Myofilament calcium sensitivity and cardiac disease: insights from troponin I isoforms and mutants

The heightened Ca2+ sensitivity of force found with hypertrophic cardiomyopathy (HCM)-associated mutant cardiac troponin I (cTnIR145G; R146G in rodents) has been postulated to be an underlying cause of hypertrophic growth and premature sudden death in humans and in animal models of the disease. Expression of slow skeletal TnI (ssTnI), a TnI isoform naturally expressed in developing heart, also increases myofilament Ca2+ sensitivity, yet its expression in transgenic mouse hearts is not associated with overt cardiac disease. Gene transfer of TnI isoforms or mutants into adult cardiac myocytes is used here to ascertain if expression levels or functional differences between HCM TnI and ssTnI could help explain these divergent organ-level effects. Results showed significantly reduced myofilament incorporation of cTnIR146G compared with ssTnI or wild-type cTnI. Despite differences in myofilament incorporation, ssTnI and cTnIR146G expression each resulted in enhanced myofilament tension in response to submaximal Ca2+ under physiological ionic conditions. Myofilament expression of an analogous HCM mutation in ssTnI (ssTnIR115G) did not further increase myofilament Ca2+ sensitivity of tension compared with ssTnI. In contrast, there was a divergent response under acidic pH conditions, a condition associated with the myocardial ischemia that often accompanies hypertrophic cardiomyopathy. The acidic pH-induced decrease in myofilament Ca2+ sensitivity was significantly greater in myocytes expressing cTnIR146G and ssTnIR115G compared with ssTnI. These results suggest that differences in pH sensitivities between wild-type ssTnI and mutant TnI proteins may be one factor in helping explain the divergent organ and organismal outcomes in TnI HCM- and ssTnI-expressing mice.     

Genetic enhancement of ventricular contractility protects against pressure-overload-induced cardiac dysfunction

In response to pressure-overload, cardiac function deteriorates and may even progress to fulminant heart failure and death. Here we questioned if genetic enhancement of left ventricular (LV) contractility protects against pressure-overload. Transgenic (TG) mice with cardiac-restricted overexpression (66-fold) of the alpha(1A)-adrenergic receptor (alpha(1A)-AR) and their non-TG (NTG) littermates, were subjected to transverse aorta constriction (TAC)-induced pressure-overload for 12 weeks. TAC-induced hypertrophy was similar in the NTG and TG mice but the TG mice were less likely to die of heart failure compared to the non-TG animals (P <0.05). The hypercontractile phenotype of the TG mice was maintained over the 12-week period following TAC with LV fractional shortening being significantly greater than in the NTG mice (42+/-2 vs 29+/-1%, P <0.01). In the TG animals, 11-week beta-AR-blockade with atenolol neither induced hypertrophy nor suppressed the hypercontractile phenotype. The hypertrophic response to pressure-overload was not altered by cardiac alpha(1A)-AR overexpression. Moreover, the inotropic phenotype of alpha(1A)-AR overexpression was well maintained under conditions of pressure overload. Although the functional decline in contractility with pressure overload was similar in the TG and NTG animals, given that contractility was higher before TAC in the TG mice, their LV function was better preserved and heart failure deaths were fewer after induction of pressure overload.     

Slow skeletal troponin I gene transfer, expression, and myofilament incorporation enhances adult cardiac myocyte contractile function

