Giorgio Olivetti, M.D., Rakesh Abbi, M.D., Federico Quaini, M.D., Jan Kajstura, Ph.D., Wei Cheng, M.D., James A. Nitahara, M.D., Eugenio Quaini, M.D., Carla Di Loreto, M.D., Carlo A. Beltrami, M.D., Stanislaw Krajewski, M.D., Ph.D., John C. Reed, M.D., Ph.D., and Piero Anversa, M.D.
Background Loss of myocytes is an important mechanism in thedevelopment of cardiac failure of either ischemic or nonischemicorigin. However, whether programmed cell death (apoptosis) isimplicated in the terminal stages of heart failure is not known.We therefore studied the magnitude of myocyte apoptosis in patientswith intractable congestive heart failure.
Methods Myocardial samples were obtained from the hearts of36 patients who underwent cardiac transplantation and from thehearts of 3 patients who died soon after myocardial infarction.Samples from 11 normal hearts were used as controls. Apoptosiswas evaluated histochemically, biochemically, and by a combinationof histochemical analysis and confocal microscopy. The expressionof two proto-oncogenes that influence apoptosis, BCL2 and BAX,was also determined.
Results Heart failure was characterized morphologically by a232-fold increase in myocyte apoptosis and biochemically byDNA laddering (an indicator of apoptosis). The histochemicaldemonstration of DNA-strand breaks in myocyte nuclei was coupledwith the documentation of chromatin condensation and fragmentationby confocal microscopy. All these findings reflect apoptosisof myocytes. The percentage of myocytes labeled with BCL2 (whichprotects cells against apoptosis) was 1.8 times as high in thehearts of patients with cardiac failure as in the normal hearts,whereas labeling with BAX (which promotes apoptosis) remainedconstant. The near doubling of the expression of BCL2 in thecardiac tissue of patients with heart failure was confirmedby Western blotting.
Conclusions Programmed death of myocytes occurs in the decompensatedhuman heart in spite of the enhanced expression of BCL2; thisphenomenon may contribute to the progression of cardiac dysfunction.
Cardiomyopathy of either ischemic or nonischemic origin is characterizedby a progressive loss of myocytes.1,2,3 Defects in coronaryblood flow develop in the overloaded myocardium,4,5 resultingin myocyte death and fibrosis at multiple sites in the ventricularwall.1,2,3,5 Recently, apoptosis in myocytes has been demonstratedexperimentally after injury due to ischemia and reperfusion,6myocardial infarction,7 cardiac aging,8 ventricular pacing,9and coronary embolization.10 Whether this form of cell deathoccurs in the failing human heart is not known, however. Apoptosisin the myocardium is complex and thus difficult to recognize.Myocyte apoptosis is scattered across the wall and is restrictedto individual cells.6,8,9 In the early stages, cell structureis preserved because the damage is limited to the internucleosomalregion of DNA, leaving the cytoplasm intact.11 Moreover, theactivation of this cellular "suicide program" may be modulatedby the expression of the proto-oncogenes BCL2 (which protectscells from apoptosis), and BAX (which opposes the effects ofBCL2, thereby promoting apoptosis).12,13,14
Studies of apoptosis in diseased hearts have shown great variabilityin the magnitude of this phenomenon,8,9,10,15,16,17,18,19,20thus raising questions about the specificity and sensitivityof DNA end-labeling by the terminal deoxynucleotidyl transferase(TdT) assay, a method commonly used to identify apoptosis. Findingsof high levels of apoptosis may be questioned, since the completionof this process may require from 20 minutes to 24 hours.21,22,23A massive loss of heart tissue may therefore occur over a veryshort period. In an attempt to clarify these contrasting findings,we used a new approach to the assessment of cell death in myocardialsamples obtained from patients with congestive heart failure.Quantitative measurements of apoptotic myocyte nuclei were obtainedby the TdT reaction with a fluorescence probe7,8,9,15,17; thisassay was complemented by characterization of the chromatinpattern in the same nuclei by confocal microscopy. This methodof analysis combined the histochemical detection of internucleosomalcleavage with the structural definition of chromatin alterations.In addition, DNA laddering was identified in comparable myocardialspecimens in order to confirm DNA fragmentation biochemically.Finally, changes in the expression of BCL2 and BAX in the cellswere evaluated.
