Pathophysiology and Etiologyof Heart Failure

Frances L. Johnson, MD

KEYWORDS

� Heart failure � Pathophysiology � Etiology � Diagnosis

KEY POINTS

� Diagnosis and treatment of heart failure require careful evaluation of each patient.

� Diagnostic testing is highly influenced by the quality of the initial evaluation and the identification ofcomorbid conditions.

� Categorizing a patient’s cardiomyopathy will help guide therapy and lend prognostic value as stan-dard and new treatments are applied.

INTRODUCTION

Examining the etiology and underlying pathophysi-ology of heart failure (HF) is an often neglected butimportant aspect of treating the condition. Identi-fying an underlying cause, whenever possible, willallow for optimal care of each patient and guiderational treatment. Treatment requires more thanrote application of evidence-based pharmaco-therapy. An example is the challenge of HF withpreserved ejection fraction. Although therapy forsystolic HF is well grounded in data from random-ized clinical trials, the large ADHERE Registryshowed that nearly half of all patients in the UnitedStates with acutely decompensated HF havepreserved ejection fraction (>50%).1 This equallymorbid condition is one for which there are few ran-domized treatment trials.2 Clinicians must still useknowledge and skills grounded in their understand-ing of pathophysiology.

This article reviews common mechanisms in thepathophysiologyofHF, and categorizes somecom-mon cardiomyopathies. Testing that is informativeabout underlying pathophysiology is discussedwithin the context of mechanisms, while tests

The author has the following financial relationships: IntelIntellectual property with stock options: XDx, Inc. Paid coSponsored Clinical Trials: BiocontrolMedical (USA), CelladSystems, Inc.Division of Cardiovascular Medicine, Carver College of MGH, Iowa City, IA 52242, USAE-mail address: frances-johnson@uiowa.edu

Cardiol Clin 32 (2014) 9–19http://dx.doi.org/10.1016/j.ccl.2013.09.0150733-8651/14/$ – see front matter � 2014 Elsevier Inc. All

used to diagnose specific cardiomyopathy typesare mentioned in the compendium of etiology.

COMMON PATHOPHYSIOLOGICMECHANISMS IN HEART FAILURE

Our understanding of cardiac pathophysiology iswell developed. Whole organ physiology hasbeen informed over the past 30 years by discov-eries of humoral and cellular mechanisms thatwere elucidated by techniques of molecularbiology. Today, genetic and proteomic discoveriesfurther deepen our understanding of old paradigmsand identify new ones. Pathophysiologic mecha-nisms of HF coexist and evolve over the courseof the condition.

Structural Heart Disease and MechanicalStress: Pressure/Volume Overload

Hemodynamic principles are centered on knowl-edge of the heart as a pump. It has propertiesthat allow for increased blood flow commensuratewith bodily needs such as exercise under normalconditions by increasing heart rate, stroke volume,

lectual property licensedwith royalties: Comentis, Inc.nsulting: Sorbent Therapeutics Executive Committee.on, Inc, CardioMEMs, Inc, Corthera, Inc, NIH, Syncardia

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Johnson10

or both. Increased ventricular preload augmentscontractility, but excessive pressure and volumecauses a plateau, then reduction in contractionforce. Frank and Starling illustrated this with land-mark hemodynamic studies in the early twentiethcentury, and the term “Starling’s Law of the Heart”was coined to describe it.3 Subsequent study ofchronic HF confirmed the validity of Starling’sLaw, but more importantly defined a spectrum ofanatomic and hemodynamic profiles associatedwith chronic pressure and/or volume overload.4