The functional significance of the developmental transition from slow skeletal troponin I (ssTnI) to cardiac TnI (cTnI) isoform expression in cardiac myocytes remains unclear. We show here the effects of adenovirus-mediated ssTnI gene transfer on myofilament structure and function in adult cardiac myocytes in primary culture. Gene transfer resulted in the rapid, uniform, and nearly complete replacement of endogenous cTnI with the ssTnI isoform with no detected changes in sarcomeric ultrastructure, or in the isoforms and stoichiometry of other myofilament proteins compared with control myocytes over 7 days in primary culture. In functional studies on permeabilized single cardiac myocytes, the threshold for Ca²⁺-activated contraction was significantly lowered in adult cardiac myocytes expressing ssTnI relative to control values. The tension–Ca²⁺ relationship was unchanged from controls in primary cultures of cardiac myocytes treated with adenovirus containing the adult cardiac troponin T (TnT) or cTnI cDNAs. These results indicate that changes in Ca²⁺ activation of tension in ssTnI-expressing cardiac myocytes were isoform-specific, and not due to nonspecific functional changes resulting from overexpression of a myofilament protein. Further, Ca²⁺-activated tension development was enhanced in cardiac myocytes expressing ssTnI compared with control values under conditions mimicking the acidosis found during myocardial ischemia. These results show that ssTnI enhances contractile sensitivity to Ca²⁺ activation under physiological and acidic pH conditions in adult rat cardiac myocytes, and demonstrate the utility of adenovirus vectors for rapid and efficient genetic modification of the cardiac myofilament for structure/function studies in cardiac myocytes.     

Overexpressed cardiac Gsalpha in rabbits

We overexpressed cardiac Gsalpha in rabbits using the beta-myosin heavy chain promoter. Gsalpha protein levels in the heart were increased 3-fold by Western blotting in both juvenile (3-4 months), adult (8-10 months), and older (11-16 months) rabbits, compared with wild type (WT) littermates. In transgenic (TG) rabbits, baseline levels of heart rate were elevated, P<0.05 (268+/-17 vs. 209+/-15 beats/min), as well as left ventricular (LV) contractility (LV dP/dt 5475+/-482 vs. 3740+/-246 mm Hg/s). These values and LV ejection fraction remained significantly elevated in older TG rabbits (11-16 months). However, maximal levels of LV dP/dt and heart rate with a high dose of isoproterenol (0.4 microg/kg/min) were similar in adult TG and WT rabbits. In isolated myocytes from the LV of adult rabbits, baseline percent contraction was increased, P<0.05, in TG (11.2+/-0.5%) compared to WT (9.3+/-0.5%), while maximal responses to isoproterenol (100 nM) were similar in adult TG (16.2+/-0.5%) and WT myocytes (15.6+/-0.4%). Although TG mice with overexpressed cardiac Gsalpha develop cardiomyopathy at 8-12 months of age, even at 16 months of age, there was no evidence of cardiomyopathy either in terms of LV function or histology in TG rabbits. In addition, Gialpha was elevated in the LV of adult (8-10 months old) TG rabbits compared to WT, but not in juvenile (3-5 months old) TG rabbits. Although both TG mice and rabbits with overexpressed cardiac Gsalpha exhibited enhanced heart rate and contractility, the TG rabbit does not develop cardiomyopathy, potentially due to a compensatory increase in Gialpha.     

Chimera analysis of troponin I domains that influence Ca(2+)-activated myofilament tension in adult cardiac myocytes

The goal of this study was to investigate isoform-specific functional domains of the inhibitory troponin subunit, troponin I (TnI), as it functions within the intact myofilaments of adult cardiac myocytes. Adenovirus-mediated gene transfer was used to deliver and express a TnI chimera composed of the amino terminus of cardiac TnI (cTnI) and the carboxy terminus of slow skeletal TnI (ssTnI) in adult rat cardiac myocytes. The TnI chimera, designated N-card/slow-C TnI, was expressed and incorporated into myofilaments after gene transfer, without detectable changes in contractile protein stoichiometry or sarcomere architecture. Interestingly, force at submaximal Ca(2+) levels was markedly elevated in single permeabilized myocytes expressing the N-card/slow-C TnI chimera relative to force generated in adult myocytes expressing ssTnI or cTnI. Based on these results, a hierarchy of myofilament Ca(2+) sensitivity is emerging by use of TnI chimera analysis, with the order of sensitivity being N-card/slow-C TnI>ssTnI>cTnI. These results also strongly suggest that independent isoform-specific domains in both the amino and carboxy portions of TnI influence myofilament Ca(2+) sensitivity. In additional studies carried out under pathophysiological ionic conditions (pH 6.2), the dramatic acidosis-induced decrease in myofilament Ca(2+) sensitivity observed in myocytes expressing cTnI was blunted in myocytes expressing N-card/slow-C TnI in a manner similar to that in ssTnI-expressing myocytes. These results demonstrate that there is a pH-sensitive domain residing in the carboxy-terminal portion of TnI. The dissection of isoform-specific functional domains under physiological and acidic pH conditions demonstrates the utility of TnI chimeras for analysis of TnI function and provides important insights into the overall function of TnI within the intact myofilament of adult cardiac myocytes.     

