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The Pathophysiology of Cardiac Hypertrophy and Heart Failure
Introduction
Heart disease is a common global cause of morbidity and mortality. In the US alone, an estimated 83 million individuals carry the diagnosis and 1 in every 3 deaths are believed due to heart disease. More than 75% of patients have hypertension-related heart disease with associated cardiac enlargement. At the cellular level, chronic hypertension results in physiologic and pathological changes that culminate in adaptive changes in left ventricular mass (LVM) or cardiac growth. Despite the overwhelming presence of non-cardiac cell types in the heart – fibroblasts, circulating blood cells, endothelial cells, smooth muscle cells and adipocytes – cardiomyocyte size accounts for at least two-thirds of cardiac mass and is the determining factor regulating LVM.
Increases in left ventricular mass, also known as cardiac hypertrophy or left ventricular hypertrophy (LVH), occur as an adaptive response to stress. This includes physiologic stresses such as exercise or pregnancy, or pathological stimuli such as pressure- or volume-overload. In early LVH, left ventricular function is conserved. With progression, LVH results in ventricular dysfunction (i.e. heart failure). Disproportionate enlargement of the left ventricle relative to its functional efficiency renders the myocardium more sensitive to ischemia and arrhythmia. Morphologically, hypertrophy is categorized as either eccentric or concentric. Eccentric hypertrophy is more commonly associated with endurance exercise training, pregnancy, and volume overload. Concentric hypertrophy is most often the result of chronic pressure overload, but is possible to a minor degree with weight training.
Left ventricular mass index (LVMI), measured using echocardiography, has long been established as one of the most robust, independent predictors of cardiovascular morbidity and mortality. In the Framingham heart study, each 50 g/m increase in LVMI caused a 1.5-fold increment in adjusted relative risk of cardiovascular disease, heart failure, and death. Electrocardiographic detection of LVH, although less sensitive, is an equally powerful predictor. Moreover, subtle increases in LVMI that do not meet the threshold criteria for LVH are still associated with increased cardiovascular disease. LVH prevalence rates range from 58–77% in patients with hypertension, obesity, and diabetes mellitus.
Over the last several decades, molecular-level research has elaborated numerous mechanisms of LVH progression. In spite of current pharmacological therapy, however, few patients achieve regression of LVH. Most patients’ disease continues to progress while on therapy, and they suffer an ever-increasing risk of cardiovascular events. Only by continuing to explore these mechanisms and advancing translational research will we devise new, more effective therapies.
Etiology of Heart Failure
Heart failure is the clinical syndrome that describes the physiologic effects of acutely or chronically decreased cardiac function. It can result from a wide range of pathologic processes. More specifically, failure is the inability to maintain a sufficient cardiac output to fulfill the metabolic requirements of organs or accommodate systemic venous return. Occasionally, a failing heart can maintain necessary cardiac output, but only at an abnormally elevated filling pressure or volume.
Approximately 5.7 million people in the United States have heart failure. In 2008, it was the underlying cause of death in more than 56000 patients. The clinical presentation of a patient with heart failure includes signs and symptoms of volume overload such as dyspnea, lower extremity edema, and ascites. Additional stigmata of insufficient tissue perfusion include fatigue, exercise intolerance, and renal hypo-perfusion. Depending on the underlying disease process leading to heart failure, both volume overload and peripheral malperfusion may be present. Heart failure usually presents with an acute onset of symptoms in a person with known chronic heart disease. Alternately, symptoms may appear abruptly with rapid progression to pulmonary edema and resting dyspnea. Diagnoses such as acute myocardial infarction, valvular heart disease, and even acute myocarditis must be identified as early as possible in order for patients to receive effective treatments.
Ischemic heart disease, resulting from either acute myocardial infarction or chronic ischemia, accounts for most cases of heart failure with systolic dysfunction. Non-ischemic causes of systolic heart failure can be classified as arising from chronic pressure overload, chronic volume overload, and dilated cardiomyopathy. Conditions resulting in pressure overload include predominantly hypertension, followed by aortic stenosis (or less commonly pulmonary stenosis), coarctation, or hypertrophic cardiomyopathy. Importantly, systolic failure is a relatively late occurrence in pressure overload – patients typically present first with diastolic dysfunction. Causes of volume overload include aortic or mitral regurgitation, intracardiac shunts (such as an atrial or ventricular septal defect), and extracardiac shunts (such as a high-flow arterio-venous dialysis fistula). Dilated cardiomyopathy is most often idiopathic, but has been linked with a host of other conditions including myocarditis, ischemic heart disease, peripartum cardiomyopathy, connective tissue disease, and HIV, among others.
