pain and ECG changes, increased CRP, and an inflammatory pericardial effusion. ECG changes may be diffuse, similar to acute pericarditis, or more localized, mimicking STEMI (local myocarditis with “pseudoinfarction” pattern). Coronary angiography frequently needs to be performed to rule out CAD in these patients with ST elevation and troponin rise.


A definitive diagnosis of myocarditis is made by endomyocardial biopsy: lymphocyte-rich inflammatory infiltrate and myocyte necrosis (Dallas criteria); or positive viral genome on molecular analysis. Because of patchy myocardial involvement, the biopsy only has a 35–50% sensitivity. The yield is higher (85%) in giant-cell myocarditis, where the myocardium is more diffusely involved and multinucleate giant cells are seen. Biopsy is only indicated in cases of very severe myocarditis, where an urgent diagnosis of giant-cell myocarditis needs to be made and immunosuppressive therapy, ventricular assist device and transplant considered. With immunosuppressive therapy (generally 2 to 3 of the following: prednisone, mycophenolate, azathioprine, cyclosporine, muromonab), the prognosis of giant cell myocarditis has improved significantly, with transplant-free survival rates of 69% at 1 year and 58% at 5 years.23,24 Steroids +/- azathioprine may be considered in fulminant lymphocytic myocarditis, although randomized trials failed to show any benefit from steroids in acute myocarditis.25

In patients acutely presenting with chest pain, troponin rise, and ST abnormality (diffuse or focal), a presumptive diagnosis of perimyo- carditis is made after coronary angiography rules out CAD, in the absence of a takotsubo pattern of LV dysfunction.

In patients presenting with HF, a presumptive diagnosis of myocarditis or genetic DCM is made when cardiomyopathy has no clear explanation. Recently, MRI has emerged as a useful modality for the diagnosis of myocarditis: (i) increased T2 signal indicates edema (acute inflammation), and (ii) late gadolinium enhancement (LGE) on T1 indicates cellular death and/or scarring. Both findings may be seen with acute MI; however, as opposed to acute MI, the abnormalities are not distributed in a particular coronary territory, and the pattern of late enhancement is different (subepicardial or mid-wall in myocarditis vs. subendocardial or transmural in MI). The subendocardium is usually spared in myocarditis, and transmural enhancement is rare.8

III. Acute eosinophilic myocarditis

Acute eosinophilic myocarditis may be due to drug hypersensitivity, Churg and Strauss vasculitis, hypereosinophilic syndrome (the latter 2 also cause chronic eosinophilic myocarditis, i.e. Loeffler syndrome), or may be idiopathic.

It is frequently accompanied by eosinophilia (75%), which sometimes is transient and not seen on admission but later. Fever, rash or constitutional symptoms may also be present.26 Even without eosinophilia, a patient with drug reaction (e.g., penicillins, sulfa) and newly reduced EF or troponin elevation should be suspected of eosinophilic myocarditis. The eosinophils attack and damage the endomyocardium, resulting in acute LV and/or RV thrombi (15-30%). This myocarditis may be severe but transient and reversible if the drug is withdrawn and corticosteroids are used. Unlike other forms of myocarditis, this form responds well to high-dose corticosteroids.25,26 Endomyocardial biopsy, which is indicated in severe progressive cases of uncertain cardiomyopathy, shows eosinophilic infiltration.

IV. HIV cardiomyopathy

HIV cardiomyopathy is often related to a direct myocardial HIV infection, but is sometimes related to an autoimmune process triggered by HIV, coinfections (e.g., cytomegalovirus, Toxoplasma, Epstein–Barr virus), or selenium deficiency. It should be distinguished from a reversible, acute illness cardiomyopathy sometimes seen in hospitalized HIV patients. HIV cardiomyopathy is typically seen in patients with CD4 counts <400 and develops in ~8% of these patients over a 5-year follow-up;27 it may present as acute myocarditis. Dilated cardiomyopathy is associated with a high mortality risk of >50% at 2 years that is partly related to the advanced HIV disease.28,29 Patients with a progressive course should undergo an endomyocardial biopsy to rule out and treat opportunistic coinfections. The effect of highly active antiretroviral therapy on stabilizing HIV cardiomyopathy is unclear. Diastolic dysfunction is common in HIV and may not affect the long-term prognosis in the absence of a reduced EF.29

V. Chagas disease

Chagas disease occurs in endemic Latin American countries. It is due to a parasite (trypanosome) that is transmitted through the bite of a bug. Acute infection is mild; it rarely leads to a picture of acute myocarditis with HF that is usually reversible. Years later, ~30% develop chronic Chagas disease, which is characterized by a progressive biventricular failure and, frequently, a characteristic large apical aneurysm. Thromboembolic complications, conduction blocks, and arrhythmias are common. Chagas disease, whether acute or chronic, is due to a combination of active and persistent myocardial infestation and a damaging immune response.30 The diagnosis is confirmed by serology. Beside HF therapy, benznidazole (antiparasitic agent) is useful in acute disease and may be useful in slowing the progression of early chronic disease, before severe HF develops. In one large randomized trial, benznidazole failed to reduce cardiovascular events in chronic Chagas cardiomyopathy that is not advanced clinically (EF mostly normal, no advanced HF), despite significant reduction of parasite detection on blood samples.31

VI. Sarcoidosis

Sarcoid cardiomyopathy is characterized by myocardial sarcoid infiltration, with granulomas and edema early on and fibrosis later on. The LV wall may be thickened by granulomas, which leads to LV diastolic dysfunction; or thinned by fibrosis with localized aneurysms, which leads to LV systolic dysfunction.

Sarcoidosis typically involves the basal septum and the lateral LV, leading to localized akinesis or dyskinesis of these segments.32,33 This basal septal involvement leads to infra-His ≥ 2 nd -degree AV block, RBBB, or LBBB, as well as pseudo-Q waves. VT, frequent PVCs, and atrial arrhythmias are also common. Echo is not very sensitive for detecting the early small granulomas and localized dysfunction, and arrhythmias or conduction blocks may be the earliest manifestation. The RV is not directly involved, but pre-capillary pulmonary hypertension may occur and lead to secondary RV failure.