The hemodynamic model of HF is one of ventric-ular remodeling. Abnormal hemodynamics leadsto remodeling, which leads to further abnormalitiesin hemodynamics. Primary and compensatorychanges in geometry and performance vary by thetype of HF. Classic examples include pressure-overload conditions such as hypertension andstenotic valves, which result in hypertrophy of theaffected ventricle, increased myocardial stiffness,and restricted stroke volume in relation to left ven-tricular mass. Volume-overload conditions such asvalvular regurgitation usually lead to ventriculardilation, elevated end-diastolic pressure, and, ulti-mately, reduced systolic function. Conditions thataffect contractility, such as myocardial infarction orprimary myopathy, produce both pressure andvolume overload. Reduced systolic function in-creases ventricular end-diastolic pressure, andcauses both ventricular dilation and increasedmass (Fig. 1). The ultimate result of all pathologic re-modeling is a reduction in cardiac output over arange of loading conditions, and dyspnea oredema associated with chronically elevated fillingpressures.All patients with HF should have the extent of

structural heart disease defined. Transthoracic

Fig. 1. Remodeling in heart failure. Gross pathologyshows marked biventricular dilation with normalthickness in a patient with chronic systolic heart fail-ure. Overall ventricular mass is increased. (Courtesyof Dennis Firchau, MD, Department of Pathology,University of Iowa Carver College of Medicine, IowaCity, IA.)

echocardiography (TTE) remains the initial test ofchoice for the assessment of structural heartdisease and hemodynamics. It can accuratelydelineate ventricular size, systolic and diastolicfunction, and valvular morphology in most pa-tients. Doppler waveform velocities can accuratelyestimate key intracardiac and extracardiac pres-sures and valve areas when image quality isgood. TTE is readily available in most practicesettings, is noninvasive, and takes little time toperform. Its principal limitation is poor imagequality in the obese, those with obstructive lungdisease, and those with chest-wall deformities orimplanted material that limits sonographic imagequality. The right ventricle can be difficult to visu-alize with sufficient detail to accurately assesssystolic function.5,6

In patients for whom TTE is not adequate, car-diacmagnetic resonance imaging (CMR) or cardiaccomputed tomography (CT) can be performed.CMR has several advantages. Measurements ofvolume, mass, and ejection fraction of both ventri-cles are very accurate and reproducible. Abnormal-ities involving the great vessels, valvular lesions,shunts, and the extent of ischemic myocardialfibrosis can be well defined. It is particularly usefulfor early-stage disease, regurgitant valves, congen-ital heart disease, and specific cardiomyopathies.7

A CMR scan performed for HF should include gad-olinium perfusion when possible, which allows forquantitation of ischemic fibrosis and inflammation(Fig. 2). Patients with metal in situ are usuallyexcluded from scans, and those with a glomerularfiltration rate of less than 30 mL/min should notreceive gadolinium because of the risk of cuta-neous sclerosis.8–15

Fig. 2. Cardiac magnetic resonance imaging (CMR) inheart failure. Gadolinium-enhanced CMR in a patientwith new-onset heart failure. Bright areas (arrow)delineate active inflammation. Myocarditis wasconfirmed by endomyocardial biopsy. (Courtesy ofRobert Weiss, MD, Cardiovascular Medicine Division,University of Iowa Carver College of Medicine, IowaCity, IA.)

Pathophysiology and Etiology of Heart Failure 11

Hemodynamic measurements (pressure, vol-ume, and flow) can often be deduced by knowl-edge of the HF etiology and structural lesions.Alternatively, they can be estimated using echo-cardiography. Understanding a patient’s hemody-namics informs the use of medications, especiallywhen side effects limit evidence-based therapies.The gold standard remains invasive right heartcatheterization with a pulmonary artery catheter.Invasive hemodynamic monitoring has not beenshown to improve mortality in the routine treat-ment of decompensated HF.16 Nonetheless, itcan still be valuable in some circumstances, thefirst of which is during diagnostic heart catheteri-zation for new or worsening HF. Hemodynamicmonitoring is the most accurate way to diagnosewhether elevated pulmonary vascular resistanceor intracardiac shunt is impeding circulatory per-formance, especially if concomitant coronaryangiography and left ventricular end-diastolicpressure do not adequately explain symptoms.Another is when assessing acute response topotent pulmonary or peripheral vasodilators. Afinal indication is critical illness that is not respond-ing to treatment. When performed, invasive hemo-dynamic measurements should be complete andperformed with high fidelity, so that all pertinentcalculations of cardiac output, intracardiac shunt,ventricular stroke work, and pulmonary and pe-ripheral vascular resistance can be performed.5,16