Diastolic dysfunction results most commonly from pressure overload conditions that lead to a pathologically hypertrophied and stiff ventricle that is unable to relax. Restrictive cardiomyopathy is an alternate pathogenesis that gives rise to the same functional outcome. Diagnoses include endo-myocardial fibrosis, endocardial fibroelastosis, cardiac amyloidosis, hemochromatosis, and radiation injury.
Less common causes of heart failure include severe chronic anemia, metabolic disorders (such as beri-beri), endocrine derangements (such as thyrotoxicosis), arrhythmias, and pulmonary heart disease. Rare instances of heart failure are reported as side effects of treatments for unrelated conditions. For instance, the cardiotoxic effects of Doxorubicin/Adriamycin can culminate in heart failure, especially if potentiated by concurrent cardiotoxic drugs, mediastinal radiotherapy, or chronic hypertension.
Left Ventricular Failure
Under physiologic conditions, the stroke volume is regulated by preload, which is the measure of myocardial fiber stretch at the end of diastole. Afterload is the resistance that needs to be overcome by the ventricle to eject blood. Contractility is the inotropic state of the heart independent of the preload and the afterload. Disease processes that result in heart failure are known to modulate one or more of these factors that affect cardiac output. Left- or right-sided heart failure may result, depending on the site of major damage. Left ventricular dysfunction can be characterized as systolic dysfunction – reduced ejection fraction due to compromised ventricular contraction, or diastolic dysfunction – reduced ventricular filling due to inadequate relaxation. Ejection fraction (EF), is defined as the fraction (%) of the end diastolic volume that is pumped by the ventricle during systole. Systolic dysfunction is typically classified by an EF <40%. In contrast, diastolic dysfunction typically maintains an EF >40%. Although 70% of cases of left ventricular heart failure are considered to be a result of systolic dysfunction, recent data suggest that a significant percentage of cardiac dysfunction occurs in the presence of preserved left ventricular systolic function. Ischemic heart disease (including myocardial infarction), and chronic uncontrolled hypertension with associated pressure overload, are leading causes of systolic left heart dysfunction, and culminate in heart failure. The impaired contractility of the left ventricle in systolic dysfunction leads to a decrease in stroke volume (SV) and cardiac output (CO), with resultant global hypoperfusion. Decrease in SV is also associated with an increase in end-systolic and end-diastolic ventricular volumes and an increase in left ventricular end-diastolic pressure (LV-EDP). These changes in left ventricular indices cause an increase in left atrial pressure and subsequent backpressure in the pulmonary capillary circulation. Dyspnea is the clinical manifestation of impaired alveolar gas exchange secondary to pulmonary venous congestion.
Diastolic dysfunction is seen most commonly in the setting of hypertension, and also complicates heart disease in diabetes mellitus, obesity, and cardiomyopathy. Contrary to systolic failure, the contractility of the heart and ejection fraction is maintained close to physiologic levels in diastolic dysfunction. Diastolic dysfunction characteristically results from abnormal stiffness of the ventricular wall and the inability of the left ventricle to relax adequately during diastole, such as is seen in cardiac pathologies with extensive fibrosis. Under conditions of increased metabolic demand, such as exercise, the heart is unable to increase cardiac output. The inability of the ventricle to adequately expand during diastole results in an increase in ventricular filling pressure with subsequent elevation of pulmonary venous pressure. Rapid changes may cause acute-onset pulmonary edema, with dyspnea and impaired exercise tolerance. Contemporary literature indicates increased awareness of heart failure with preserved systolic function (including diastolic dysfunction), especially in elderly and female populations.