Approximately 20–30% of patients with sarcoidosis have myocardial involvement, but only 5% have clinical myocardial involvement. Even in patients with no known extracardiac manifestations, pulmonary/mediastinal involvement is highly prevalent and seen in 80-90% of patients with cardiac sarcoidosis. Yet, ~5-20% of cardiac sarcoidosis is limited to the heart, i.e. isolated cardiac sarcoidosis. Sudden death from ventricular tachyarrhythmias or conduction blocks is the most common cause of death in cardiac sarcoidosis, accounting for 30–65% of deaths.32 Progressive cardiomyopathy is the second most common cause of death.

Diagnosis- Cardiac sarcoidosis is considered in 2 settings:

  1. Patients with established extra-cardiac sarcoidosis, even if asymptomatic from a cardiac standpoint:

    Any patient with extracardiac sarcoidosis should be screened for cardiac involvement with clinical history, ECG (RBBB, LBBB, ≥2nd-degree AV block, frequent PVCs, VT, SVT), echo, and Holter. Any significant abnormality on the latter tests dictates cardiac MRI, which, if abnormal strongly suggests the diagnosis of cardiac sarcoidosis; if normal, it implies a low probability of cardiac sarcoidosis. Cardiac MRI assesses for scar tissue which correlates with sudden death (→ need for ICD), and may capture the earlier stage of inflammation and edema.3436 The location of late gadolinium enhancement is characteristic of sarcoidosis: basal septum and basal inferolateral wall (patchy, subepicardial or midwall involvement, rarely transmural). Fluorodeoxyglucose PET assesses for active myocardial inflammation which may improve with steroid therapy (cases when AV block, VT, and LV dysfunction may improve with steroid therapy). MRI and PET may be used as complementary tests, each addressing one stage of cardiac sarcoidosis.33

  2. Patients with no known extracardiac sarcoidosis but with suggestive cardiac findings:

    • Young patient with VT, conduction block, cardiomyopathy with RBBB or LBBB
    • Non-ischemic cardiomyopathy with thick walls, segmental dysfunction, or pseudo-Q waves

The diagnosis is suggested by non-cardiac sarcoid involvement (CT chest, eye exam) and MRI finding of either edema or late gadolinium enhancement at the basal septal and inferolateral walls. A histological diagnosis is generally needed, and often may be achieved via mediastinal or pulmonary biopsy. RV endomyocardial biopsy has a low sensitivity (~25%) as the septal infiltration is patchy. Septal biopsy guided by EP electroanatomic mapping, targeting the low voltage areas, increases the biopsy yield.

Treatment- At an early stage, granulomas, MRI defects, and myocardial contractility improve with steroid therapy; however, AV block and the risk of VT do not reliably improve with steroids.32,33 The prognosis of sarcoid cardiomyopathy is similar to idiopathic DCM, and much better than other infiltrative cardiomyopathies (e.g., amyloid).28

Patients with high-degree AV block have a high risk of VT on follow-up (up to 50% at 2–3 years), justifying ICD therapy early on. Also, patients with cardiac sarcoidosis and unexplained syncope, low RVEF, LVEF<35%, or LVEF>35% with late gadolinium enhancement on MRI (especially of the RV) have a high risk of sudden death and qualify for ICD (ACC guidelines 2017).36 NSVT and bundle branch blocks, per se, do not warrant ICD but may justify further risk stratification with EP study and/or MRI and require careful follow-up (HRS 2014).33

VII. LV non-compaction

Embryologically, the normal myocardium has subendocardial and subepicardial layers that are initially loose then become packed and thin, i.e., compacted. In LV non-compaction or “spongy myocardium,” the subepicardium becomes compacted but the subendocardial meshwork remains loose, leading to prominent trabeculations and deep recesses, particularly in the mid-LV and apex. Doppler flow is seen through the

recesses and thus helps define the excessively trabeculated morphology. LV non-compaction has been defined as an end-systolic ratio of the loose inner myocardium to the compacted outer myocardium ≥ 2, with an impaired or normal LVEF. Occasionally, LV non-compaction may be mistaken for LV thrombus, but echo contrast allows the differentiation. Early reports suggested that non-compaction is frequently associated with severe LV dysfunction and high incidence of arrhythmia and thromboembolic complications.37 In fact, the deep sluggish recesses allow for thrombus formation. Later reports suggested that non-compaction, per se, may not carry any additional diagnostic or prognostic value beyond that provided by EF and HF status.38

Viral and hypertensive cardiomyopathies may lead to prominent trabeculations, that, at times, may fulfill the definition of LV non-compaction (false-positive diagnosis).39 In the latter cases, the prominent trabeculations are acquired rather than congenital. In fact, in one analysis, ~25% of patients with systolic HF fulfilled the diagnostic criteria of LV non-compaction,40 including many patients with underlying CAD (CAD was present in 29% of HF with LV non-compaction).41 In addition, up to 8% of normal individuals, particularly black individuals, have prominent trabeculations that fulfill the diagnosis of LV non-compaction.40 One analysis has shown that 8% of healthy women develop a non-compaction morphology during pregnancy, which reverses in the few months postpartum without any untoward clinical events or EF deterioration.42 Also, 8% of athletes have a non-compaction morphology. Thus, LV non-compaction is a non-specific phenotype induced by physiological adaptation or by volume overload. In a subgroup of patients, particularly those with LV dysfunction or familial cardiomyopathy, LV noncompaction may be a genetic cardiomyopathy: 9-32% of patients with LV noncompaction test positive on a general cardiomyopathy gene panel, particularly if they have LV dysfunction, with no one gene specific for noncompaction.43,44

The prognosis depends on the underlying LVEF and HF functional status, and the impact of the non-compaction morphology, per se, is unclear. Patients with normal EF at baseline have an excellent prognosis, with no increased risk of death or HF and no deterioration of LV function at 9.5 years.38,41,45

VIII. Takotsubo and other stress-related cardiomyopathies

A. Takotsubo cardiomyopathy (TC, also called “stress-induced cardiomyopathy” or “apical ballooning syndrome”)

This is a transient form of cardiomyopathy that occurs after a major stress and typically leads to dyskinesis and “ballooning” of the ventricular apex. Massive catecholamine surge leads to contraction band necrosis, which is actually a form of stunning rather than necrosis, similar to what is seen with cocaine overdose. Multivessel spasm and microvascular spasm have been incriminated as well; in fact, acetylcholine-induced vasospasm is common in TC. Atypical variants of TC have been described, such as the mid-ventricular ballooning and the basal ballooning (inverted TC).