Neurohormonal Dysregulation

The neurohormonal model of HF is largely respon-sible for improved treatment outcomes in chronicsystolic HF. Acutely reduced cardiac output orvascular underfilling leads to baroreceptor-medi-ated sympathetic nervous activity with consequentelevation of heart rate, blood pressure, and vaso-constriction. Although this adaptation mitigatesan acute drop in cardiac output, it is ultimately mal-adaptive and leads to myocardial b-receptordownregulation and uncoupling of contractilityfrom normal stimuli. In chronic HF, increasedadrenergic tone is accompanied by pathologicactivation of the renin-angiotensin-aldosteronesystem (RAAS). Overproduction of angiotensin IIstimulates the adrenal glands to release more cat-echolamines, which in turn stimulate the juxtaglo-merular apparatus in the kidney to release renin.Renin increases vascular tone and pressure over-load on a heart susceptible to hemodynamic injury.Angiotensin II also stimulates the adrenal secretionof aldosterone. Nonosmotic release of vasopressinand elevated aldosterone levels reduce renalexcretion of water and sodium, leading to ex-cessive preload, edema, and dyspnea. It is now

appreciated that neurohormonal imbalances havedirect tissue effects as well.17

The neurohormonal model of HF was a paradigmshift from the hemodynamic model. HF became asystemic disease amenable to pharmacologicblockade of hormonal pathways. This model hasbeen highly effective and remains the foundation ofchronic systolic HF therapy. Other neurohormonelevels are altered inHF, including thenatriuretic pep-tides atrial natriuretic peptide and brain natriureticpeptide (BNP), and endothelin-1, but they have notbeen proven as targets for effective therapy.18

Assessment and monitoring of neurohormonalactivation is largely done on clinical grounds,such as heart rate, blood pressure, and volumestatus. The basic metabolic panel is informative ifhyponatremia is present. Biomarkers such asBNP and its precursor N-terminal proBNP havebeen used to diagnose HF in patients with dys-pnea of unclear etiology.19 It is less clear whetherit can be used to effectively guide medication titra-tion. A study funded by the National Institutes ofHealth, GUIDE-IT (Guiding Evidence Based Ther-apy Using Biomarker Intensified Treatment), willtest this hypothesis.

Ischemic Injury: Replacement Fibrosis andHibernating Myocardium

Ischemic heart disease is thought to be the mostcommon cause of HF in developed countries.Structural changes after myocardial infarction aredue to permanent injury and remodeling. Ischemicreplacement fibrosis leads to elevated intracardiacpressure and myocardial strain. The hemody-namic model of HF explains the consequencesof myocardial infarction well.20

By contrast, hibernating myocardium is a poten-tially reversible condition. The term is used todescribe poorly contracting myocardium resultingfrom constant hypoperfusion without acute injury.The subendocardium is most vulnerable to thistype of injury. Canine models show that adequatesubendocardial myocardial blood flow (SE-MBF)is requisite for normal systolic function. SE-MBFis disproportionately affected by a ratio of 2:1to reductions in transmyocardial blood flow(TM-MBF), meaning that even small reductions inthe transmyocardial pressure gradient will causelarge changes in systolic function. For example,in dogs a 20% reduction in SE-MBF results in se-vere regional systolic dysfunction.21 It is importantto appreciate that conditions associated with HF,such as systemic hypotension and elevated ven-tricular end-diastolic pressures, further reduceTM-MBF and worsen systolic dysfunction inde-pendent of coronary disease.

Fig. 3. Ultrastructural changes in heart failure. Micro-scopic pathology using trichrome staining to high-light excess collagen deposition (blue) and myocytehypertrophy with cell drop-out (red). (hematoxylin-eosin, original magnification 4�). (Courtesy of DennisFirchau, MD, Department of Pathology, University ofIowa Carver College of Medicine, Iowa City, IA.)