Single amino acid substitutions define isoform-specific effects of troponin I on myofilament Ca2+ and pH sensitivity

Troponin I isoforms play a key role in determining myofilament Ca2+ sensitivity in cardiac muscle. The goal here was to identify domain clusters and residues that confer troponin I isoform-specific myofilament Ca2+ and pH sensitivities of contraction. Key domains/residues that contribute to troponin I isoform-specific Ca2+ and pH sensitivity were studied using gene transfer of a slow skeletal troponin I (ssTnI) template, with targeted cardiac troponin I (cTnI) residue substitutions. Substitutions in ssTnI with cognate cTnI residues R125Q, H132A, and V134E, studied both independently and together (ssTnIQAE), resulted in efficient stoichiometric replacement of endogenous myofilament cTnI in adult cardiac myocytes. In permeabilized myocytes, the pCa50 of tension ([Ca2+] required for half maximal force), and the acidosis-induced rightward shift of pCa50 were converted to the cTnI phenotype in myocytes expressing ssTnIQAE or ssTnIH132A, and there was no functionally additive effect of ssTnIQAE versus ssTnIH132A. Interestingly, only the acidosis-induced shift in Ca2+ sensitivity was comparable to cTnI in myocytes expressing ssTnIV134E, while ssTnIR125Q fully retained the ssTnI phenotype. An additional ssTnIN141H substitution, which lies within the same structural region of TnI as V134, produced a shift in myofilament Ca2+ sensitivity comparable to cTnI at physiological pH, while the acidic pH response was similar to the effect of wild-type ssTnI. Analysis of sarcomere shortening in intact adult cardiac myocytes was consistent with the force measurements. Targeted substitutions in the carboxyl portion of TnI produced residue-specific influences on myofilament Ca2+ and pH sensitivity of force and give new molecular insights into the TnI isoform dependence of myofilament function.     

Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure

Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II-mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20%; 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (approximately 45% reduction in dP/dtmax and dP/dtmin at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca2+ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.     

Altered signaling surrounding the C-lobe of cardiac troponin C in myofilaments containing an alpha-tropomyosin mutation linked to familial hypertrophic cardiomyopathy

A region of interaction between the near N-terminal of cardiac troponin I (cTnI) and the C-lobe of troponin C (cTnC), where troponin T (cTnT) binds, appears to be critical in regulation of myofilament Ca(2+)-activation. We probed whether functional consequences of modulation of this interface influence the function of tropomyosin (Tm) in thin filament activation. We modified the C-lobe of cTnC directly by addition of the Ca(2+)-sensitizer, EMD 57033, and indirectly by replacing native cTnI with cTnI-containing Glu residues at Ser-43 and Ser-45 (cTnI-S43E/S45E) in myofilaments from hearts of non-transgenic (NTG) and transgenic (TG) mice expressing a point mutation on alpha-Tm (E180G) linked to familial hypertrophic cardiomyopathy. Introduction of cTnI-S43E/S45E induced a significantly greater reduction in tension in TG myofilaments compared to NTG controls. Furthermore, the effect of EMD 57033 to restore Ca(2+)-sensitivity was higher in TG compared to NTG fiber bundles containing cTnI-S43E/S45E and compared to TG or NTG fiber bundles containing native TnI. Our results indicate that alterations in regions of interaction among the N-terminal of cTnI, the C-lobe of cTnC, and the C-terminus of cTnT are important in the regulation of myofilament activity. Although levels of phosphorylation at protein kinase C-dependent sites were the same in TG and NTG myofilaments, our data indicate that the effects of phosphorylation were more depressive in TG hearts.     