Methods
Ventricular Function
Measurements of systolic and diastolic ventricular dimensionsand fractional shortening were performed by two-dimensionalechocardiography one to six months before transplantation. Thestroke-volume index, cardiac output, cardiac index, ejectionfraction, right ventricular end-diastolic pressure, and pulmonary-arterywedge pressure were determined by cardiac catheterization.
Tissue Fixation
Samples were collected from the explanted hearts of 36 patientsundergoing cardiac transplantation. Three additional sampleswere obtained two to six hours after death from patients, previouslyin good health, who died within four days after an acute myocardialinfarction. Specimens were fixed in 10 percent buffered formalinor frozen in liquid nitrogen. Control samples of myocardiumwere obtained within six hours after death from eight patientswho died of causes other than cardiovascular disease.24 Threeright ventricular endomyocardial specimens obtained before cardioplegicarrest in brain-dead cardiac donors were also used as controls.
TdT Assay
Myocardial sections were incubated with a solution containing5 units of TdT, 2.5 mM cobalt chloride, 0.2 M potassium cacodylate,24 mM TRIS–hydrochloride, 0.25 percent bovine serum albumen,and 0.5 nM biotin-16–deoxyuridine triphosphate (dUTP).After exposure to a solution containing 5 µg of fluoresceinisothiocyanate–Extravidin per milliliter, myocytes werestained with -sarcomeric actin antibody (clone 5C5, Sigma),and the nuclei were visualized with bisbenzimide.7,8,9,15,17
DNA-Strand Breaks in Myocytes
Myocyte nuclei labeled with dUTP were measured by examinationwith an ocular reticle containing 42 sampling points, coveringa minimum of 45 mm2 and a maximum of 423 mm2 of tissue in eachheart. The volume fraction of replacement fibrosis was alsoevaluated.9 The number of myocyte nuclei per unit of area oftissue was determined by counting an average of 50 fields, each6084 µm2 in size, in each ventricular sample. By combiningthese data with the estimated numbers of dUTP-labeled myocytenuclei, the number of apoptotic myocyte nuclei per 106 nucleiwas determined.7,8,9,15,17 Myocyte diameter was determined bymeasuring 100 cells in the region of the nucleus in each leftventricle and averaging these measurements.
Confocal Microscopy
To correlate chromatin alterations with the presence or absenceof dUTP labeling, histologic sections were analyzed by confocalmicroscopy (MRC-1000, Bio-Rad). Chromatin was visualized bystaining with propidium iodide (10 µg per milliliter).Sections were examined at a magnification of 100 (numericalaperture, 1.3). Nine specimens, six from patients with ischemiccardiomyopathy and three from patients with idiopathic dilatedcardiomyopathy, were evaluated. In each case, 11 to 16 nucleithat showed only dUTP labeling, both chromatin alterations anddUTP labeling, and chromatin or nuclear damage with no dUTPlabeling were collected. A total of 126 myocyte nuclei wereanalyzed.