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Discrimination of hibernating myocardiumfrom ischemic fibrosis has prognostic value.Revascularization procedures in persons withviable myocardium by imaging result in improvedleft ventricular systolic function, exercise capacity,and survival in comparison with medical therapyalone.22,23 Diagnostic tests capitalize on 2 charac-teristics of hibernating myocardium: (1) restingmetabolism that is more like normal myocardiumthan fibrotic scar, and (2) the presence of contrac-tile reserve when stimulated with inotropic agents.Metabolic activity is typically assessed using18F-fluorodeoxyglucose positron emission tomog-raphy (FDG PET). Combination perfusion andmetabolic imaging on a CT/PET scanner allowsrest and stress 82Rb perfusion images to be over-laid with FDG-uptake images. In half a day one canaccurately identify areas of hibernating myocar-dium relative to areas of inducible ischemia andreplacement fibrosis. Alternatively, CMR can beused to quantify ischemic fibrosis using late gado-linium enhancement, and contractile reservecan be evaluated with the low-dose dobutaminestress.8,24

Survival benefit appears to be present evenwhen restoration of perfusion does not lead toimproved systolic function.25,26 It should be notedthat published outcomes may censor patients withperioperative mortality. Preoperative risk assess-ment for revascularization procedures such ascoronary artery bypass grafting and open trans-myocardial laser should include the use of the So-ciety of Thoracic Surgeons (STS) risk-assessmenttool for calculating perioperative mortality. TheSTS Risk Calculator can be found online athttp://riskcalc.sts.org/.

Ultrastructural Abnormalities: Hypertrophy,Fibrosis, and Apoptosis

Cardiac remodeling depends on changes in cellstructure, the relative number and activity of cellspresent, and changes in the extracellular matrix(ECM). Increased ventricular mass and varyingdegrees of myocyte hypertrophy, fibrosis, andmyocyte drop-out are consistent histopathologicfindings in cardiomyopathy (Fig. 3). In pathologichypertrophy, myocyte size, volume, and sarco-mere number all increase while the rate ofapoptosis increases. Pressure and volume over-load combine with neurohormonal and cytokinesignaling to create a complex pro-hypertrophicmilieu. The tissue mediators of hypertrophy arenumerous. Key pathways involve catecholaminestimulation of G-protein–coupled b-adrenergicreceptors, myocyte and fibroblast stretch activa-tion of integrins, G-protein–mediated intracellular

signaling by way of numerous protein kinases,and the regulatory-action microRNAs. At thegene expression level, these histologic changesare associated with changes toward a fetalpattern.27–29

The ECM provides essential scaffolding for theheart, and is an important factor in determiningits mechanical properties and function. TheECM is a complex and biologically active mixtureof cross-linked collagen fibers, proteoglycans,and signaling molecules. In HF, cardiac fibro-blasts and smooth muscle cells proliferate andproduce abundant ECM that is rich in fibrillarcollagen. The abnormal ECM quantity andcomposition is not merely the result of changesin production. There is also dysregulation of ma-trix metalloproteinases (MMPs), which degradeECM and tissue inhibitors of matrix metalloprotei-nases (TIMPs). There is experimental evidencethat transcriptional regulation of MMPs andTIMPs play a key role the different patterns of hy-pertrophy and fibrosis seen in cardiomyopathyphenotypes.30–32

Another cardinal feature of cardiomyopathy isan increased rate of myocyte apoptosis, or pro-grammed cell death. Increased apoptosis maybegin with an initiating ischemic, inflammatory, ortoxic injury, but is perpetuated by continual oxida-tive stress and elevation of death, promoting in-flammatory cytokines such as tumor necrosisfactor a, norepinephrine, and angiotensin II.Increased apoptosis, which is important whendifferentially regulated in fetal heart development,may be part of a comparatively unregulated fetalgene program induced by HF. The result overtime is a gradual depletion of myocytes and lossof contractile function.33–35