MCIP1 overexpression suppresses left ventricular remodeling and sustains cardiac function after myocardial infarction

Pathological remodeling of the left ventricle (LV) after myocardial infarction (MI) is a major cause of heart failure. Although cardiac hypertrophy after increased loading conditions has been recognized as a clinical risk factor for human heart failure, it is unknown whether post-MI hypertrophic remodeling of the myocardium is beneficial for cardiac function over time, nor which regulatory pathways play a crucial role in this process. To address these questions, transgenic (TG) mice engineered to overexpress modulatory calcineurin-interacting protein-1 (MCIP1) in the myocardium were used to achieve cardiac-specific inhibition of calcineurin activation. MCIP1-TG mice and their wild-type (WT) littermates, were subjected to MI and analyzed 4 weeks later. At 4 weeks after MI, calcineurin was activated in the LV of WT mice, which was significantly reduced in MCIP1-TG mice. WT mice displayed a 78% increase in LV mass after MI, which was reduced by 38% in MCIP1-TG mice. Echocardiography indicated marked LV dilation and loss of systolic function in WT-MI mice, whereas TG-MI mice displayed a remarkable preservation of LV geometry and contractility, a pronounced reduction in myofiber hypertrophy, collagen deposition, and beta-MHC expression compared with WT-MI mice. Together, these results reveal a protective role for MCIP1 in the post-MI heart and suggest that calcineurin is a crucial regulator of postinfarction-induced pathological LV remodeling. The improvement in functional, structural, and molecular abnormalities in MCIP1-TG mice challenges the adaptive value of post-MI hypertrophy of the remote myocardium. The full text of this article is available online at http://circres.ahajournals.org.     

肌浆网钙ATP酶高表达对大鼠心肌梗死的影响

目的心肌梗死后心力衰竭主要表现为肌浆网钙释放减少和舒张期细胞浆钙浓度的增加。心肌细胞的肌浆网钙ATP酶(SERCA)起重要的作用。心肌梗死后常伴有SERCA表达的下降。我们通过转基因方法增加SERCA的表达,研究其对心梗后的心肌功能、左心室重构和心律失常的作用。方法将月龄匹配的过表达37%心肌SERCA2a蛋白质的转基因大鼠(TG)和对照野生型(WT)大鼠,通过结扎左冠状动脉诱发心肌梗死。采用动态心电图和心脏超声对心梗后的心律失常和左心室功能进行测定。结果心肌梗死后24hTG的死亡率高于WT(71%对35%,P<0.001),并伴有较高的室性心律失常发生率,后者可被利多卡因所预防。1个月后TG心肌舒张功能明显较WT改善,左心室重构减少,但左室收缩功能无明显改变。结论转基因高表达SERCA2a可以改善心梗后1个月的心肌舒张功能、减少重构,但同时伴有心梗急性期死亡率和心律失常发生率的增高。     

Haemodynamics and left ventricular function in heart failure patients: comparison of awake versus intra-operative conditions