Right Ventricular Failure
Most often, right-sided heart failure occurs at a late stage in patients with left-sided heart failure, when the elevated pressure in the pulmonary circuit affects the right ventricle and atrium. Pure right-sided heart failure is a rare event that occurs secondary to pulmonary diseases and is termed as cor pulmonale. Pulmonary diseases that result in cor pulmonale are associated with vasoconstriction, pulmonary hypertension, and increased afterload of the right ventricle. These include interstitial lung disease, primary pulmonary hypertension, and pulmonary thromboembolic disease. Conditions such as chronic sleep apnea and altitude sickness cause pulmonary vasoconstriction through hypoxia. In right-sided heart failure, hypertrophy of the right ventricle helps to overcome the elevated pulmonary vasculature resistance, and reduce congestion of systemic and portal venous circulations (which are proximal to the right heart). In a pure right-sided heart failure, there is minimal pulmonary congestion – instead the systemic venous and portal venous systems become congested. The clinical presentation of a right-sided failure is thus characterized by edema, ascites, pleural effusions, hepatosplenomegaly, renal hypoperfusion, and azotemia. Because left ventricular failure is the most common cause of right-sided heart failure, a clinical syndrome of biventricular failure is common.
Neurohormonal Adaptation
Many neurohormonal compensatory mechanisms, including the sympathetic nervous system ( Fig. 4.1 ) and the renin–angiotensin–aldosterone axis, increase the mean arterial pressure and total peripheral resistance by vasoconstriction ( Fig. 4.2 ). In addition, by augmenting sodium and water retention, these processes contribute to increasing cardiac output via the Frank-Starling mechanism. Although initially beneficial, chronically elevated activity of these systems eventually adds to pressure and volume overload, with resultant cardiac decompensation.
Physiologic Hypertrophy
Hypertrophy is derived from the Greek hyper , meaning over, and trophy , meaning growth. It is widely believed to be an adaptive response to increased workload. By undergoing hypertrophy, ventricular wall stress remains constant at higher intraventricular pressures (LaPlace’s law). Since cardiomyocytes make up 80–85% of the ventricular volume and are largely thought to be terminally differentiated, the bulk of cardiac hypertrophy results from cardiomyocyte growth (i.e. increase in size). From both clinical and mechanistic standpoints, two fundamental types of cardiac hypertrophy occur: physiologic and pathologic.
Physiologic hypertrophy occurs in very limited circumstances. The most dramatic example is postnatal, or maturational, where the heart grows more than twofold in size. Although some cardiomyocytes become binucleate, most growth results from an increase in cardiomyocyte length and diameter. Ventricular hypertrophy observed in pregnant women and professional endurance athletes results in more limited growth. Typical changes are only about a 10–20% increase in size compared to age-matched, sedentary, non-pregnant controls.
Ventricular Function
The most important characteristic of physiologic hypertrophy, compared with pathologic hypertrophy, is that ventricular function remains normal or even improved, rather than impaired. Both systolic and diastolic functions are normal or enhanced in both athletes and pregnancy when measured by echocardiogram. In further contrast to pathologic hypertrophy, both states are fully reversible. Post-partum women undergo complete mass regression within 8 weeks, and athletes regress even faster, losing most additional mass within a few weeks of deconditioning.
Angiogenesis, Fibrosis, Energy Substrates, and Gene Activation
Critical cellular and molecular events further separate physiologic and pathologic hypertrophy. Angiogenesis is significantly increased in the myocardium during exercise training, as measured by coronary blood flow capacity, coronary artery diameter, and capillary density. Pathologic models are associated with increased fibroblast activity and fibrosis, while physiologic hypertrophy is associated with unchanged levels of fibroblast activity and collagen deposition. In mitochondria, fatty acid oxidation (FAO) accounts for 80–85% of the energy production in the adult cardiomyocyte. In pathologic hypertrophy, there is increased utilization of less efficient glycolytic pathways. In physiologic hypertrophy, the ratio of FAO to glycolysis is preserved. At the gene expression level, pathologic hypertrophy models classically demonstrate induction of a fetal gene expression program including atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), skeletal muscle α-1-actin, (SMα1actin) and β-myosin heavy chain (β-MHC) – all of which are absent in exercise models of hypertrophy.