Pathophysiology and Etiology of Heart Failure 13

Abnormal Intracellular Calcium Handling

Cytoplasmic calcium flux is central to the functionof the myocyte contractile apparatus. Thick(myosin) and thin (actin) myofilaments couple anddecouple via calcium-dependent events. Intracel-lular calcium rises by entry of Ca21 from outsidethe cell via L-type Ca21 channels in the transversetubules, and by release of calcium from stores inthe sarcoplasmic reticulum (SR) through calciumchannels known as ryanodine receptors (RyR2).Release of calcium from the SR is the primaryactivator of contraction, while active reuptake ofcalcium into the SR concludes contraction andpromotes relaxation. Calcium is sequestered inthe SR by the action of the adenosine triphos-phate–driven Ca21 pump (SERCA2a). In HF, cyto-solic calcium levels are elevated. The 2 primarymechanisms by which this occurs are reducedSERCA2a activity and depletion of SR storesfrom excessive efflux from RyR2 receptors.36

Both of these mechanisms are potential new tar-gets of therapy. A phase II gene therapy trial totest whether increasing SERC2a gene expressionwill improve HF outcomes, CUPID 2b, is ongoing.Another active area of research is whether modu-lation of enzymes that regulate the phosphor-ylation of the RyR2 receptor, such as Ca21/calmodulin-dependent kinase II or phosphokinaseA, may improve SR reuptake and reduce RyR2receptor “leak.”37,38

Fig. 4. World Health Organization cardiomyopathy phenotrophic cardiomyopathy. (B) Dilated cardiomyopathy. (C)ventricular cardiomyopathy. (E) Left ventricular noncompof Pathology, University of Iowa Carver College of Medici

Genetic Mutations

Once considered rare, it is now clear that many ge-netic mutations cause cardiomyopathy, eithersingly or in the context of a specific genetic back-ground. From an etiologic perspective, geneticabnormalities can be classified as structural dis-ease caused by errant development (complexcongenital heart disease), mutations of structuraland contractile proteins, muscular dystrophies,and mutations of ion channels. From a phenotypicviewpoint, the World Health Organization (WHO)recognizes 4 phenotypes of cardiomyopathy: hy-pertrophic (HCM), dilated (DCM), restrictive(RCM), and arrhythmogenic right ventricular car-diomyopathy (ARVC). It is now appreciated thatARVC can also affect the left ventricle, and theterm arrhythmogenic cardiomyopathy (ACM) isalso used. Left ventricular noncompaction(LVNC) is an additional phenotype that is nowwidely recognized (Fig. 4).39

Guidelines exist for genetic testing in all the HFphenotypes, and gene test panels are availablefor the most common mutations. Genetic testingis strongly recommended for individuals withHCM, and is recommended for those with familialcardiomyopathy of other phenotypes. Familial car-diomyopathy is defined as a cardiomyopathy of un-known cause in 2 or more close family members.Testing is recommended for the most affectedindividual in the family, followed by “cascade

types and left ventricular noncompaction. (A) Hyper-Restrictive cardiomyopathy. (D) Arrhythmogenic rightaction. (Courtesy of Dennis Firchau, MD, Departmentne, Iowa City, IA.)

Table 1AHA/ACC recommendations for diagnostictesting for occlusive CAD

PatientCharacteristics

CoronaryAngiography

NoninvasiveImaging

Typical angina ordemonstratedischemia

Class ILOE B

—

CP of uncertainetiology, no priorCAD screening,revascularizationeligible

Class IIALOE C

—

No CP, known orsuspected CAD,revascularizationeligible

Class IIALOE C

Class IIALOE B

No CP, no prior CADscreening,reduced LVEF,revascularizationeligible

— Class IIBLOE C

Abbreviations: ACC, American College of Cardiology;AHA, American Heart Association; CAD, coronary arterydisease; Class I, should be performed; Class III, not benefi-cial/harmful; Class IIA, reasonable to perform; Class IIB,may be considered; CP, chest pain; LOE, level of evidence;LOE A, multiple randomized clinical trials; LOE B, single ornonrandomized trials, registries; LOE C, expert opinion;LVEF, left ventricular ejection fraction.

