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Departments of Medicine, Division of Cardiovascular Medicine,. Henry Ford Heart and Vascular Institute, Henry Ford Health. System, Detroit, Michigan. Abstract.
Heart Failure Reviews, 10, 157–163, 2005  C 2005 Springer Science + Business Media, Inc. Manufactured in The Netherlands.

Reversal of Maladaptive Gene Program in Left Ventricular Myocardium of Dogs with Heart Failure Following Long-Term Therapy with the Acorn Cardiac Support Device Sharad Rastogi, MD, Sudhish, Mishra, PhD, Ramesh C. Gupta, PhD, and Hani N. Sabbah, PhD Departments of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Henry Ford Health System, Detroit, Michigan

Abstract. Progressive left ventricular (LV) dilation is a characteristic feature of heart failure and is associated with poor long-term prognosis. One of the characteristic changes that occur in the failing heart is a change in gene expression wherein fetal genes that were turned off shortly after birth are re-activated in heart failure and may play a key role in the progressive worsening of the heart failure state. This review discusses reversal of maladaptive gene expression in dogs with chronic heart failure treated long-term with the Acorn Cardiac Support Device (CSD); a passive mechanical device designed to prevent progressive LV enlargement and to restore normal LV chamber geometry. Studies in our laboratories have shown that, in addition to preventing LV dilation and improving LV ejection fraction, long-term therapy with the CSD reverses the maladaptive gene program observed in LV myocardium of dogs with heart failure. Therapy with the CSD was associated with up-regulated mRNA expression for α-myosin heavy chain and down-regulated mRNA expression of A- and B- type natriuretic peptides, cytokines and favorably modulated cytoskeletal proteins. These findings provide an explanation for mechanisms that may be partly responsible for the improvement in LV systolic and diastolic function seen in dogs with heart failure after long-term CSD therapy. Key Words. maladaptive gene program, cardiomyopathy, congestive heart failure, cytokines, natriuretic peptides, myosin heavy chain

Introduction Left ventricular (LV) dilation and hypertrophy along with sustained neurohumoral activation are adaptive response to an acute cardiac injury as in myocardial infarction. While these adaptation to myocardial injury are initially beneficial in maintaining homeostasis, when sustained over long time, can themselves contribute to the development of progressive LV dysfunction and ultimately, to intractable heart failure. Even though myocardial infarction and coronary artery disease contribute in a significant way to the development of heart failure, other chronic condition such as long-standing hypertension, diabetes, valvular heart disease and viral infections as well as inher-

ited gene mutations in sarcomeres, cytoskeletal proteins and mitochondria also contribute importantly to the development of dilated cardiomyopathy [1]. Once established, cardiac hypertrophy and failure are accompanied by the reprogramming of many cardiac genes along with reactivation of fetal gene program [2–4]. This so-called gene reprogramming or re-activation/de-activation includes alterations in the regulation of genes encoding atrial natriuretic peptides (ANP) or A-type natriuretic peptide, brain natriuretic peptide (BNP) or B-type natriuretic peptide, α- and β-myosin heavy chain isoforms, pro-inflammatory cytokines including tissue necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) as well as cytoskeletal protein that include titin and α-tubulin and β-tubulin isoforms [5–11]. This disregulation of key genes can clearly contribute, albeit in part, to LV structural and functional abnormalities characteristic of the heart failure state [6–11]. While there is little doubt that other genes and signal transduction pathways involved in the beneficial effects of the CSD in heart failure, this review will only address the alteration in the above listed genes with respect to their regulation following long-term CSD therapy in dogs with heart failure. At the present time, heart transplantation is the most effective therapy for end-stage heart failure, but this therapy cannot reach the millions of affected individuals that need it and is not the therapy of choice for patients with milder forms of the disease. Treatment with angiotensinconverting enzyme inhibitors, β-adrenergic receptor blockers, and, more recently, with aldosterone Supported, in part, by a grant from Acorn Cardiovascular, Inc. and by a grant from the National Heart, Lung and Blood Institute PO1 HL074237-02. Address for correspondence: Hani N. Sabbah, Ph.D., Director, Cardiovascular Research, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202. Tel.: 313-916-7360; Fax: 313-916-3001; E-mail: [email protected] 157