DNA Gel Electrophoresis
Fragments of myocardium were homogenized, fixed in 70 percentethanol, and incubated in 40 µl of phosphate–citratebuffer (pH 7.8) for one hour. The supernatant was concentratedby vacuum and digested with RNase (1 mg per milliliter) andproteinase K (1 mg per milliliter). Samples were subjected toelectrophoresis on 1 percent agarose gel containing 5 µgof ethidium bromide per milliliter.7,8,9,15,17
Localization of BCL2 and BAX
Sections were incubated with anti-BCL2 peptide (position ofamino acids, 41 to 54) antiserum at a dilution of 1:2000 andanti-BAX peptide (position of amino acids, 43 to 61) antiserumat a dilution of 1:800. After washing with phosphate-bufferedsaline, sections were incubated for one hour with 2.8 µgof biotinylated goat antirabbit antibody per milliliter andthen with an avidin–biotin complex reagent containinghorseradish peroxidase.7
Western Blotting
Specimens were lysed, and aliquots containing 50 µg ofprotein were fractionated by sodium dodecyl sulfate–polyacrylamide-gelelectrophoresis (12 percent gels) and transferred to nitrocellulosefilters. Blots were washed with phosphate-buffered saline, treatedwith 2 percent hydrogen peroxide, and saturated for unspecificbinding sites with a buffer containing 10 mM TRIS, 150 mM sodiumchloride, and 0.1 percent Tween 20 (pH 7.9; TNT), supplementedwith 5 percent nonfat dry milk, 2 percent bovine serum albumen,and 1 percent goat serum. Subsequently, membranes were incubatedat 4°C in TNT containing 0.1 to 0.05 percent anti-BCL2 or0.1 percent anti-BAX antiserum. Blots were washed in phosphate-bufferedsaline and incubated with peroxidase-conjugated antirabbit IgG.Irrelevant antibodies (rabbit antirat IgG and rabbit antimouseIgG) were used as negative controls.25
Statistical Analysis
All tissue samples were coded, and the code was broken at theend of the studies. Results are presented as means ±SD.Statistical significance (P<0.05) in comparisons betweentwo measurements and among groups was determined by the two-tailedStudent's t-test and by analysis of variance with the Bonferronimethod, respectively.26
Results
Patients
Twenty of the 39 patients whose hearts were studied had ischemiccardiomyopathy, and 18 had idiopathic dilated cardiomyopathy(Table 1). One patient had mitral stenosis and aortic regurgitation.These patients each had a marked reduction in ejection fractionand a substantial increase in left ventricular diastolic andsystolic diameter (Table 2). The ratio of wall thickness tochamber radius was reduced, and left ventricular end-diastolicvolume was nearly twice the control value in all patients. Atthe time of surgery, 20 patients were being treated with intravenousinotropic drugs, and 28 were receiving diuretics. Angiotensin-converting–enzymeinhibitors were administered to 13 patients, and digitalis to10. Seventeen of the 20 patients with ischemic cardiomyopathyhad previously had a myocardial infarction; bypass surgery hadbeen performed in 8.
Table 2. Echocardiographic and Hemodynamic Measurements According to the Type of Heart Failure.
dUTP Labeling of the Myocardium
We analyzed tissue from 8 control and 15 diseased hearts withdUTP labeling. Control myocardium was restricted to the leftventricle, whereas 15 specimens of the left ventricle and 11of the right ventricle were available from the 15 diseased hearts.Apoptotic myocyte nuclei were rare in normal myocardium (Figure 1Aand Figure 1B). Scattered dUTP labeling was seen in failinghearts (Figure 1C). At times, DNA-strand breaks affected groupsof two to three myocytes (Figure 1D). Nine of the 15 samplesof left ventricular tissue and 4 of the 11 samples of rightventricular tissue from failing hearts included areas of scarringconsistent with necrotic cell death. The degree of myocardialfibrosis in these 13 specimens varied from 1 to 44 percent (mean,10±12 percent). Foci of reparative fibrosis were seenin three of eight control hearts (mean degree of myocardialfibrosis, 2±2 percent). The myocyte diameter was 21±2µm in control hearts, 26±3 µm (24 percentlarger, P = 0.0018) in samples from patients with ischemic cardiomyopathy,and 25±3 µm (19 percent larger, P = 0.017) in samplesfrom patients with idiopathic dilated cardiomyopathy. Therewas no correlation between the diameter of myocytes and thedegree of apoptosis. Moreover, the distribution of dUTP-labeledmyocyte nuclei was independent of the sites of scarring.
Figure 1. Sections of Left Ventricular Myocardium Showing DNA-Strand Breaks (Arrowheads) in a Myocyte Nucleus (Panels A, B, and C) and in Three Myocyte Nuclei (Panel D) in Control and Diseased Hearts.
Panels A, C, and D show the labeling with deoxyuridine triphosphate; Panel B shows the same microscopical field as Panel A, but after labeling with -sarcomeric actin antibody (the arrowhead indicates the nuclear region). Panels A and B show tissue from a control heart (x1200), Panel C tissue from the heart of a patient with ischemic cardiomyopathy (x900), and Panel D tissue from a patient with idiopathic dilated cardiomyopathy (x900).