TC typically involves post-menopausal women (~95% of cases), and only 2% of affected patients are <50 years of age. TC uncommonly presents as HF and more typically mimics ACS, particularly STEMI, and presents with chest pain, anterior ST elevation with deep anterior T-wave inversion, and elevated troponin. ST elevation is seen in >80% of the cases and involves the anterior and lateral leads, with rare inferior extension but also rare reciprocal ST depression (<10%); isolated inferior ST elevation is not seen. ST elevation evolves into deep anterior T-wave inversion and prolonged QT within 24–48 hours; patients frequently present at the stage of T-wave inversion without residual ST elevation, T-wave inversion being the most universal finding. Transient anterior/lateral Q waves are seen in 30% of the cases. On echo and left ventriculography, the apex is akinetic/dyskinetic while the base is hypercontractile, and the overall EF is ~30% (20–40%). RV is commonly involved (~1/3 of cases). Up to 17% of TCs are mid-cavitary rather than apical and 2% are basal.46,47

The ECG and echo findings characterize anterior MI as much as TC, and coronary angiography should be performed in all these cases to rule out LAD disease. In TC, no significant CAD is found. Troponin increases to mild degrees (up to 5 ng/ml), much less than in anterior STEMI. As opposed to STEMI and myocarditis, MRI does not show any LGE (while helpful, MRI is not a necessary diagnostic tool).

All cases of TC are reversible within 2 months (half of them resolve within a week). In fact, the diagnosis can only be made in retrospect, once recovery of LV function is confirmed. A risk of recurrence of 11% has been described over a 4-year follow-up.48

TC has a good prognosis, with ~1% in-hospital mortality. Complications similar to STEMI complications may be seen acutely but are much less common than in STEMI: HF (17%), shock (4%), VT/VF (1–6%), LV thrombus (2.5%) with a stroke risk of ~1%, usually within 48 hours.

HF and cardiogenic shock may result from the poor LV function but also from the basal hypercontractility that leads to LVOT obstruction, the latter being seen in ~15% of TCs. These two forms of HF or shock need to be differentiated by echo and are treated differently. In LVOT obstruction, inotropes are avoided; β-blockers are used if HF is present (carefully), while α-agonists are used if shock is present. Functional MR is seen in ~20% of TCs, and results from either LV dilatation or LVOT obstruction/SAM.

There are 3 types of trigger for TC (each accounting for a third of cases), and the prognosis varies according to the trigger:49 (1) emotional stress→ benign short- and long-term prognosis (1% acute mortality); (2) physical stress (acute medical or neurological illness, procedures, physical exertion)→ much higher short-term (~7-10% vs 1%) and long-term mortality, mainly related to the underlying illness and comorbidities; (3) no clear trigger→ intermediate prognosis (2% short-term mortality).

B. Other stress-related transient cardiomyopathies

  • Neurogenic stress cardiomyopathy is seen in up to 20–30% of patients with subarachnoid hemorrhage, and less often in ischemic stroke. As opposed to TC, it usually involves the basal and mid-ventricular segments and spares the apex (inverted TC pattern).
  • Septic or acute medical illness cardiomyopathy: ~50% of septic patients develop a septic cardiomyopathy. It results from the myocardial depressant effect of cytokines (TNF-α) and is usually characterized by diffuse global hypokinesis rather than a TC pattern. A subgroup of patients develops a typical TC pattern, depending on the relative effect of catecholamine surge vs. cytokines. The RV is involved as well. Septic cardiomyopathy always normalizes within 7–10 days.

IX. Infiltrative restrictive cardiomyopathy: Amyloidosis

Amyloidosis is the aggregation of misfolded proteins, called amyloids. There are three forms of cardiac amyloidosis:

  1. Amyloid light-chain (AL) amyloidosis results from myocardial light chain deposition and may be primary or secondary to multiple myeloma. It is seen at an age over 40–50 and is associated with amyloid renal failure and nephrotic syndrome, macroglossia, jaw claudication, and bruising around the eyes.
  2. Mutant transthyretin amyloidosis results from the amyloid deposition of transthyretin fragments (autosomal dominant). It leads to cardiomyopathy and peripheral or autonomic neuropathy (no renal involvement). Nearly 3.4% of African Americans carry a specific transthyretin mutation, which is autosomal dominant but has a low penetrance (~10-20%), and late expression (mean age 69), mimicking senile transthyretin amyloidosis.
  3. Wild-type (senile) transthyretin amyloidosis occurs most commonly in elderly men (median age 75) but may be seen in women (5-50% of cases are women). It may lead to neuropathy as well, in ~10% of the cases, albeit less commonly and less severely than genetic amyloidosis. It is the most common form of cardiac amyloidosis.

Transthyretin (TTR) is a tetramer, which means it is made up of 4 copies of the same protein. As long as the 4 copies remain linked, no pathology occurs. Should the tetramer break apart, the resulting monomers misfold and aggregate in the heart and peripheral nerves causing amyloid fibrils. Both mutant and senile transthyretin amyloidosis result from this same process of transthyretin dissociation; mutation (in the former) or aging (in the latter) results in an unstable transthyretin that is more likely to break, particularly in areas of high shear stress, like the heart. Both are more slowly progressive than AL amyloidosis (survival after HF onset: 5 years vs. 15 months); patients with TTR amyloidosis typically have more pronounced abnormalities of wall thickness and hemodynamics than AL amyloidosis, yet look better clinically. AL amyloidosis is clinically more severe despite more subtle echocardiographic findings.50,51

Carpal tunnel syndrome, typically bilateral, is prevalent in all types of amyloidosis and may precede clinical presentation by several years. Spinal stenosis may be seen in senile amyloidosis from spinal ligament infiltration.

