997-90 Right (RV) and Left Ventricular (LV) Geometry and Myocyte Contractile Processes with Dilated Cardiomyopathy (DCM): Disparity Between Myocyte Growth and β-Adrenergic Responsiveness

The progression of DCM has been assumed to be a homogenous process for both the RV and LV. However, this assumption has never been tested. Accordingly, we measured myocyte contractile performance (velocity of shortening, VELSHORT; percent shortening, PERSHORT) at baseline (BASE) and after β-adrenergic receptor stimulation (βAR, 25 nM isoproterenol) of isolated myocytes taken from the RV and LV of 5 pigs with pacing induced DCM (240 bpm, 3 weeks) and 5 control pigs (CON). RV and LV mass/body weight (MASS) and myocyte length and cross-sectional area (CSA) were also determined.CON-RVCON-LVDCM-RVDCM-LVVELSHORT-BASE (μm/s)90±5+50±148±2*,+32±1*VELSHORT-βAR (μm/s)206±8+150±5123±8*111±9*PERSHORT-BASE (%)5.8±0.2+4.6±0.13.1±0.1*,+2.2±0.1*PERSHORT-βAR (%)11.5±0.3+10.2±0.359±0.3*5.2±0.4*Length (μm)150±2+137±1179±2*,+173±2*CSA (μm2)176±4+362±8232±4*,+292±5*Mass (gm/kg)0.8±0.1+2.8±0.11.6±0.1*,+2.9±0.2+p<0.05 vs LV*p<005 vS CONIn controls, RV myocytes were longer and had a smaller CSA, but enhanced contractile performance at baseline and with β-adrenergic stimulation. With DCM, no LV hypertrophy occurred. In contrast, RV chamber and cellular hypertrophy occurred and was associated with a persistent increase of RV myocyte baseline contractile function.SummaryThis study demonstrated, for the first time, that differences in RV and LV myocyte function and β-adrenergic responsiveness exist in normal and DCM states. More importantly, a disparity in RV and LV myocyte growth with DCM occurred. Thus, in this model of DCM, RV and LV growth and changes in contractile performance are not a homogenous process, and suggest that inherent differences exist in the response of RV and LV myocytes to stress

Developmental differences in myocyte contractile response after cardioplegic arrest

AbstractAlthough developmental differences in left ventricular function after cardioplegic arrest and rewarming have been postulated, whether differences exist at the level of the myocyte remains unexplored. This project tested the hypothesis that there is a differential effect of hypothermic hyperkalemic cardioplegic arrest with subsequent rewarming on contractile function of immature compared with adult ventricular myocytes. Myocytes were isolated from the left ventricular free wall of five immature and five adult rabbits and incubated for 2 hours in hyperkalemic modified Ringer's solution at 4° C (cardioplegia) or for 2 hours in cell culture medium at 37° C (normothermia). Myocytes were resuspended (“rewarmed”) in 37° C cell culture medium after the incubation protocol. Normothermic baseline contractile performance was lower in immature, compared with adult, myocytes. Specifically, myocyte shortening velocity was 62 ± 4 μm/sec in immature and 112 ± 6 μm/sec in adult myocytes (p < 0.01). After cardioplegia and rewarming, immature myocyte contractile function was unchanged, whereas adult myocyte contractile function was significantly diminished. For example, myocyte shortening velocity was 65 ± 4 μm/sec in immature and 58 ± 3 μm/sec in adult myocytes (p < 0.01 versus normothermic). Myocyte surface area, which reflects myocyte volume, was increased after cardioplegia and rewarming in adults (3582 ± 55 versus 3316 ± 46 μm2, p < 0.01), but remained unchanged in immature myocytes (2212 ± 27 versus 2285 ± 28 μm2, p = not significant). These unique findings demonstrate a preservation of myocyte contractile function and volume regulation in immature myocytes after cardioplegic arrest and rewarming. Thus this study directly demonstrates that developmental differences exist in myocyte responses to hypothermic hyperkalemic cardioplegic arrest with subsequent rewarming. (J THORAC CARDIOVASC SURG 1996;111:1257-66

The effect of basic fibroblast growth factor on the blood flow and morphologic features of a latissimus dorsi cardiomyoplasty