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antagonists have improved survival in patients with heart failure partly as a result of attenuating or preventing and, in some cases, reversing LV remodeling [11–14]. In recent years, several surgical approaches have been implemented with the objective of improving LV function through amelioration of progressive LV remodeling. These include surgical reduction of LV size; the so-called Batista procedure [15], dynamic cardiomyoplasty [16] mitral valve repair to limit or eliminate functional mitral regurgitation [17], and endoventricular circular patch plasty repair or Dor procedure [18]. Although the Batista procedure and dynamic cardiomyoplasty have, for all practical purposes, been abandoned, the lessons learned from these procedures gave rise to a new generation of devices aimed at preventing progressive LV dilation and restoring LV shape by passive mechanical containment of the failing left ventricle. One such device is the Acorn Cardiac Support Device (CSD; St Paul, Minnesota) or the CorCapTM . This review will highlight the reversal of maladaptive gene program in dogs with coronary microembolizationinduced heart failure that were treated long-term (3 months) with the CSD [6,19]. In studies described in this review, the CSD was surgically implanted through a mid sternotomy with the pericardium open. The CSD was placed over the left and right ventricles, anchored with sutures to the atrioventricular groove and tailored anteriorly to snugly fit over the surface of the heart [6,12].

Effects of Long-Term CSD Therapy on Contractile Proteins Myosin heavy chain plays a major role in the cardiac contractile machinery. Two isoforms of MHC are expressed in the mammalian heart, α- MHC and β- MHC. α- MHC has a higher ATPase activity compared to β- MHC and is associated with a faster velocity of shortening [20–23]. Recent studies have shown a downregulation in the expression of α-MHC and an upregulation in the expression of β-MHC isoforms in LV myocardium of patients with heart failure [21]. Shifts in MHC isoforms towards greater dependency on β-MHC could have an adverse impact on LV systolic function in heart failure because of attendant reduction in contractile shortening velocity. In a study conducted in dogs with coronary microembolization-induced heart failure, we examined whether long-term therapy with the CSD restores mRNA expression of α-MHC. In this study, the CSD was surgically implanted in 6 dogs with moderate heart failure (LV ejection fraction 30%–40%). Six other dogs with heart failure that were untreated and 6 normal dogs served as controls. All heart failure dogs were followed for 3 months. LV tissue obtained at

Table 1. mRNA expression of α- and β-myosin heavy chain in left ventricular myocardium of normal dogs, dogs with heart failure that were untreated and dogs with heart failure treated for 3 months with the cardiac support device

α-MHC (% of total MHC) β-MHC (% of total MHC)

Normal

HF-Untreated

HF + CSD

23.5 ± 1.0

14.1 ± 1.0∗

24.6 ± 0.6†

76.5 ± 1.0

85.9 ± 1.0∗

75.4 ± 0.6†

HF = heart failure; CSD = cardiac support device; MHC = myosin heavy chain. ∗ = p < 0.05 vs. Normal; † = p < 0.05 vs. HF-Untreated.

sacrifice was used to extract total RNA. Using specific primers in reverse transcriptase polymerase chain reaction (RT-PCR) and restriction enzyme analysis of the RT-PCR product, α-MHC and βMHC isoforms were measured and each normalized to total MHC (αMHC + βMHC). mRNA expression for α-MHC was significantly reduced in untreated heart failure dogs compared to normal dogs, whereas mRNA for β-MHC increased (Table 1). Therapy with the CSD was associated with restoration of mRNA expression of α-MHC and β-MHC to near normal levels. The results indicate that long-term therapy with the CSD in dogs with heart failure is associated with normalization of mRNA expression of both cardiac α-MHC and β-MHC suggesting that therapy with the CSD can reverse this molecular maladaptation and in doing so, possibly contribute to the improvement in LV function seen after long-term CSD therapy [6,10,11].