A. ECG and echo features

Amyloidosis leads to severe myocardial thickening (mean septal thickness 15 mm in AL amyloidosis, 18 mm in senile amyloidosis), mimicking hypertrophic cardiomyopathy. The thickening may occasionally (20-25%) be asymmetric and lead to LVOT obstruction. Think of amyloidosis whenever hypertrophic cardiomyopathy (HCM) or hypertensive cardiomyopathy is considered and before finalizing the diagnosis, whether in the young (mutant TTR amyloidosis) or the elderly (wild-type TTR or AL amyloidosis). Hints to amyloidosis are initially derived from the ECG. Amyloidosis’ ECG classically shows: (1) low-voltage QRS and (2) pseudo-Q waves. A truly low voltage is insensitive and is only seen in 30 % (transthyretin) to 50% (AL) of the cases. However, the near universal finding is that the QRS voltage is not high and is disproportionately low relatively to the LV thickness.

Additional hints are derived from the echo, specifically the 2D speckle strain echo: the longitudinal strain is abnormal at the base but normal “red” at the apex (=apical sparing, apical/base ratio >1). This abnormal base/normal apex differentiates amyloidosis from HTN or HCM with 70-80% sensitivity and specificity (in HCM and HTN, strain may be abnormal in a different, patchy way, or may be normal).55 Also, valvular thickening, RV thickening, and especially interatrial thickening are characteristic of amyloidosis. AS may be combined with senile amyloidosis: the shear stress of AS increases TTR deposition, causing ~10% of elderly AS to be associated with TTR amyloidosis.

B. Diagnosis

After being suspected by ECG and echo features, the diagnosis of amyloidosis is established via ordering 2 tests (Figure 5.1):50,51,54

  1. For the diagnosis of TTR-amyloidosis (genetic or senile): Myocardial nuclear scan using bone scintigraphy tracers (e.g., technetium pyrophosphate), which are taken up by the cardiac amyloid tissue. A cardiac uptake that equals or exceeds rib uptake is highly sensitive (>99%) and specific (86%) for transthyretin amyloidosis (occasionally positive with AL amyloidosis, ~30%).
  2. For the diagnosis of AL-amyloidosis: Serum and urine immunofixation electrophoresis (more sensitive than simple electrophoresis) looking for a monoclonal M peak, and serum free light chain (sFLC) assay (the latter measures the levels of free light chains kappa and lambda and reports the kappa/lambda ratio, which could be abnormally high or low in AL amyloidosis). The combination has a 99% sensitivity for the diagnosis of AL amyloidosis.

Additional supportive tests may be performed:

  • Cardiac MRI, showing global subendocardial LGE and/or marked extracellular volume expansion is 90% sensitive and specific for any cardiac amyloidosis. The atrial thickening manifests as atrial LGE.
  • Genetic testing may be performed once myocardial scan confirms TTR amyloidosis, to distinguish mutant TTR from wild-type TTR amyloidosis.
Schematic illustration of diagnosis of amyloid cardiomyopathy.

Figure 5.1 Diagnosis of amyloid cardiomyopathy. If both tests are positive, the diagnosis is generally AL amyloidosis, but may be TTR amyloidosis with incidental monoclonal gammopathy: biopsies are needed to establish a diagnosis.

Incidentally, 2-8% of elderly patients have monoclonal gammopathy of undetermined significance and may have a monoclonal peak unrelated to the cardiomyopathy.50,51 Biopsy is needed when monoclonal protein testing is abnormal, even when scintigraphy is positive, to establish amyloidosis and distinguish AL vs TTR:

  • Periumbilical fat pad biopsy (sensitivity 60-80% in AL amyloidosis and mutant TTR amyloidosis, but only 14% in senile TTR amyloidosis).
  • Bone marrow biopsy, looking for amyloid deposits (AL or TTR) and for plasma cells (>10% plasma cells in multiple myeloma and sometimes in primary AL amyloidosis).
  • Endomyocardial biopsy if the above 2 biopsies do not show amyloid deposits (~100% sensitivity for the diagnosis of cardiac amyloidosis). The tissue sample should be subjected to protein analysis to confirm the subtype of amyloid (light chain vs. transthyretin).

C. Treatment

LV cavity is small and stiff and is unable to expand and accept the increased venous return (limited preload reserve). Hence PCWP is severely elevated despite a normal or reduced preload, which precludes the use of significant doses of diuretics. Digoxin should be avoided as it has a high affinity for the amyloid material and thus a high toxicity even at therapeutic doses. The severely limited stroke volume reserve may lead to profound hypotension with vasodilator therapy, such as ACE-I, as stroke volume cannot rise to match the dilated circulation. Also, this limited stroke volume makes cardiac output dependent on heart rate and explains the intolerance to β-blockers. Autonomic dysfunction further compounds hypotension. AF is highly prevalent in senile amyloidosis and is challenging to rate control: first, a higher heart rate should be respected in restrictive cardiomyopathy, as cardiac output depends on it; and second, amyloid patients very poorly tolerate CCB and β-blockers. Amiodarone may be the only option, even for rate control.

Transthyretin amyloidosis, whether senile or mutant, has a better prognosis than AL amyloidosis and is responsive to 2 agents: tafamidis or diflusinal. Tafamidis binds to transthyretin and prevents its dissociation into monomers and has shown a large reduction of all-cause mortality (29% vs 42% at 2.5 years, ATTR-ACT trial).52 Diflusinal is another transthyretin stabilizer but it is a NSAID and thus, may be risky in HF.

Regarding amyloidosis concomitant to severe AS: one prospective study tested all AS patients undergoing TAVR (mean age 83.4) with scintigraphy and found ~10% prevalence of amyloidosis (vs. <1% in an unselected population aged over 80). TAVR dramatically improved their outcomes, with a similar 2-year survival to TAVR performed for lone AS, despite a limited use of tafamidis.53 TAVR reduces LV shear stress and may slow the amyloid process.

AL amyloidosis is treated with chemotherapy, immunotherapy, and bone marrow transplant. When cardiac involvement is advanced with severe, refractory HF, the prognosis is guarded, and the patient is unlikely to tolerate high-dose chemotherapy.

The myocardial thickness does not usually change with therapy; however, myocardial strain and diastolic function improve in responders, and NT-pro BNP declines by >30%.

X. Other infiltrative restrictive cardiomyopathies

A. Sarcoidosis

See Section 1.VI.