BACKGROUND: Heart failure patients are increasingly subjected to surgery. Left ventricular (LV) function is generally assessed in awake patients, but intra-operative LV function is not well studied. AIM: To investigate the relation between LV function indices obtained in the catheterization laboratory and those obtained intra-operatively. METHODS: We enrolled 11 patients with heart failure (NYHA III-IV) scheduled for surgical interventions. LV function was assessed by pressure-volume loops (conductance catheter) during diagnostic catheterizations and intra-operatively under anaesthetized conditions. RESULTS: Compared to awake conditions, cardiac output was unchanged intra-operatively but ejection fraction was significantly reduced (-16%) due to increased end-diastolic volume (+13%). Systolic and diastolic LV pressure and afterload (E(A)) dropped significantly (-32%, -22%, -35%, respectively). LV systolic function assessed by dP/dt(MAX) and the end-systolic pressure-volume relation (E(ES)) was significantly reduced (-34%, -35%). LV diastolic stiffness was reduced (-44%). Ventricular-arterial coupling (E(A)/E(ES)) was maintained. CONCLUSION: Intra-operative cardiac output was unchanged compared to awake conditions due to a balance between reduced systolic and improved diastolic function. Ventricular-arterial coupling was maintained by a reduced afterload. Presumably, systolic function and afterload were reduced by anaesthesia, whereas diastolic function improved after pericardectomy. These findings provide insight into the combined effects of anaesthesia, thoracotomy and pericardectomy, and help to interpret LV function measurements in intra-operative conditions.     

Cardiac troponin I threonine 144: role in myofilament length dependent activation

Myofilament length-dependent activation is the main cellular mechanism responsible for the Frank-Starling law of the heart. All striated muscle display length-dependent activation properties, but it is most pronounced in cardiac muscle and least in slow skeletal muscle. Cardiac muscle expressing slow skeletal troponin (ssTn)I instead of cardiac troponin (cTn)I displays reduced myofilament length-dependent activation. The inhibitory region of troponin (Tn)I differs by a single residue, proline at position 112 in ssTnI versus threonine at position 144 in cTnI. Here we tested whether this substitution was important for myofilament length-dependent activation; using recombinant techniques, we prepared wild-type cTnI, ssTnI, and 2 mutants: cTnI(Thr>Pro) and ssTnI(Pro>Thr). Purified proteins were complexed with recombinant cardiac TnT/TnC and exchanged into skinned rat cardiac trabeculae. Force-Ca2+ relationships were determined to derive myofilament Ca2+ sensitivity (EC50) at 2 sarcomere lengths: 2.0 and 2.2 microm (n=7). Myofilament length-dependent activation was indexed as deltaEC50, the difference in EC50 between sarcomere lengths of 2.0 and 2.2 microm. Incorporation of ssTnI compared with cTnI into the cardiac sarcomere reduced deltaEC50 from 1.26+/-0.30 to 0.19+/-0.04 micromol/L. A similar reduction also could be observed when Tn contained cTnI(Thr>Pro) (deltaEC50=0.24+/-0.04 micromol/L), whereas the presence of ssTnI(Pro>Thr) increased deltaEC50 to 0.94+/-0.12 micromol/L. These results suggest that Thr144 in cardiac TnI modulates cardiac myofilament length-dependent activation.     