Effects of Long-Term CSD Therapy on Natriuretic Peptides The natriuretic peptides are a family of three peptide hormones: ANP or A-type, BNP or B-type and CNP or C-type natriuretic peptides. CNP is synthesized in high concentrations in the brain [24], and only minor amounts can be detected in atria or ventricles of the heart [25]. ANP and BNP are mainly synthesized in the heart. Under physiological conditions, ANP is synthesized in the atria [26], whereas BNP is produced by atrial and ventricular cardiomyocytes [27]. The main actions of ANP and BNP include natriuresis, diuresis, and inhibition of the renin-angiotensinaldosterone system [28]. In heart failure, plasma concentrations of ANP and BNP are elevated and are associated with poor long-term outcome [29]. Compared with ANP, plasma concentrations of BNP were shown to be a better marker for impaired LV function and to be of higher prognostic value in heart failure [30]. Previous studies have demonstrated that cardiac BNP mRNA

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was upregulated in heart failure. In end stage human heart failure, BNP and ANP mRNA expression in cardiac tissue from explanted hearts were elevated [31]. A similar increase in ANP and BNP was also reported in dogs with coronary microembolization-induced heart failure [7]. In this study, total RNA was extracted from LV myocardium of 6 normal dogs, 6 untreated heart failure dogs and 6 dogs treated with the CSD [7]. Using specific primers, mRNA expression for BNP and ANP was measured by RT-PCR and identified on agorose ethidium bromide gel electrophoresis. Fluorescent bands corresponding to BNP and ANP were quantified in densitometric units [7]. The results showed a significant increase in mRNA expression for both BNP and ANP in untreated heart failure dogs compared to normal dogs. Treatment with the CSD reduced mRNA expression of both BNP and ANP to near normal levels (Figs. 1 and 2). These data indicate that in dogs with heart failure, long-term therapy with the Acorn CSD is associated with reduced mRNA expression of both BNP and ANP. Various factors have been shown to regulate secretion of ANP and BNP from the heart into the circulation, but the primary acute stimulus for secretion is increased stretch of the myocardium [28–32]. The observed normalization of mRNA expression of ANP and BNP in LV myocardium of dogs with heart failure treated with the CSD support the concept that the reverse remodeling benefits of the CSD in heart failure are mediated, in part, through prevention of myocardial stretch.

Fig. 1. Top: Bar graphs (mean ± SEM) depicting mRNA expression for atrial natriuretic peptide (ANP) from left ventricular (LV) myocardium of normal (NL) dogs, dogs with heart failure that were untreated (HF) and dogs with heart failure treated with the cardiac support device (HF + CSD) Bottom: Gel electrophoresis of the reverse transcriptase polymerase chain reaction (RT-PCR) product in 2 dogs from each of the 3 groups (NL, HF and HF + CSD).

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Fig. 2. Top: Bar graphs (mean ± SEM) depicting mRNA expression for brain natriuretic peptide (BNP) from left ventricular (LV) myocardium of normal (NL) dogs, dogs with heart failure that were untreated (HF) and dogs with heart failure treated with the cardiac support device (HF + CSD) Bottom: Gel electrophoresis of the reverse transcriptase polymerase chain reaction (RT-PCR) product in 2 dogs from each of the 3 groups (NL, HF and HF + CSD).

Modulation of Cytoskeletal Proteins by Long-Term CSD Therapy The cytoskeleton maintains the cell’s structural integrity with the help of cytoskeletal proteins. Titin and tubulin are the among the most important cytoskeletal proteins. Titin is a giant 300 kDa cytoskeletal protein that spans in a spring like-fashion from the Z-disc to the M-band and, under normal conditions, ensures elasticity and extensibility of the sarcomere. Titin has the capability of restoring original sarcomere length after application of a passive stretch and is a pre-requisite for sarcomerogenesis. In heart failure, down-regulation of titin contributes to reduction of the contractile apparatus and leads to increased ventricular stiffness due to loss of sarcomere elasticity [33]. In a recent study, we examined the effects of long-term therpay with the CSD on mRNA expression of titin in dogs with coronary microembolization-induced HF. RNA was extracted from LV tissue of 6 normal dogs, 6 dogs with heart failure that were untreated and 6 dogs with heart failure that were treated with the CSD [34]. mRNA expression for titin was measured using RT-PCR [34]. Compared to normal dogs, titin mRNA expression decreased dogs with heart failure that were untreated but returned to near normal levels follwing 3 months monotherpay with the CSD [34] (Fig. 3). Tubulin, is a heterodimer 55 kDa molecule consisting of a α- and β-isoforms that form microtubules; the latter transmit mechanical and chemical stimuli within and between cells. Microtubules also contribute to cell stability by