Data from Yancy CW, Jessup M, Bozkurt B, et al. 2013ACCF/AHA guideline for the management of heart failure:a report of the American College of Cardiology Founda-tion/American Heart Association Task Force on PracticeGuidelines. Circulation 2013. [Epub ahead of print]; andJessup M, Abraham WT, Casey DE, et al. 2009 Focused Up-date: ACCF/AHAGuidelines for the Diagnosis andManage-ment of Heart Failure in Adults. Circ 2009;119:1977–2016.

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screening” of asymptomatic first-degree relatives ifa causative gene is identified.40,41 Despite pub-lished guidelines, rates of genetic testing remainlow, perhaps reflecting a lack of physician aware-ness combined with economic and social bar-riers.42 If genetic testing is not performed or isnegative for a known mutation, clinical screeningof first-degree relatives is recommended at inter-vals that vary by phenotype, but typically rangefrom 1 to 5 years.43

HEART FAILURE BY ETIOLOGY

Although theWHO recognizes 4 classes of primarycardiomyopathy, there are many specific typesthat can be categorized either by phenotype orunderlying etiology. Common types are detailedhere.

Ischemic Cardiomyopathy

Occlusive coronary artery disease (CAD) is widelyacknowledged as the most common reason forsymptomatic HF in United States adults, but prev-alence data are sparse. Ischemic cardiomyopathyis typified by regional hypokinesis, ventricularenlargement, and thinning of the ventricles in areasof full-thickness injury. One or both ventricles oftenbecome more spherical and exhibit atrioventric-ular valve incompetence, owing to annular dilata-tion over time. The result is combined systolicand diastolic HF, with systolic dysfunction pre-dominating in the majority of patients.Because of its prevalence, it is imperative that

occlusive coronary disease be excluded in adultpatients presenting with new-onset HF. In childrenand young adults, ischemia from coronary anoma-lies and other congenital malformations shouldalso be excluded; this can be done either inva-sively or noninvasively. The American Heart Asso-ciation/American College of Cardiology (AHA/ACC) guidelines for CAD diagnostic testing are pri-marily driven by the presence or absence of typicalangina and the patient’s suitability for undergoinga revascularization procedure. Coronary angiog-raphy remains the gold standard for accuracy,but carries an average procedural complicationrate of 7.4 in 1000 and a mortality rate of 0.7 in1000.44 Noninvasive testing is therefore recom-mended for patients with a low ejection fractionwho are free of angina or evidence of activeischemia (Table 1).5,45

Noninvasive imaging studies, although lesssensitive and less specific than invasive coronaryangiography, all carry less procedural risk. Riskis generally confined to the potential toxicity ofperfusion agents and radiation exposure. Pharma-cologic or exercise stress testing combined with

single-photon emission CT or PET imaging remainthe primary screening methods for CAD in patientswith HF, because of the accuracy and wide avail-ability of the equipment. 64-Slice multidetectorCT (MDCT) has excellent coronary imaging resolu-tion and CMR has acceptable resolution; both arereasonable alternatives.15,46 The primary limitationof both MDCT and CMR is the need for long breathholds, a regular heart rhythm, and a low enoughheart rate to accurately gate the imaging se-quences in patients.47 Echocardiography alone isinadequate for CAD detection, even when re-gional wall-motion abnormalities exist. Dobut-amine stress echo can be used if the baselineejection fraction is preserved, but should be inter-preted with caution when the baseline left ventric-ular ejection fraction is depressed, as differencesin contractility with stress may be subtle. Testing

Pathophysiology and Etiology of Heart Failure 15

should be tailored to minimize risk and optimizediagnostic accuracy in a given individual.48–50