Thyroid Hormone
The role of thyroid hormone tri-iodothyronine (T3) on physiologic growth is best understood in the context of postnatal cardiac growth. Within a few weeks after birth, T3 levels spike 2000-fold, and then fall back down by the third week. Rodent studies demonstrate that T3 regulates the perinatal change in transcription from β-MHC to α-MHC. T3 additionally increases the expression of SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase-2, critical for maintaining Ca ++ concentrations in the sarcoplasmic reticulum), the β1 adrenergic receptor, cardiac troponin I (cTNI), atrial natriuretic factor (ANF), sodium/calcium exchanger (NCX), thyroid receptor alpha (TRα1) and adenylyl cyclase subtypes. Given this array of proteins whose function enhances cardiac performance, it is logical that T3 stimulation of cardiomyocytes can result in enhanced cardiac performance.
Insulin
Insulin acts by binding to the tyrosine kinase insulin receptor (IR), which ultimately activates the phosphatidylinositol 3’-kinase–protein kinase B (PI3K-AKT) signaling pathway. Cardiac specific IR knockout mice show smaller hearts with smaller individual cardiomyocyte volumes, indicating that physiologic hypertrophy is inhibited. When challenged with aortic constriction, however, these mice are more prone to the development of pathologic hypertrophy. In short, the insulin-signaling pathway is essential for normal cardiac growth, and its absence may promote or enable pathologic hypertrophy.
Insulin-like Growth Factor 1
Insulin-like growth factor 1 (IGF1) has roles in both systemic and organ-specific regulatory mechanisms. IGF1 binds to the insulin receptor (IR) and the IGF1 receptor (IGF1R). IGF1R is a transmembrane tyrosine kinase receptor that activates PI3K-AKT-phosphoinositide-dependent protein kinase 1 (PDK1) and subsequently glycogen synthase kinase 3β (GSK3b). IGF1 and IGF1R knockout mice have severe growth retardation and die at birth. IGF1 transgenic mice, in which IGF1 is linked to the α-MHC or SM-α-1-actin promoters, show early development of physiologic hypertrophy, but over time the phenotype becomes pathologic, with development of fibrosis and decreased function. Transgenic overexpression of IGF1R using the α-MHC promoter results in development of physiologic hypertrophy without subsequent development of pathology. Conversely, IGF1R conditional deletion does not affect cardiac growth, but does make mice resistant to exercise-induced hypertrophy.
Mechanotransduction
Mechanotransduction is a well-known phenomenon in the cardiomyocyte in which physical contacts are converted into intracellular signals by transmembrane proteins. One stretch receptor expressed by all cells (including myocytes) is the transient receptor potential channel (TRPC). Two subtypes of this receptor – TRPC1 and TRPC6 – are each activated by stretching and are overexpressed in hypertrophy. When knocked out, mice are more resistant to pathologic hypertrophic stimuli. Integrins are another class of transmembrane protein that transmit stretch-related changes in the extracellular matrix through an intracytoplasmic tail. This signals intracellular focal adhesion complexes that include focal adhesion kinase (FAK) and integrin-linked kinase (ILK). These kinases then phosphorylate and activate RHO GTPases, PI3K, and protein kinase C (PKC). Cardiac-specific ablation of the intracytoplasmic integrin signaling tail exacerbates pressure-overload-induced hypertrophy. Within the cardiomyocyte, numerous proteins at the Z-line are involved in stretch sensing including: muscle LIM protein, myopalladin, palladin, ankyrin, and cardiac ankyrin repeat domain protein (CARP). Of these, muscle LIM protein and CARP have known associations with hypertrophy. CARP overexpression transgene is resistant to the development of isoproterenol and pressure-overload-induced hypertrophy. Titin is a protein that spans the length of the sarcomere, from Z-line to Z-line, with over 20 known ligands, many of which are believed to be stretch receptors, yet its precise relationship with hypertrophy remains to be explored.
Intracellular Pathways
PI3K
PI3K is one of the common effectors of insulin, insulin-like growth factor, and integrin signaling pathways ( Fig. 4.3 ). Overexpression of the catalytic subunit of PI3K, p110α, in mouse hearts promotes physiologic hypertrophy. Conversely, overexpression of a dominant negative form of p110α results in atrophy. Phosphatase and tensin homolog (PTEN) is a lipid phosphatase that acts to inhibit phosphatidylinositol 3,4,5 triphosphate (PIP3). Cardiac-specific PTEN deletion has also been shown to promote cardiac growth.