AbstractPrevious studies designed to determine whether latissimus cardiomyoplasty could be used to revascularize ischemic myocardium showed that after operation the latissimus was ischemic and had severely deteriorated. This study was undertaken to determine whether basic fibroblast growth factor, a potent angiogenic peptide, would improve the vascularity of the latissimus and enhance collateral formation between the muscle of the cardiomyoplasty and ischemic myocardium. In goats, myocardial ischemia was induced with an ameroid constrictor and cardiomyoplasty performed. The latissimus was continuously stimulated electrically at 2 Hz for 6 weeks and given four weekly bolus injections of human recombinant basic fibroblast growth factor (80 μg infused into the left subclavian artery). In eight animals, rates of regional blood flow were measured and both the heart and latissimus were evaluated histochemically. The latissimus blood flow rate was 0.114 ± 0.029 ml/gm per minute, which was three times greater than that of historical controls (chronically stimulated latissimus cardiomyoplasty without basic fibroblast growth factor treatment; 0.042 ± 0.007 ml/gm per minute, p < 0.05). Associated with the improved blood flow, there was significantly less evidence of skeletal muscle fiber dropout and muscle fibrosis in the animals treated with basic fibroblast growth factor. Latissimus-derived collateral flow to ischemic myocardium developed in five of the eight goats and averaged 0.288 ± 0.075 ml/gm per minute. This flow was 42.8% ± 15.7% ( n = 5) of the flow required by normal myocardium (which was 0.728 ± 0.095 ml/gm per minute). This value for latissimus-derived collateral blood flow was almost twice that of the historical controls (24.0% ± 3.9%), but the increase did not achieve statistical significance ( p = 0.08). These results hold the promise that basic fibroblast growth factor treatment might enhance the formation of extramyocardial collaterals to the heart and improve skeletal muscle function. (J THORAC CARDIOVASC SURG 1996;111:19-28

799-2 Left Ventricular (LV) and Myocyte Electrophysiology with the Development of Dilated Cardiomyopathy (DCM); Effects of Angiotensin II Receptor (AT1 AT-II) Blockade

Ventricular arrhythmias are a significant cause of morbidity and mortality with DCM, and AT1 AT-II receptor activation has been implicated to play a role in arrhythmogenesis. However, the effects of AT1, AT-II receptor activation on changes in LV function and myocyte electrophysiology during the progression of DCM remain unexplored. Accordingly, this study measured weekly changes in LV function (ejection fraction, LVEF; peak systolic wall stress, LVWS) and surface electrocardiography (R-R interval, QRS duration, QTc interval), and myocyte action potentials (resting membrane, RM; upstroke velocity, Vmax; duration at 90% repolarization, APD90) at terminal study in 3 groups of dogs (n=6/group): DCM, chronic pace (216 bpm, 4 weeks); DCM/AT-BLOCK, chronic pace and treatment with a specific non-peptide AT1 AT-II antagonist (SR 47436 (BMS 186295); 30mg/kg BID); and control (CON). All measurements were made with the pacemaker deactivated.LVEF (%)LVWS (g/cm2)R-R (ms).QRS (ms).QTc (ms)Week 2:CON68.7±3.2133±14646±9958.4±1.3291±13DCM40.9±4.1*184±16*519±4060.7±1.9316±9DCM/AT-Block44.1±3.7*138±10+540±566.32±1.2*325±9Week4:CON73.1±2.4127±10629±4557.6±1.4314±9DCM35.2±3.5*223±16*505±41*62.0±1.9313±9DCM/AT-Block35.2±2.7*160±13*+578±4865.7±1.5*296±6*p&lt;0.05 vs CON+p&lt;0.05 vs DCMWith DCM, RM (-71±l* vs -78±1mV) and APD90 (257±9* vs 226±7ms) increased, and Vmax decreased (121±5* vs 158±9V/s) compared to CON. In contrast, with AT-BLOCK, RM became more negative (-76±1+mV), APD90 was reduced (183±14*+) and Vmax increased (165±13+).SummaryAT1 AT-II receptor blockade during the progression of DCM caused significant changes in LV myocardial conduction and myocyte action potentials. These results suggest that AT1 AT-II receptor activation plays a contributory role toward the changes in LV electrophysiology with DCM

Doxorubicin-Induced Cardiotoxicity in Collaborative Cross (CC) Mice Recapitulates Individual Cardiotoxicity in Humans.

Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Genetic determinants contributing to this variation are difficult to study using current mouse models. Our objective was to determine whether a spectrum of anthracycline induced cardiac disease can be elicited across 10 Collaborative Cross mouse strains given the same dose of doxorubicin. Mice from ten distinct strains were given 5 mg/kg of doxorubicin intravenously once weekly for 5 weeks (total 25 mg/kg). Mice were killed at acute or chronic timepoints. Body weight was assessed weekly, followed by terminal complete blood count, pathology and a panel of biomarkers. Linear models were fit to assess effects of treatment, sex, and sex-by-treatment interactions for each timepoint. Impaired growth and cardiac pathology occurred across all strains. Severity of these varied by strain and sex, with greater severity in males. Cardiac troponin I and myosin light chain 3 demonstrated strain- and sex-specific elevations in the acute phase with subsequent decline despite ongoing progression of cardiac disease. Acute phase cardiac troponin I levels predicted the ultimate severity of cardiac pathology poorly, whereas myosin light chain 3 levels predicted the extent of chronic cardiac injury in males. Strain- and sex-dependent renal toxicity was evident. Regenerative anemia manifested during the acute period. We confirm that variable susceptibility to doxorubicin-induced cardiotoxicity observed in humans can be modeled in a panel of CC strains. In addition, we identified a potential predictive biomarker in males. CC strains provide reproducible models to explore mechanisms contributing to individual susceptibility in humans

Progressive induction of left ventricular pressure overload in a large animal model elicits myocardial remodeling and a unique matrix signature