Idiopathic Dilated Cardiomyopathy

Idiopathic dilated cardiomyopathy describes aDCM for which no clear etiology has been identi-fied. It is second in prevalence, and the most com-mon reason for heart transplantation recorded inthe International Society of Heart and Lung Trans-plant registry. DCM is a heterogeneous group. Thisdiagnosis of exclusion reflects how difficult it is todiagnose early inciting events and uncommon ge-netic mutations. The natural history of myocarditissuggests that many of these cases can be attrib-uted to remodeling after acute inflammation, andan additional 20% to 35% of cases are estimatedto be hereditary in nature.40 Typical features are bi-ventricular enlargement and global hypokinesis.Mitral and tricuspid valve annular dilatation andcentral valve regurgitation are common. The echo-cardiographic appearance of the myocardium isnormal. Wall thickness is normal to thin, and CMRusually shows faint midmyocardial late gadoliniumenhancement. Histology is bland, with diffuse my-ocyte hypertrophy, fibrosis, and reduced capillarydensity.

Specific cardiomyopathies should be excluded,with AHA/ACC strongly recommending diagnosticsincluding a 3-generation family history, completephysical examination, and the following screeningtests: complete blood count, comprehensivemetabolic panel, fasting lipids, thyroid-stimulatinghormone,BNP level, chest radiograph,12-leadelec-trocardiogram (ECG), and 2-dimensional echocar-diogram with Doppler. Further diagnostics arerecommendedwhen there is suspicion for a specificdisease; these include stress and myocardialviability testing for CAD, and screening tests forautoimmune diseases, amyloidosis, hemochroma-tosis, human immunodeficiency virus, and second-ary forms of hypertension. Endomyocardial biopsyisnot recommended for the routinediagnosisofHF.5

Hypertensive Heart Disease

The strongest risk factor for the development ofHF remains hypertension, and it is a common co-morbidity in persons with ischemic heart dis-ease.51 As the population ages and HF withpreserved ejection fraction (HFpEF) increases inprevalence, the terms hypertensive heart diseaseand HFpEF may become almost synonymous.The cardinal features include left ventricular hy-pertrophy and abnormal diastolic function ascer-tained by echo Doppler or cardiac catheterizationin a patient with a history of systemic hyperten-sion. If left ventricular hypertrophy and diastolic

dysfunction are present without a history of hy-pertension, an infiltrative etiology should bestrongly suspected.

Valvular Cardiomyopathy

Valvular cardiomyopathy can be either inherited oracquired. Excluding complex congenital and syn-dromic heart disease, the most common congen-ital valvular lesions are bicuspid aortic valve, with aprevalence of approximately 1%, and myxoma-tous mitral valve, with a prevalence of 2% to 3%in adults.52,53 Acquired lesions are typically calcificdegeneration or are caused by postinflammatorychanges from infective endocarditis, rheumaticfever, rheumatologic disorders, carcinoid, or fen-fluramine/phentermine exposure. Among acquiredlesions, calcific aortic stenosis is the most com-mon, and primarily affects the elderly. The HFphenotype in valvular cardiomyopathy is deter-mined by the hemodynamic profile caused by thelesion, and compensatory changes in the heartand pulmonary vascular bed. Transthoracic andtransesophageal echocardiography are excellentdiagnostic tests for defining valvular pathology,and have largely replaced invasive cardiac cathe-terization. The advent of transcatheter aortic valvereplacement is a significant advance for HF pa-tients with calcific aortic stenosis who are poorsurgical candidates.54

Familial Cardiomyopathy

In contrast to idiopathic cardiomyopathy, familialcardiomyopathy is defined by a clear family historyof HF or sudden cardiac death in at least 2 closefamily members, or positive genetic testing for aspecific mutation. Most familial cardiomyopathiesare autosomal dominant in inheritance and aredescribed by WHO phenotypes. One must beaware that phenotypic overlap can exist in familiesand that our understanding of the genotype-phenotype connection remains incomplete.

Familial HCM is the most common form offamilial cardiomyopathy, with an estimated fre-quency of 1 in 500 adults.42 There are severalwell-defined mutations in sarcomeric proteins forHCM. The genetic mutations for DCM and theirprevalence are less well defined, but include muta-tions in structural proteins, ion channels, andmembrane transporter proteins. Several gene mu-tations have also been identified for ARVC andLVNC.55,56 Duchenne and Becker muscular dys-trophies, which may also lead to DCM, are remark-able for X-linked rather than an autosomaldominant inheritance pattern.