AKT
AKT, also known as protein kinase B, is activated by 3-phosphoinositide-dependent protein kinase-1 (PDK1), another kinase recruited to the cell membrane by PIP3 synthesis. PDK1 inactivation reduces cardiomyocyte volume and heart mass. Similarly, Akt null mice are resistant to physiologic hypertrophy in response to swimming. Constitutively active Akt1 mutant mice initially develop physiologic LVH, although pathologic conversion occurs over time. Similar effects are observed in a membrane-localized mutant of Akt1. By comparison, nuclear-targeted Akt1 results in hyperplasia without hypertrophy. One of the mechanisms of AKT is to promote protein translation by inhibiting glycogen synthase kinase 3-β (GSK3β), itself a negative regulator of protein translation. Mouse overexpression models of GSK3β fail to hypertrophy in the post-natal period and die shortly thereafter from heart failure. Lastly, AKT shifts the balance of protein turnover to anabolism by phosphorylating and inactivating the pro-catabolic transcription factor forkhead box protein 03 (FOX03). This prevents transcription of the pro-catabolites ubiquitin ligase atrogin-1 and muscle-specific RING finger protein-1 (MURF1). Altogether, AKT appears to promote hypertrophic growth of the heart; the timing, duration, and precise nature of the action determine if this is ultimately beneficial or pathologic.
mTOR
The mammalian target of rapamycin (mTOR) regulates adaptive growth of the heart at the level of mRNA translation. mTOR and regulatory associated protein of mTOR (RAPTOR) combine with other proteins to make up mTOR complex-1 and -2 (mTORC1 and mTORC2). mTORC1 is activated via an AKT-led pathway, as well as by certain amino acids, and is inhibited by 5’ adenosine monophosphate-activated protein kinase (AMPK). Activated mTORC1 initiates translation activity by directly regulating S6K ribosomal proteins, and by liberating eukaryotic translation initiation factor 4E from its binding protein. Experimentally, treatment with rapamycin is effective in reversing hypertrophy produced through Akt overexpression. However, blocking the mTOR pathway by overexpression of a dominant negative mTOR is insufficient to inhibit the hypertrophic response in exercised mice. In summary, the mTOR pathway is one of several redundant pathways that contribute to the development of physiologic LVH.
C/EBPβ
CCAAT/enhancer binding protein-β (C/EBPβ) is a transcription factor that is commonly associated with regulation of cellular proliferation, but has recently been tied to the regulation of physiologic hypertrophy. C/EBPβ is down-regulated during exercise-induced physiologic hypertrophy, but remains constant during pressure-overload-induced pathologic hypertrophy. siRNA silencing of C/EBPβ in rat neonatal cardiomyocytes induces both cardiomyocyte proliferation and hypertrophy. In adult mice, C/EBPβ heterozygotes are resistant to the pathologic effects of pressure overload. Relative to wild-type mice, C/EBPβ heterozygotes have a comparable increase in cardiomyocyte size, but with improved fractional shortening and decreased pulmonary weight (signifying less heart failure). C/EBPβ inhibition, as a means of inducing physiologic hypertrophy, represents a potential therapeutic modality for patients with heart failure.
ERK1/2
Extracellular signal related kinases 1/2 (ERK1/2) are kinases activated by extracellular signals that translocate to the nucleus, phosphorylate targets, and initiate transcription. Also called mitogen activated kinase 3/1 (MAPK3/1), these kinases are stimulated by growth factors and stretching. Overexpression of an active mutant ERK1 induces physiologic hypertrophy that is protective from ischemia reperfusion injury. Conversely, inhibition of ERK1/2 leads to increased dilated cardiomyopathy in the face of pressure overload. ERK1/2 therefore represents an important aspect of physiologic hypertrophic signaling, both in the response to exercise and in the balance of response to pathologic stresses.
AMPK
5’ Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic switch that balances energy supply with metabolic demand. During exercise, activated AMPK increases the available energy supply by stimulating catabolic pathways including fatty acid oxidation, glucose uptake and glycolysis, and shuttering anabolic pathways like fatty acid synthesis and protein transcription. Although similarly named to cyclic AMP-activated protein kinase (protein kinase A), the actions of AMPK are very different and should not be confused. Long-term inhibition of AMPK leads to pathologic hypertrophy and heart failure. Treatment with a constitutively active mutant or rapamycin restores normal ventricular shape and function. AMPK is thus a vital control in maintaining the heart’s ability to respond to different stresses, both physiologic and pathologic.