Right ventricular dysfunction in adult severe cystic fibrosis

STUDY OBJECTIVES: This study sought to assess the extent of impairment of cardiac function in adult patients with end-stage cystic fibrosis (CF) and to examine the relationship between cardiovascular abnormalities and the degree of hypoxemia and hypercapnia. DESIGN AND SETTING: A retrospective study in a tertiary cardiac and CF center. PARTICIPANTS AND INTERVENTIONS: A total of 103 adult patients with end-stage CF awaiting lung or heart and lung transplantation (mean age [+/- SD], 26+/-7 years; 54 men) underwent Doppler echocardiography and arterial blood gas analysis (mean PaO(2), 54+/-10 mm Hg; mean PaCO(2), 47+/-8 mm Hg). The findings were compared to those of 17 healthy control subjects (mean age, 24+/-7 years; 13 men) who had no history of cardiac or pulmonary disease. MEASUREMENTS AND RESULTS: All patients were in sinus rhythm with a mean tachycardia of 112+/-18 beats/min (control subjects, 76+/-16; p<0.0001) and had a cardiac output of 5.3 L/min (control subjects, 4.3 L/min; p<0.04). In the patient group, the left ventricular (LV) dimensions, systolic and diastolic function, and wall thickness were all within normal limits. The mean amplitude of long-axis excursion in patients was normal at the LV site, but that of the right ventricular (RV) free wall was significantly reduced as compared with control subjects (1.6+/-0.4 vs. 2.2+/-0.4 cm, respectively; p<0.001), which was found to correlate with the degree of hypoxemia (r = 0.63; p<0.02) and hypercapnia (r = -0.68; p<0.01). RV diastolic function, which was represented by the relative isovolumic relaxation time to cardiac cycle length, was longer in patients than in control subjects (8.7+/-4.8% vs. 5.0+/-3.0%, respectively; p<0.03). The pulmonary flow acceleration time (90+/-22 vs 121+/-34 ms, respectively; p<0.01) and the systolic stroke distance (7.0+/-2.2 vs. 10.5+/-1.9 cm/s(2); p<0.001) were both lower than normal. CONCLUSIONS: This study confirms the presence of significant RV systolic and diastolic dysfunction in the setting of consistent tachycardia and increased cardiac output in adult CF patients with severe disease. No specific LV abnormalities were detected in these patients.     

Sex hormones and cardiomyopathic phenotype induced by cardiac beta 2-adrenergic receptor overexpression

Sex differences in cardiomyopathic phenotype and the role of gonadal status were studied in mice with cardiac overexpression of beta(2)-adrenergic receptors (ARs) over 6-15 months (mo) of age. Survival to 15 mo was 96% in wild-type mice but was poorer in transgenic (TG) mice and lower for males than females (13% vs. 56%, P < 0.001). Echocardiography demonstrated progressive left ventricular (LV) dilatation and reduction in LV fractional shortening in male but much less marked changes in female TG mice. Incidences of atrial thrombosis, pleural effusion and lung congestion were higher and myocyte size and fibrosis in the LV were greater in TG males than females. Deprivation of testicular hormones by castration during 3-15 mo of age improved survival and significantly ameliorated LV dysfunction, remodeling, and hypertrophy compared with intact TG males. No significant effect, except for a trend of a better survival, was detected by ovariectomy in TG females. In conclusion, cardiac beta(2)-AR overexpression at a high level leads to cardiomyopathy and heart failure with aging. Female mice had less cardiac remodeling, dysfunction, and pathology and a marked survival advantage over male mice, and this was independent of prevailing levels of ovarian hormones. TG males showed benefit from orchiectomy, suggesting a contribution by testicular hormones to the progression of the cardiomyopathic phenotype.     

Transgenic alpha1A-adrenergic activation limits post-infarct ventricular remodeling and dysfunction and improves survival

OBJECTIVE: Myocardial contractility is enhanced in transgenic (TG) mice with cardiac-restricted overexpression of the alpha1A-adrenergic receptors (alpha1A-AR). We tested the hypothesis that this enhanced inotropy protects against dysfunction and remodeling after myocardial infarction (MI). METHODS: We subjected alpha1A-TG and non-TG mice (NTG) to MI and determined changes in left ventricular (LV) function and diastolic dimension (LVDd) by echocardiography prior to and at 1, 3, 7, 12 and 15 weeks thereafter. RESULTS: Although infarct size was similar in the NTG and alpha1A-TG groups (32+/-2 vs. 29+/-2% of LV, P=NS), mortality due to heart failure was lower after MI in the alpha1A-TG (37%, n=39) than that in the NTG animals (63%, n=56, P=0.026). NTG and alpha1A-TG mice showed similar reductions in LV fractional shortening (FS) and increases in LVDd at week-1 after MI. However, whereas NTG mice showed continuous deterioration over a 15-week period after MI in FS (fell by 40%, from 30+/-2 to 18+/-1%, P<0.01) and LVDd (increased by 24%, from 4.2+/-0.1 to 5.2+/-0.1 mm, P<0.01), the changes in both FS (fell by 14%, from 42+/-2 to 36+/-2%) and LVDd (increased by 8%, from 3.8+/-0.1 to 4.1+/-0.1 mm, both changes P<0.01 vs. NTG) were significantly less severe in the alpha1A-TG mice and did not progress after 3 weeks. At 15 weeks after MI, LV catheterization revealed better preservation of dP/dtmax in the alpha1A-TG vs. NTG mice (7270+/-324, vs. 5938+/-372 mmHg/s, P<0.05). CONCLUSION: Enhanced inotropy resulting from transgenic overexpression of alpha1A-AR is well maintained chronically after MI and limits echocardiography-determined LV remodeling, preserves function, and reduces acute heart failure death.     