B. Hemochromatosis

Hemochromatosis is an autosomal recessive disorder characterized by multi-organ iron deposition leading to infiltrative cardiomyopathy, diabetes, skin tanning, and cirrhosis. Ferritin and iron saturation are elevated.

C. Fabry disease: genetic metabolic storage disorder

Fabry disease, an X-linked deficiency of α-galactosidase, leads to deposition of glycosphingolipids in the myocardium (LV ± RV thickening) and the kidneys (advanced renal failure), and sometimes the skin and the nervous system. It manifests in men but also heterozygous women. Accessory pathways are common. As opposed to the low QRS voltage of amyloidosis, high voltage (LVH) is seen in Fabry. The severe manifestations are usually seen in the third or fourth decade of life, but sometimes later, especially in women. The diagnosis may be established by a tissue biopsy, genetic testing, but also by checking galactosidase activity on peripheral leukocytes. The disease is treatable with α-galactosidase infusions.

D. Loeffler endocarditis is secondary to chronic severe systemic eosinophilia: Churg-and-Strauss disease, primary (neoplastic) hypereosinophilic syndrome, or systemic parasitic infection. It leads to severe eosinophilic endocardial infiltration with secondary restrictive cardiomyopathy, MR/TR, and cavitary thrombus formation. It is treated with steroids ± antiparasitic agents in case of systemic parasitic infection.

An overlapping disorder, endomyocardial fibrosis, is a form of Loeffler endocarditis that progresses to extensive endocardial fibrosis. It is seen in tropical Africa, tropical America, and the Middle East.

E. Autoimmune rheumatic diseases: Scleroderma, lupus, rheumatoid arthritis, mixed connective tissue disease, polymyositis/dermatomyositis, vasculitis. Those disorders may lead to: (i) myocardial inflammation then fibrosis with a variety of patterns on MRI: epicardial, subendocardial, transmural or diffuse; (ii) microvascular disease with abnormal vasoreactivity, or CAD; and (iii) even valvular disease (valvular disease only with lupus and scleroderma).


I. Stages of HF

  • Stage A: Patients at risk for HF, but without structural heart disease or HF (e.g., HTN, CAD without MI, diabetes)
  • Stage B: Structural heart disease but no HF (e.g., previous MI, LVH, reduced EF, or severe valvular disease)
  • Stage C: Structural heart disease with prior or current HF functional class II, III, or IV (unlike stage D, it is not refractory to medical therapy)
  • Stage D: HF functional class IV or advanced class III refractory to medical therapy, recurrently hospitalized

Stage D Neurohormonal therapies (ACE-Is, β-blockers, spironolactone) should be sequentially tried at very low doses in stage D patients if SBP is ≥85 mmHg and in the absence of severe signs of hypoperfusion. Medical therapy is, however, poorly tolerated at this stage (hypotension and worsening of renal failure occur with ACE-Is; hypotension and worsening of HF occur with β-blockers).

In addition, stage D patients may not be able to be weaned off inotropic therapy because of severe low output and low organ perfusion, and these patients may require chronic outpatient inotropic support. IABP, including long-term ambulatory IABP support for weeks via axillary access, may be used while awaiting LVAD or transplant. IABP is superior to inotropes in raising SvO2 and cardiac power output.56

II. Cardiac transplantation

A. Indications

The 5-year survival after cardiac transplantation is ~70–75%. Transplant is indicated in HF patients whose 2-year survival is <50% (ACC and transplant society):57,58

  • Patients dependent on IABP or percutaneous ventricular assist device (highest priority for transplantation); and patients dependent on inotropes. Patients with a properly functional LVAD have a lower priority for transplantation.
  • Patients with class III or IV HF that is refractory to medical therapy (stage D), with peak O 2 consumption ≤14 ml/kg/min on a maximal cardiopulmonary stress testing where anaerobic threshold is achieved (it is quickly achieved in severe HF, e.g., 1 min), and with objective evidence of impaired hemodynamics on right heart catheterization (high filling pressures, reduced CO). These patients have typically had multiple HF hospitalizations in the last year. LVEF is usually <30% but not necessarily (e.g., restrictive cardiomyopathy). A 12 ml/kg/min cutoff is used in patients receiving β-blockers.*
  • Young patients (<50) with peak O2 consumption ≤50% of the predicted value have a relative indication for transplant. The muscles of a young patient, particularly a former athlete, have a large capacity to extract O2 even with poor O2 delivery, which allows the patient to maintain borderline O2 consumption even at an advanced HF stage. As such, a higher value may qualify him for transplant.*

B. Contraindications

  • Severe precapillary pulmonary hypertension with PVR >3 Wood units, which is associated with a high risk of postoperative RV failure. Patients with any PVR elevation should undergo a vasodilator challenge (e.g., nitroprusside) to assess PVR reduction. If PVR does not decrease acutely, short-term (24–48 hours) therapy with inotropes, diuretics, and vasodilators (milrinone, nitroprusside), +/- IABP may be performed with continuous hemodynamic monitoring. If PVR can be reduced to <3 Wood units, the patient becomes a transplant candidate with perioperative vasoactive therapy.57 In those with refractory pulmonary hypertension, the complete LV unloading with LVAD is often effective in reversing pulmonary hypertension 3 to 6 months later and bridging the patient to transplant.58
  • Uncontrolled diabetes, irreversible renal dysfunction (GFR <40), cirrhosis, or treated cancer in the last 5 years.
  • Active tobacco usage in the last 6 months, current or ± recent (2 years) alcohol or drug use.
  • Obesity (BMI >30) is a strong relative contraindication, as it is associated with twice the 5-year mortality and a higher risk of rejection and allograft vasculopathy.
  • Age >70 is a relative contraindication.

C. Notes

ABO compatibility is important but not Rh compatibility (Rh is not expressed on myocardial cells). Testing for preformed HLA-reactive antibodies, or panel reactive antibodies, is performed in the recipient, and is repeated after blood transfusions, as those can trigger HLA antibodies (anti-leukocytes).

A hyperacute rejection occurs within minutes to hours and results from ABO incompatibility or anti-HLA antibodies, and is usually fatal unless treated urgently with retransplantation or mechanical support. Acute cellular rejection is T-cell mediated and is the most common type of rejection, the one for which immune therapies are used. It is most common in the first 3 months, but late rejections can occur. It is caught early on surveillance biopsies.