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Fig. 3. Top: Bar graphs (mean ± SEM) depicting mRNA expression for titin from left ventricular (LV) myocardium of normal (NL) dogs, dogs with heart failure that were untreated (HF) and dogs with heart failure treated with the cardiac support device (HF + CSD) Bottom: Gel electrophoresis of the reverse transcriptase polymerase chain reaction (RT-PCR) product in 2 dogs from each of the 3 groups (NL, HF and HF + CSD).

anchoring subcellular structures such as mitochondria, nuclei and myofibrils [33,35]. Tubulin has been reported to increase in failing cardiomyocytes [33,35]. It’s accumulation in heart failure can contribute to myofirillogenesis, loss of contractile function and loss of compliance [33,35]. We examined the effects of long-term therpay with the CSD on mRNA expression of both αtubulin and β-tubulin also in dogs with coronary microembolization-induced HF. Again, RNA was extracted from LV tissue of 6 normal dogs, 6 dogs with heart failure that were untreated and 6 dogs with heart failure that were treated with the CSD [9]. mRNA expression for α-tubulin and β-tubulin was measured using RT-PCR [9]. Compared to normal dogs, mRNA expression for α-tubulin and βtubulin decreased in dogs with heart failure that were untreated compared to normal dogs but returned to near normal levels following 3 months monotherpay with the CSD [9] (Fig. 4). These observation of restoration of mRNA expression for titin and tubulin with CSD therpay partly explains the improvement in LV diastolic function seen with long-term CSD therpay as previously described by Kass et al. [36].

Modulation of Pro-Inflammatory Cytokines Long-Term CSD Therapy When expressed at concentrations that are observed in heart failure, inflammatory mediators such as tissue necrosis factor alpha (TNFα) and interleukin-6 (IL-6) are sufficient to mimic some

Fig. 4. Top: Bar graphs (mean ± SEM) depicting mRNA expression for α-tubulin from left ventricular (LV) myocardium of normal (NL) dogs, dogs with heart failure that were untreated (HF) and dogs with heart failure treated with the cardiac support device (HF + CSD) Bottom: Gel electrophoresis of the reverse transcriptase polymerase chain reaction (RT-PCR) product in 3 dogs from each of the 3 groups (NL, HF and HF + CSD).

aspects of the heart failure phenotype including progressive LV dysfunction, fetal gene expression, LV remodeling and cardiomyopathy [37]. These observations led to suggestions that inflammatory mediators may indeed contribute to progression of heart failure by virtue of their toxic effects on the heart and circulation [37]. The functional role of TNF in modulating myocardial structure and function was brought to light as a results of studies by Torre-Amione and colleagues who observed the TNF mRNA and protein expression is increased in patients with ischemic and dilated cardiomyopathy [38]. These seminal observations and others that followed, raised the possibility that, when over expressed, TNF may contribute to progressive LV remodeling. This concept was bolstered by preliminary studies that showed that administration of TNF antagonist to patients with heart failure lead to increased LV function and decreased LV size [39]. We examined the effects of long-term CSD therapy on mRNA and protein expression of TNF-α in dogs with coronary microembolization-induced heart failure. Six untreated HF dogs served as controls [8]. LV tissue from all heart failure dogs and from 6 normal dogs was used to extract RNA. mRNA expression was measured using RT-PCR and protein levels were determined in SDS-extract of LV homogenate using specific antibodies. Bands obtained from RT-PCR and Western blots were quantified in densitometeric units [8]. The results of these studies showed that compared to normal dogs, mRNA and protein expression of TNF-α increased in

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Table 2. mRNA and protein expression of tissue necrosis factor alpha and interleukin-6 in left ventricular myocardium of normal dogs, dogs with heart failure that were untreated and dogs with heart failure treated for 3 months with the cardiac support device