Effects of antianginal therapy on left ventricular systolic and diastolic performance: comparison of the response to bepridil, propranolol, and diltiazem.

Abnormalities of left ventricular (LV) systolic performance develop during exercise in patients with coronary artery disease (CAD) as a result of ischemia-induced regional wall motion abnormalities. Like patients with hypertension and those with hypertrophic cardiomyopathy, patients with CAD display abnormalities of LV diastolic performance under basal conditions in the absence of ischemia. The purpose of these studies was to compare the effects of bepridil versus those of propranolol or diltiazem in patients with exertional angina pectoris. LV systolic and diastolic performance were assessed at rest and during peak upright bicycle exercise by first-pass radionuclide ventriculography. Compared with propranolol, bepridil increased exercise capacity, cardiac output, and stroke volume and decreased systemic vascular resistance. Compared with diltiazem, bepridil increased exercise capacity, peak filling rate, and early diastolic filling fraction and decreased systemic vascular resistance, heart rate, time to peak filling rate, and atrial filling volume. Bepridil therapy is associated with improved exercise capacity and decreased anginal frequency and nitroglycerin consumption. In addition, its use is accompanied by favorable changes in LV systolic and diastolic function at rest and during exercise. These changes are consistent with benefits resulting from resolution of myocardial ischemia as well as from positive lusitropic effects of bepridil on the ventricular myocardium.     

Expression of slow skeletal TnI in adult mouse hearts confers metabolic protection to ischemia

Changes in metabolic and myofilament phenotypes coincide in developing hearts. Posttranslational modification of sarcomere proteins influences contractility, affecting the energetic cost of contraction. However, metabolic adaptations to sarcomeric phenotypes are not well understood, particularly during pathophysiological stress. This study explored metabolic adaptations to expression of the fetal, slow skeletal muscle troponin I (ssTnI). Hearts expressing ssTnI exhibited no significant ATP loss during 5 min of global ischemia, while non-transgenic littermates (NTG) showed continual ATP loss. At 7 min ischemia TG-ssTnI hearts retained 80 ± 12% of ATP versus 49 ± 6% in NTG (P < 0.05). Hearts expressing ssTnI also had increased AMPK phosphorylation. The mechanism of ATP preservation was augmented glycolysis. Glycolytic end products (lactate and alanine) were 38% higher in TG-ssTnI than NTG at 2 min and 27% higher at 5 min. This additional glycolysis was supported exclusively by exogenous glucose, and not glycogen. Thus, expression of a fetal myofilament protein in adult mouse hearts induced elevated anaerobic ATP production during ischemia via metabolic adaptations consistent with the resistance to hypoxia of fetal hearts. The general findings hold important relevance to both our current understanding of the association between metabolic and contractile phenotypes and the potential for invoking cardioprotective mechanisms against ischemic stress. This article is part of a Special Issue entitled "Possible Editorial".     