D. Immune therapies

Immune therapies consist of a calcineurin inhibitor (cyclosporine, tacrolimus) and an antimetabolite (azathioprine, mycophenolate), an inhibi- tor of cell proliferation. Steroids are used early on but are tapered and sometimes discontinued later on. Sirolimus is frequently used instead of a calcineurin inhibitor. Sirolimus has the advantages of less allograft vasculopathy and less renal failure than calcineurin inhibitors. Sirolimus needs to be stopped 1 week before and 4–6 weeks after elective surgery and replaced by calcineurin inhibitors to allow wound healing.

Statin therapy started early after transplantation reduces mortality, rejection, and cardiac allograft vasculopathy.59

E. Complications

  1. Acute rejection occurs most frequently in the first few months after transplant but may occur later. It is the leading cause of death in the first month after transplant. Surveillance biopsies are performed weekly early on, then monthly up until 6 months, then every 3–6 months.

    A clinical acute rejection is an emergency. It should be suspected in any transplant patient presenting with acute HF, especially if fever is present. When suspected clinically, it should be treated emergently with IV steroids, even before a biopsy is performed.

  2. RV failure is the second leading cause of death in the first month, particularly in patients with irreversible pulmonary hypertension.
  3. Nosocomial infections occur in the first 30 days and are followed by opportunistic infections, such as pneumocystis, cytomegalovirus, toxoplasmosis, especially in the first 6 months. The latter are prevented by trimethoprim/sulfamethoxazole and antiviral prophylaxis.
  4. Malignancy, especially skin cancers and lymphomas.
  5. Renal dysfunction, mainly from calcineurin inhibitors.
  6. Cardiac allograft vasculopathy: this is a diffuse and progressive coronary arteriopathy characterized by excessive proliferation of the intimal layer. The mechanism is both immune and non-immune (metabolic syndrome, hyperlipidemia, older age, prolonged ischemic time), and it is the leading cause of death beyond the first year of cardiac transplantation, with an estimated incidence of 8% in the first year, 30% within 5 years, and 50% within 10 years. Since it is a progressive process, the definitive treatment is eventually retransplantation, which is required when the diffuse disease becomes severely obstructive. Being diffuse, the disease is missed or underestimated by coronary angiography and is better assessed by IVUS. Preliminary therapy consists of PCI for focal stenoses, statin, switching to sirolimus, and aggressive therapy of the metabolic syndrome. Many centers recommend yearly coronary angiography with IVUS as a screening modality for this vasculopathy, although it does not change immediate management. IVUS is more sensitive than angiography for detection of this diffuse process, which is characterized by diffuse intimal thickening >0.5 mm over >180 degrees arc.60 Also, IVUS can assess the true severity of coronary obstruction.

III. Left ventricular assist devices (LVADs)

LVADs may be used as a bridge to transplant. They help stabilize patients hemodynamically so they can tolerate medical therapy (ACE-Is, β-blockers, spironolactone). They improve organ perfusion and kidney function, PA pressure and survival rate, and make patients better candidates for transplant. LVADs may also be used as a destination therapy in patients ineligible for heart transplant, or a bridge to a possible myocardial recovery (e.g., reperfused MI with cardiogenic shock, severe myocarditis, post-cardiac surgery shock, severe but possibly reversible non-ischemic cardiomyopathy). The destiny of the LVAD is sometimes only elucidated with time. Many patients with non-ischemic cardiomyopathy improve significantly with the combination of LVAD and medical therapy, their ventricles recover, and LVAD may be explanted after 1–2 years (~15–20%).61

In the REMATCH trial of refractory class IV HF, HeartMate LVAD drastically improved survival at 1 and 2 years in patients with any advanced cardiomyopathy who were not transplant candidates (survival at 1 year was 52% with LVAD vs. 25% without LVAD).62

A. Types of ventricular assist devices

LVAD supports the LV and consists of a pump, an inflow cannula inserted in the LV apex and an outflow cannula inserted in the ascending aorta. Those three components are intracorporeal, with the pump in the preperitoneal or pericardial space; in older devices, the pump was extracorporeal. The pump is connected to an external controller and an external battery through a transcutaneous driveline, a potential source of infection.

A right ventricular assist device (RVAD) supports the RV, the inflow cannula being inserted in the RA or RV and the outflow cannula in the PA. BiVAD consists of LVAD and RVAD. RVAD is not as effective in supporting the right circulation as LVAD is for the left circulation. This is because the reduced vascular resistance on the right side can induce excessive pump flow into the pulmonary circulation, with a resultant pulmonary congestion and flow-induced severe pulmonary hypertension. Pump speed must be adjusted to a lower speed, and RVAD only used temporarily. Also, the requirement for additional surgeries for implantation and explantation increases the bleeding and infectious risk.

There are several pump designs:

  1. The first-generation devices, such as HeartMate, had a pulsatile pump with two valves. Despite improving mortality, the HeartMate device had a high malfunction rate of 35% at 2 years in the REMATCH trial, which translated into a drop of 2-year survival to 24% (albeit much better than no device).
  2. Continuous-flow axial pump, such as HeartMate II: since no reservoir is needed, these devices are much smaller and require less energy, with less risk of malfunction. In the HeartMate II trial, the HeartMate II device was associated with a substantially lower rate of reoperation to repair or replace the pump at 2 years (10% vs. 36%), and less infection and bleeding (less surgical dissection), which translated into a better 2-year survival in comparison with HeartMate (58% vs. 24%).63
  3. Continuous-flow centrifugal pump (such as HeartMate 3 and HeartWare). The rotor is magnetically levitated with no mechanical

bearings, allowing a smaller size with fully intrathoracic positioning; one trial suggested less pump thrombosis and need for reoperation with HeartMate 3 vs HeartMate 2 (Momentum 3 trial).

The flow generated by the continuous-flow devices depends on the pump’s “delta pressure,” which is the uphill outflow pressure (aorta) minus the inflow pressure.35 The lower this delta pressure, the higher the flow. A higher outflow pressure translates into a lower pump flow, hence the importance of keeping a low afterload (mean BP <90 mmHg) and a high preload.