Diagnosis of familial cardiomyopathy dependson a combination of family history and imaging

Johnson16

that defines the phenotype. CMR is especiallyhelpful in establishing whether structural criteriafor HCM, ARVC, or LVNC are met. Confirmatorygene testing for known mutations is beneficial forprognosis in some cases, but is primarily helpfulin family screening. Genetic counseling resourcesshould be made available to all those who undergogenetic testing.

Inflammatory Cardiomyopathy

This heterogeneous group of secondary cardio-myopathies is caused by inflammatory injury tothe myocardium, pericardium, and/or valvularstructures. The archetype is acute lymphocyticmyocarditis attributed to viral infection. There isstrong experimental evidence that postviral auto-immune reactions lead to DCM after the acutephase, and some evidence in humans that viralpersistence and the formation autoantibodies toheart proteins are poor prognostic signs.57,58 Todate, human studies have not shown that routineapplication of immunosuppression preventsprogression to DCM or improves clinical out-comes.59–61 Giant-cell myocarditis is worth spe-cial mention because of its fulminant course andassociation with life-threatening ventricular ar-rhythmias. This diagnosis can only be made withendomyocardial biopsy. Cardiac manifestationsof autoimmune disease or hypersensitivity areoften overlooked, but should be considered inthe differential diagnosis. Peripartum cardiomy-opathy is probably also autoimmune mediated inmost cases.Expert panel recommendations on the diag-

nosis and management of acute myocarditis andinflammatory cardiomyopathy encourage greateruse of viral polymerase chain reaction tests,CMR to identify focal inflammation, and immuno-histochemistry when endomyocardial biopsiesare obtained.59 Screening for collagen-vasculardiseases and hypereosinophilia should be donein suspected cases. At present, endomyocardialbiopsy is strongly recommended only when symp-toms are short in duration, hemodynamic compro-mise is present, and/or if the patient is notresponding to conservative treatment.5,62

Infiltrative Cardiomyopathy

Though uncommon, the infiltrative cardiomyopa-thies are important to distinguish from hyperten-sive heart disease and HCM. Amyloidosis,sarcoidosis, glycogen and liposomal storage dis-eases, and hemochromatosis can all be consid-ered in this category. Left ventricular hypertrophyis typically present without a history of high bloodpressure or elevated voltage on 12-lead ECG.

CMR is especially helpful in detecting abnormalmyocardial tissue characteristics that discriminatethese entities from “benign” left ventricular hyper-trophy. Appropriate treatment of infiltrative cardio-myopathies requires confirmatory biochemical orgenetic testing, and sometimes tissue sampling.

Toxic Cardiomyopathy

The most common toxic injuries to the heartinclude excessive alcohol ingestion, allergensthat cause allergic myocarditis, radiation exposurefrom radiation therapy for cancer, and exposure tochemotherapeutic agents. Newer chemothera-peutic agents are of particular interest, and clini-cians should be aware of the potentiallyreversible nature of HF caused by these agents.Traditional cytostatic agents such as anthracy-clines, cyclophosphamide, and cisplatins causeirreversible damage through myofibrillar changesand cell death. By contrast, newer agents targetcellular signaling pathways and blood vessels.Examples include monoclonal antibodies againstgrowth factor receptors (including HER2 andepidermal growth factor), tyrosine kinase inhibi-tors, and antiangiogenic drugs. After cessation ofthe causative agent and medical management ofHF, chemotherapy can often be resumed.63

SUMMARY

The diagnosis and treatment of HF require carefulevaluation of each patient. Diagnostic testing ishighly influenced by the quality of the initial evalu-ation and the identification of comorbid condi-tions. Categorizing a patient’s cardiomyopathywill help guide therapy and lend prognostic valueas standard and new treatments are applied.

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