Prognostic implications of left ventricular diastolic dysfunction with preserved systolic function following acute myocardial infarction

The contribution of diastolic dysfunction in patients with preserved left ventricular (LV) systolic function to impaired functional status and cardiac mortality in myocardial infarction (MI) is unknown. In the present study, assessment of LV diastolic function was performed by Doppler analysis of the mitral and pulmonary venous flow, and the propagation velocity of early mitral flow by color M-mode Doppler echocardiography in 183 consecutive patients at day 5-7 following their first acute MI. Patients were classified into four groups: group A: preserved LV systolic and diastolic function (n = 73); group B: LV systolic dysfunction with preserved diastolic function (n = 10); group C: LV diastolic dysfunction with preserved systolic function (n = 60); group D: combined LV systolic and diastolic dysfunction (n = 40). The cardiac mortality rate at 1 year was significantly higher in groups C (13%) and D (38%) compared to A (2%) (p < 0.01). Multivariate regression analysis identified LV diastolic dysfunction (p = 0.001), Killip class >or=II (p = 0.006), and age (0.008) as predictors of cardiac death or readmission due to heart failure. The presence of LV diastolic dysfunction with preserved systolic dysfunction is associated with increased morbidity and mortality following acute MI.     

Reflex alpha-adrenergic coronary vasoconstriction during hindlimb static exercise in dogs

We studied 18 alpha-chloralose-anesthetized dogs to determine if alpha-adrenergic coronary vasoconstriction occurs with hindlimb static exercise. Exercise was elicited by spinal cord ventral nerve root stimulation. Regional coronary blood flow was determined by the radioactive microsphere method. Animals were studied under four experimental conditions: control rest and static exercise, rest and static exercise after beta-adrenergic blockade with propranolol (2 mg/kg), rest and exercise after alpha-adrenergic blockade with phentolamine (.35 mg/kg), and rest and exercise after combined alpha- and beta-adrenergic blockade. Myocardial oxygen consumption during exercise was determined during control and during alpha-adrenergic blockade conditions. Control hindlimb static exercise resulted in significant increases in systolic (10.6%) and diastolic (12.5%) arterial pressures, heart rate (12.2%), and double product (24.6%). Associated with the increased demand for oxygen, myocardial oxygen consumption increased (33.6%) as did left ventricular myocardial flow (29.6%). However, left ventricular coronary vascular resistance was unchanged during static exercise. After beta-adrenergic blockade, systolic (12.2%) and diastolic (11.6%) arterial pressures and double product (10.7%) still increased significantly, but heart rate did not change with static exercise. In contrast, alpha-adrenergic vasoconstriction was unmasked as left (LV) and right (RV) ventricular myocardial blood flow decreased (LV: -30.0%, RV: -25.0%) and coronary vascular resistance increased (LV: 52.5%, RV: 45.3%) with static exercise. Combined alpha- and beta-adrenergic blockade abolished the reduction in myocardial blood flow and the increase in coronary vascular resistance which occurred with static exercise after beta-adrenergic blockade. These data suggest that, during static exercise, reflexes from skeletal muscles can cause alpha-adrenergic coronary artery vasoconstriction.     

Left ventricular systolic function in young women with hyperkinetic syndrome--echocardiographic evaluation]

In twenty two young (mean age 31.6 years) normotensive women with hyperkinetic heart syndrome (HHS) we assessed echocardiographically left ventricular (LV) function indexes before and after 40 mg of oral propranolol. At baseline the HHS group differed from controls with respect to higher heart rate heart and diastolic blood pressure (BPs), lower systolic and systolic LV volumes, greater corrected mean circumferential fiber shortening, ejection fraction, cardiac index and contractility index (systolic blood pressure x body surface area/LV end-systolic volume ratio). Propranolol normalized nearly all analyzed indexes except for BPs which remained increased compared to controls. In young women with HHS enhanced cardiac performance is expressed by higher cardiac index and speed of blood ejection from the left ventricle, is related to tachycardia and higher contractility but not to increased preload. Results post propranolol administration speak in favour of significant role of increased beta-adrenoceptor stimulation in HHS.