Depending on the remaining intrinsic cardiac output, some pulsatility is seen with non-pulsatile devices. The residual LV contraction generates an inflow pressure that is higher in systole than diastole, and thus flow through the pump is higher in systole than diastole. Hypotensive patients with severely reduced LV systolic pressure and increased LVEDP have the lowest pulsatility. Overall, the extra flow provided by the pump is highest in patients with the worst intrinsic function, where aortic pressure is reduced and inflow is high in diastole. A centrifugal pump is more sensitive to delta pressure changes and may shut off its flow if delta pressure is high.64

B. Indications for LVAD and other considerations

The hemodynamic indications for LVAD are similar to those for transplant:

  • Refractory NYHA class IIIB or IV, including patients with frequent readmissions for HF despite appropriate medical therapy, or low-output patients who cannot tolerate β-blocker/ACE-I therapy
  • and EF ≤25%
  • and Peak O2 consumption ≤14 ml/kg/min, or inotrope dependence for over 2 weeks, or IABP dependence for over a week (HeartMate II trial criteria).63,65

The most definitive indication for LVAD is inotrope dependence. It is unclear whether the risk of LVAD therapy (stroke, bleeding, sepsis, AI) is warranted in patients who are not inotrope-dependent, but may be so in severe functional limitation (ROADMAP study).66

Patients may be treated with IABP for weeks while awaiting LVAD placement. Transaxillary IABP permits ambulation.56

Age and obesity are not significant contraindications to LVAD.

Fixed pulmonary hypertension, a contraindication to cardiac transplantation, is not a contraindication for LVAD, which frequently allows the reversal of pulmonary hypertension. On the other hand, it is important to address baseline RV failure prior to LVAD implanta- tion. In fact, in patients with RV dysfunction, a high PA pressure may be more favorable for LVAD implantation than a normal PA pressure, as a high PA pressure predicts better RV function. RV failure is a major complication that occurs in up to 20% of patients post-LVAD and is predicted by the presence of elevated RA pressure (RA pressure >20 mmHg or RA pressure >0.63 × PCWP), reduced RV stroke work index, PA pulsatility index <2,* or preoperative signs of RV dysfunction on echocardiography. LV unloading by LVAD is beneficial for the RV, and the RV eventually improves in most of these patients. Early on, however, total LV unloading can shift the septum to the left and further exaggerate RV dilatation and reduce the septal contribution to RV function. Also, the surging LV output increases the preload of the RV and overwhelms it. RV failure is treated conservatively with inotropes and pulmonary vasodilators but may require RVAD if refractory.65

Patients with severe AI need to have AVR concomitant to LVAD placement, to avoid a closed loop circulation between the LV and the aorta. Bioprosthetic rather than mechanical AVR is used to reduce the risk of thrombosis of this unloaded valve; if the patient has a prior mechanical AVR, it may need to be replaced with a bioprosthetic AVR.

C. Some technical aspects

The following LVAD parameters are displayed:

  1. Pump speed, in rpm, is the only adjustable LVAD variable.
  2. Power is the energy generated by the LVAD. Power correlates with pump speed and pump flow (it takes more work to move more blood), and inversely correlates with the resistance that opposes the LVAD flow (delta pressure).
  3. Pulsatility index (range 1-10) corresponds to how much cardiac output is generated by the native LV. The lower the pulse index, the higher the amount of support provided by the pump, reflecting severe LV dysfunction, although a low preload is also a possibility.
  4. Flow correlates with pump speed and inversely correlates with delta pressure (like power). It is not directly measured, but rather calculated based on pump power and speed, and blood viscosity (hemoglobin).

Power and pulse index are measured by the LVAD; flow is not directly measured but calculated.

Causes of increased power – For the same speed, an increase in power may correspond to an increase in flow. This may result from high metabolic demands or vasodilatation, in which case the pulse index is also high as the intrinsic LV flow increases; or may simply be an excessive pump flow with a resultant HTN. The latter case dictates a reduction of the pump speed.

+An increase in power may also indicate rotor pump thrombosis; the flow estimate is paradoxically and falsely increased.

Causes of reduced power – Reduced power correlates with reduced flow and indicates low preload or high afterload. For example, it may indicate an empty LV with a suckdown of the LV walls. It may also indicate RV failure, tamponade, inflow or outflow obstruction (kink or thrombosis), or HTN (mean BP should be kept <90 mmHg).

Since pulsatility is significantly attenuated with continuous-flow devices, the pulse is often not palpable and blood pressure measure- ment may be difficult non-invasively. An arterial Doppler is used during non-invasive BP measurement; the continuous noise heard during BP cuff deflation corresponds to mean BP. The mean BP goal is 65–90 mmHg.

HTN dramatically increases stroke risk in LVAD patients. It may be due to high pump flow, or more often, to vasoconstriction that actually impedes pump flow. The latter case requires antihypertensives.

In a patient with VAD, hypotension may be:

  • VAD-related: RV failure; VAD pump failure or thrombosis; LV suction or excessive pump speed
  • Not VAD-related: sepsis, tamponade, hemorrhage

LV suction onto the inflow cannula, per se, is secondary to hypovolemia, RV failure, or high pump speed and is treated with fluid administration and slowing the pump speed. On echo, the septum should be kept in the middle; a septum that is excessively pulled towards the LV mandates a reduction of the LVAD speed. A dilated LV may imply LVAD pump thrombosis or low speed.

Ramp test consists of progressively incrementing LVAD pump speed in patients with suboptimal LV unloading or suboptimal PCWP, while assessing: (i) by echo, LV size (reduce it without bowing the septum to the left) and RV size (avoid dilating it); (ii)+/- by RHC, PCWP and RA pressure; and (iii) LVAD parameters.

D. Complications

  1. Device failure:

    • Continuous-flow axial pumps: the failure of axial pumps can be catastrophic, as these pumps lack valves, which creates the equivalent of severe AI.
    • Pulsatile pumps: failure of the pump is less catastrophic than with an axial pump, as the valves protect from severe regurgitation of flow. However, failure of one of the valves can create the equivalent of severe AI.