TNF-α mRNA (du) TNF-α Protein (du) IL-6 mRNA (du) IL-6 Protein (du)

Normal

HF-Untreated

HF + CSD

41 ± 2 42 ± 7 20 ± 2 70 ± 6

8∗

49 ± 4† 71 ± 13† 45 ± 1† 112 ± 16†

71 ± 130 ± 6∗ 73 ± 1∗ 140 ± 10∗

HF = heart failure; CSD = cardiac support device; TNF = tissue necrosis factor; IL = interleukin; du = densitometric units. ∗ = p < 0.05 vs. Normal; † = p < 0.05 vs. HF-Untreated.

Fig. 6. Top: mRNA expression of tissue necrosis factor alpha (TNFα) depicted from gel electrophoresis of the reverse transcriptase polymerase chain reaction (RT-PCR) product in left ventricular myocardium of 3 normal (NL) dogs, 3 dogs with heart failure that were not treated (HF) and 3 dogs with heart failure treated with the cardiac support device (HF + CSD). Bottom: Protein expression Western blots from the same dogs of each of the same 3 groups

Fig. 5. Top: Bar graphs (mean ± SEM) depicting mRNA expression for β-tubulin from left ventricular (LV) myocardium of normal (NL) dogs, dogs with heart failure that were untreated (HF) and dogs with heart failure treated with the cardiac support device (HF + CSD) Bottom: Gel electrophoresis of the reverse transcriptase polymerase chain reaction (RT-PCR) product in 3 dogs from each of the 3 groups (NL, HF and HF + CSD).

untreated heart failure controls. CSD therapy reduced mRNA and protein expression of TNF-α (Table 2, Fig. 5). Interleukin-6 is a multifunctional cytokine produced by a plethora of different cell types and is a member of a larger family of structurally related cytokines with overlapping biological effects [40]. Circulating levels of IL-6 are elevated in patients with heart failure with a progressive increase in direct relation to decreasing functional status [41,42]. Elevated plasma levels of IL-6 are a strong and independent prognostic marker in patients with heart failure regardless of etiology [43]. Furthermore, it is now well established that IL-6 and related cytokines are potent inducers of cardiomyocyte hypetrophy in response to mechanical stress/stretch [44]. We tested the hypothesis that

therapy with the CSD by virtue of its effects on mechanical stress and stretch, will down-regulate the expression of IL-6 in dogs with heart failure. In the study, the CSD was implanted in 6 dogs with coronary microembolization-induced HF. Six untreated heart failure dogs served as controls. LV tissue from all heart failure dogs and from 6 normal dogs was used to extract RNA. mRNA expression was measured using RT-PCR. Protein levels were determined in SDS-extract of LV homogenate using specific antibodies. Compared to normal dogs, mRNA and protein expression of IL-6 increased in untreated heart failure dogs. Longterm CSD therapy reduced mRNA and protein expression of IL-6 (Table 2, Fig. 6). The downregulation of these key cytokines namely TNF-α and IL-6 may explain, in part, the attenuation of adverse LV remodeling reported with long-term CSD therapy.

Conclusions The findings of several studies reviewed in this section indicate that long-term therpay with the CSD in dogs with heart failure is associated with reversal of many components of the maladaptive gene program. Normalization of mRNA expression for both cardiac α-MHC and β-MHC suggest that therapy with the CSD can reverse this molecular maladaptation and in doing so, possibly contribute to the improvement in LV function seen after longterm CSD therapy. The observed normalization of

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mRNA expression of ANP and BNP with the CSD support the concept that the reverse remodeling benefits of the CSD in heart failure are mediated, in part, through prevention of myocardial stretch. Furthermore, restoration of mRNA expression for titin and tubulin with CSD therpay may also provide an explanation for the improvement in LV diastolic function also seen with long-term CSD therapy and finally, the observed down-regulation of key cytokines specifically TNF-α and IL-6 may further explain the observed attenuation of adverse LV remodeling including amelioration of cardiomyocyte hypertrophy reported in animals with heart failure following long-term CSD therapy.

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