ObjectivePatients with severe left ventricular pressure overload secondary to aortic stenosis can present with signs and symptoms of heart failure despite normal left ventricular ejection fraction. This process occurs, at least in part, as a result of left ventricular pressure overload–induced extracellular matrix remodeling that promulgates increased left ventricular stiffness and impaired diastolic function. However, the determinants that drive extracellular matrix remodeling in this form of left ventricular pressure overload remain to be fully defined.MethodsLeft ventricular pressure overload was induced in mature pigs (n = 15) by progressive ascending aortic cuff inflation (once per week for 4 weeks), whereby left ventricular mass, left ventricular ejection fraction, and regional myocardial stiffness (rKm) were compared with referent controls (n = 12). Determinants of extracellular matrix remodeling were assessed by measuring levels of mRNA expression for fibrillar collagens, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinase 1 and 4.ResultsWith left ventricular pressure overload, left ventricular mass and rKm increased by 2- and 3-fold, respectively, compared with control, with no change in left ventricular ejection fraction. Left ventricular myocardial collagen increased approximately 2-fold, which was accompanied by reduced solubility (ie, increased cross-linking) with left ventricular pressure overload, but mRNA expression for fibrillar collagen and matrix metalloproteinases remained relatively unchanged. In contrast, a robust increase in mRNA expression for tissue inhibitors of matrix metalloproteinase-1 and 4 occurred with left ventricular pressure overload.ConclusionsIn a progressive model of left ventricular pressure overload, which recapitulates the phenotype of aortic stenosis, increased extracellular matrix accumulation and subsequently increased myocardial stiffness were not due to increased fibrillar collagen expression but rather to determinants of post-translational control that included increased collagen stability (thereby resistant to matrix metalloproteinase degradation) and increased endogenous matrix metalloproteinase inhibition. Targeting these extracellular matrix post-translational events with left ventricular pressure overload may hold both diagnostic and therapeutic relevance

Preoperative statin treatment is associated with reduced postoperative mortality and morbidity in patients undergoing cardiac surgery: An 8-year retrospective cohort study

BackgroundCardiac surgical procedures can be associated with significant morbidity and mortality. Recently, it has been recognized that statins might induce multiple biologic effects independent of lipid lowering that could potentially ameliorate adverse surgical outcomes. Accordingly, this study tested the central hypothesis that pretreatment with statins before cardiac surgery would reduce adverse postoperative surgical outcomes.MethodsDemographic and outcomes data were collected retrospectively for 3829 patients admitted for planned cardiac surgery between February 1994 and December 2002. Statin pretreatment occurred in 1044 patients who were comparable with non–statin-pretreated (n = 2785) patients with regard to sex, race, and age. Primary outcomes examined included postoperative mortality (30-day) and a composite morbidity variable.ResultsThe odds of experiencing 30-day mortality and morbidity were significantly less in the statin-pretreated group, with unadjusted odds ratios of 0.43 (95% confidence interval [CI], 0.28-0.66) and 0.72 (95% CI, 0.61-0.86), respectively. Risk-adjusted odds ratios for mortality and morbidity were 0.55 (95% CI, 0.32-0.93) and 0.76 (95% CI, 0.62-0.94), respectively, by using a logistic regression model and 0.51 (95% CI, 0.27-0.94) and 0.71 (95% CI, 0.55-0.92), respectively, in the propensity-matched model, demonstrating significant reductions in 30-day morbidity and mortality. In a subsample of patients undergoing valve-only surgery (n = 716), fewer valve-only patients treated with statins experienced mortality, although these results were not statistically significant (1.96% vs 7.5%).ConclusionsThese findings indicate that statin pretreatment before cardiac surgery confers a protective effect with respect to postoperative outcomes

Human Cardiac-Specific cDNA Array for Idiopathic Dilated Cardiomyopathy: Sex-Related Differences

Idiopathic dilated cardiomyopathy (IDCM) constitutes a large portion of patients with heart failure of unknown etiology. Up to 50% of all transplant recipients carry this clinical diagnosis. Female-specific gene expression in IDCM has not been explored. We report sex-related differences in the gene expression profile of ventricular myocardium from patients undergoing cardiac transplantation. We produced and sequenced subtractive cDNA libraries, using human left ventricular myocardium obtained from male transplant recipients with IDCM and nonfailing human heart donors. With the resulting sequence data, we generated a custom human heart failure microarray for IDCM containing 1,145 cardiac-specific oligonucleotide probes. This array was used to characterize RNA samples from female IDCM transplant recipients. We identified a female gene expression pattern that consists of 37 upregulated genes and 18 downregulated genes associated with IDCM. Upon functional analysis of the gene expression pattern, deregulated genes unique to female IDCM were those that are involved in energy metabolism and regulation of transcription and translation. For male patients we found deregulation of genes related to muscular contraction. These data suggest that 1) the gene expression pattern we have detected for IDCM may be specific for this disease and 2) there is a sex-specific profile to IDCM. Our observations further suggest for the first time ever novel targets for treatment of IDCM in women and men