Pathologic Hypertrophy
Risk Factors
The most common risk factor for LVH is advanced age, making pathologic LVH one of the most common conditions of elderly North Americans. Intuitively, longer exposure to a physiologic stress will increase the likelihood of symptoms resulting from that stress. Coincident with age are the additional risk factors of increased blood pressure and increased body weight. Both have an increased incidence in the elderly, and are themselves independent risk factors for LVH. Additional independent risk factors for LVH include hypercholesterolemia, prior myocardial infarction, and diabetes. Other forms of pressure overload, such as aortic stenosis, are similarly powerful predictors. Valvular insufficiency is more commonly associated with myocardial dilation, but may involve hypertrophy as well. The African-American race is also linked to hypertrophy, as are dietary preferences such as high sodium intake (independent of blood pressure), and social stressors such as ‘job strain.’
Clinical Sequelae of Pathologic Hypertrophy
Ventricular Arrhythmias
Left ventricular hypertrophy is strongly associated with both atrial and ventricular arrhythmias. When detected by electrocardiogram, there is a significant increase in arrhythmias leading to sudden cardiac death (SCD). LVH is one of the biggest risk factors for ventricular tachycardia; there is a 40-fold increase in ventricular tachyarrhythmia in patients with electrocardiographic LVH. In patients with both ventricular tachycardia and LVH, the risk of SCD is increased 10-fold. More recent evidence suggests that with regression of LVH, the risk of SCD is reduced. The incidence and prevalence of atrial fibrillation are also increased with LVH. In one study, for each standard deviation increase in LV mass, there was a 20% increase in the incidence of atrial fibrillation.
Coronary Flow Reserve
Coronary flow reserve (CFR) is a descriptor of myocardial blood supply, specifically the ability of the coronaries to increase blood flow under stress. Patients with LVH have decreased CFR, especially in the context of pressure overload. Essentially, the muscular growth of the heart outstrips the vascular supply. This leads to myocardial ischemia, even in the context of normal epicardial coronary anatomy. When atherosclerotic coronary disease is combined with LVH, there is a significantly increased risk of mortality. Decreased coronary flow reserve may also explain the increased prevalence of ventricular arrhythmia and sudden death in the LVH patient population.
Ventricular Function
Although ejection fraction (EF) is the most widely used descriptor of cardiac function, EF may overstate cardiac function in the setting of LVH. With LVH, patients may even present with clinical heart failure with a normal EF. Mechanistically, increased ventricular wall thickness and increased interstitial fibrosis create a stiffer ventricle with impaired diastolic relaxation. Less filling of the ventricle during diastole results in a smaller stroke volume, and therefore less cardiac output is produced at a given heart rate, even though the ejection fraction may be within normal range. Progressive ventricular wall thickness and fibrosis may go on to impair contraction as well as relaxation, resulting in both a small stroke volume and a depressed ejection fraction. This strong association between LVH and heart failure and mortality has been borne out in numerous studies from the last several decades.
Animal Models of Pathologic LVH
Experimental models used to induce cardiac hypertrophy in animals have remained remarkably constant over the last 50 years. The underlying constants are pressure overload and increased myocardial work, buttressed by different types of neurologic, hormonal, and biochemical stresses. Aortic constriction is by far the most widely used method for the initiation of pathologic LVH. The robust nature of the response enables the technique to be applied to any area of the thoracic aorta, including the ascending, transverse, or descending thoracic aorta. Over time, transverse aortic constriction (TAC) has become the dominant model in the mouse because it is the most technically feasible. Pulmonary artery constriction yields a similarly consistent response with right ventricular hypertrophy. Renal artery constriction activates the renin–angiotensin–aldosterone axis, causes hypertension, and yields rapid progression of LVH. Hyperthyroidism, like the preceding three mechanisms, also produces rapid results, with measurable hypertrophy developing in mere days. A more gradual hypertrophy may be induced by treatment with sympathomimetic agents, repeat bleeding to produce anemia, certain nutritional deficiencies, and low environmental oxygen similar to extreme elevation. In rats, the spontaneously hypertensive rat is a well-established model of cardiovascular disease including hypertrophy. The model is limited by the absence of many knockout strains, as well as the longer lifespan, increased gestation time, increased size, and housing costs.
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