  2. Sensitivity to low preload: axial pumps generate such a negative pressure that there is a risk of collapse of the ventricle leading to flow cessation, thrombus formation, hemolysis, and VF. This issue is further compounded by the fact that the flow of axial pumps does not cease with a low inflow pressure and keeps sucking. Conversely, centrifugal pumps stop pumping when the inflow pressure is very low and the inflow–outflow uphill gradient is high (better response to physiology).
  3. RV failure (~20%, early or late after LVAD placement). It is acutely treated with inotropes and inhaled pulmonary vasodilators (NO), then RVAD if it is refractory.
  4. Infections (~20% at 2 years).
  5. Thromboembolic complications: except for the first HeartMate, LVAD implants require warfarin therapy. HeartMate II requires INR of 2–3.34 In the HeartMate II post-approval study, ~12% of patients had a stroke at 2 years.
  6. Hemorrhagic complications (54% at 2 years), including a high risk of postoperative bleeding because of liver congestion, poor nutrition, and warfarin therapy. Also, the continuous flow may lead to arteriovenous malformations and may degrade von Willebrand factor, resulting in GI bleed. If bleeding persists, urgent cardiac transplantation may be needed to allow withdrawal of LVAD and anticoagulation.
  7. AI: as blood flows through the LVAD, it bypasses the aortic valve and causes it to remain closed and eventually fuse. Aortic valve fusion leads to AI, a serious complication that may develop in up to 30% of LVAD patients at 3 years and requires AVR. Adjusting LVAD speed to have intermittent aortic valve opening reduces this risk.
  8. Hemolysis with continuous pumps, more so in case of pump thrombosis.
  9. Arrhythmias such as VF. When stable LVAD patients develop VF, they feel tired but they do not develop circulatory arrest. The LV becomes fully dependent on the pump. The RV arrests but in stable patients with low PA pressure, blood flows passively through the arrested RV, similarly to a Fontan circulation. This does not apply to the early postoperative period, where the RV function is critical in surpassing the left septal pull and the high PA pressure.


I. LV diastolic pressure in normal conditions and in HF (whether systolic or diastolic)

Normally, LV diastolic pressure slightly increases throughout diastole and has an initial dip in early diastole that “sucks” blood from the LA, particularly in young patients with a highly compliant LV (“suckers”). LV end-diastolic pressure (LVEDP) is the LV pressure that immediately follows the A wave; in normal individuals, this pressure approximates LV diastolic pressure before the A wave.

An elevated LVEDP (>16 mmHg) usually signifies LV dysfunction and is the most used surrogate of LV dysfunction (systolic or diastolic dysfunction). In fact, an elevated LVEDP with normal EF and normal LV volume equates with LV diastolic dysfunction and is a prerequisite for defining diastolic heart failure. In patients with clinically compensated LV systolic or diastolic dysfunction, LV pressure only increases significantly at the end of diastole, particularly after atrial contraction, which may lead to an elevated LVEDP and an increased LV “A” wave despite a normal or mildly elevated pre-A LV diastolic pressure and mean LV diastolic pressure (Figure 5.2). This correlates with S4 on physical exam and transmitral E/A reversal on echocardiography. A compliant LA will accommodate the volume load during systole and early diastole, keeping its pressure normal or minimally elevated until late diastole. Thus, mean LA pressure is normal and is discrepant with the elevated end-diastolic LV and LA pressure. The patient is not in pulmonary edema at rest but may increase LA pressure with any stress.

Schematic illustration of simultaneous LA and LV pressure recordings in diastole.

Figure 5.2 Simultaneous LA and LV pressure recordings in diastole.

  1. Normal. Assess:

    1. LV relaxation pattern, as manifested by the sharpness of LV descent. The relaxation descent of the LV is evaluated by the variable tau, which corresponds to the full duration of relaxation. On tissue Doppler, LV relaxation is best characterized by the annular velocity E’ (E’= myocardial recoil or relaxation).
    2. LV stiffness and compliance, as manifested by the slope of LV diastolic pressure (the sharper it is, the less compliant the LV is), and by the post-A LV pressure or LVEDP.
    3. Early diastolic gradient between LA and LV. This early gradient is determined by LV relaxation (sucking effect of the black curve) and by LA pressure (pushing effect of the blue curve), and corresponds to E wave on Doppler.

  2. Diastolic dysfunction is characterized by two features: poor LV relaxation and reduced LV compliance. Poor LV relaxation explains the absence of the LV dip in early diastole. This leads to poor early diastolic LV filling. Reduced LV compliance explains the elevated LVEDP: when the volume that has cumulated in the LA in early diastole suddenly rushes into the LV during A wave, LV pressure strikingly increases leading to elevated LVEDP (arrow). Note that LV diastolic pressure and LA pressure are normal outside A wave, particularly when LA is compliant enough to prevent an increase in LA pressure outside A wave. E/A is reversed and E’ is reduced.
  3. In decompensated LV diastolic or systolic dysfunction, LA pressure is high with an early LA–LV diastolic gradient (= LA pressure is a “pusher” in early diastole). The LV relaxation slope is slow, hence the diminished early LV diastolic dip. LV is also poorly compliant, more so than in compensated dysfunction, and this manifests as a sharp increase in LV pressure after the dip, which quickly attenuates the LA–LV pressure gradient and LV filling. E is high but narrow because the flow is very brief, which explains the short E deceleration time. Despite the increase in LV pressure during A wave, there is no significant flow during A wave (small A with E/A >1.5–2). Since E = LA pressure × LV relaxation; and E’ = LV relaxation → E/E’ = LA pressure.

In decompensated or acute LV failure (systolic or diastolic failure), the early diastolic LV compliance is overwhelmed, leading to increased LV pressure throughout diastole. LA compliance is also overwhelmed, which increases LA pressure and allows it to “push” flow into the LV. A high early diastolic LA–LV gradient corresponds to a large E wave and a high E/A ratio on echocardiography. The large early filling leads to S3 on physical exam, which is heard at the end of the LV diastolic dip, when the LV is stretched to its limit. Thus, isolated S4 represents elevated LVEDP but normal pre-A LV diastolic pressure, while S3 represents volume overload of the LV and LA and a “push” from LA to LV in early diastole.67

Nov 27, 2022 | Posted by in CARDIOLOGY | Comments Off on Additional Heart Failure Topics

Full access? Get Clinical Tree

Get Clinical Tree app for offline access