Table 3 lists the numbers of dUTP-labeled myocyte nuclei insamples from 8 control hearts and 15 failing hearts. Since themagnitude of DNA-strand breakage in myocytes was similar inthe two ventricles, data from the left and right ventriclesin diseased hearts were combined. In normal myocardium, apoptoticmyocytes were absent or affected at most 28 nuclei per million.This value was markedly increased in patients with congestiveheart failure, from a minimum of 673 to a maximum of 6549 nucleiper million. The average 232-fold increase in the extent ofapoptosis in patients with congestive heart failure, as comparedwith controls, was significant (P = 0.0036).
Table 3. Deoxyuridine Triphosphate Labeling of Myocyte Nuclei.
Myocyte Apoptosis as Assessed by Confocal Microscopy
The analysis by confocal microscopy involved 126 myocyte nucleicollected from six samples from patients with ischemic cardiomyopathy(samples 1, 2, 3, 5, 6, and 7 in Table 3) and three from patientswith idiopathic dilated cardiomyopathy (samples 2, 4, and 5in Table 3). Figure 2A, Figure 2B, and Figure 2C show a myocytenucleus with preserved chromatin structure and a smaller nucleuswith chromatin that appears condensed, uniform, and smooth inthe same microscopical field. These modifications in the characteristicsof chromatin were associated with dUTP labeling, indicatingDNA-strand breaks and morphologic changes consistent with apoptosis.dUTP-positive nuclei with normal chromatin were also seen inthese myocardial samples (Figure 2D, Figure 2E, and Figure 2F).Nuclear fragmentation in the presence and absence of dUTP labelingwas seen as well (Figure 2G, Figure 2H, Figure 2I, and Figure 2J).Of the 126 nuclei we studied, 96 exhibited dUTP labelingand chromatin and nuclear alterations, 18 showed dUTP labelingonly, and 12 had chromatin or nuclear damage but were negativefor dUTP labeling. These values corresponded to 77±5percent, 14±5 percent, and 9±2 percent of allnuclei examined, respectively.
Figure 2. Myocyte Nuclei from Patients with Ischemic and Idiopathic Dilated Cardiomyopathy, Seen on Confocal Microscopy.
In Panel A an apoptotic small, homogeneous, condensed nucleus (arrow) and a normal nucleus (arrowhead) show red fluorescence after propidium iodide staining. Panel B shows the same nuclei after labeling with deoxyuridine triphosphate (dUTP); the apoptotic nucleus is recognizable by its green fluorescence. The combination of propidium iodide and dUTP labeling is shown in Panel C, in which -sarcomeric actin staining of the myocyte cytoplasm produces red fluorescence. The visualization of -sarcomeric actin labeling required an increase in the gain of the photomultiplier of the confocal microscope, which resulted in overexposure of the propidium iodide staining of both nuclei in Panel C. Panels D, E, and F show a myocyte nucleus with apparently normal morphologic features after staining with propidium iodide, labeling with dUTP, and the combination of labeling with propidium iodide and dUTP, along with -sarcomeric actin, respectively. Panels G and H show dUTP labeling of a myocyte nucleus undergoing fragmentation; propidium iodide staining alone is not shown. Panels I and J show a fragmented nucleus as seen with propidium iodide staining alone (Panel I) and in combination with -sarcomeric actin labeling (Panel J). The negative dUTP labeling of this fragmented myocyte nucleus is not shown. (Panels A through F, I, and J, x1500; Panels G and H, x3000.)
DNA Gel Electrophoresis
The electrophoretic analysis included tissue from the heartsof three control subjects, five patients with ischemic cardiomyopathy,and six with idiopathic dilated cardiomyopathy. Samples of bothventricles were available from the 11 failing hearts, whereasnormal myocardium came only from the left ventricle. DNA nucleosomeladders were present in the myocardium of patients with idiopathicdilated cardiomyopathy and ischemic cardiomyopathy (Figure 3Aand Figure 3B). DNA laddering was seen in all 22 samples examinedfrom diseased hearts. In contrast, no DNA fragments were detectedin the three control hearts (Figure 3A). A diffuse pattern ofDNA indicative of cell necrosis was apparent in one heart froma patient with idiopathic dilated cardiomyopathy and three frompatients with ischemic cardiomyopathy (Figure 3B).
Figure 3. Electrophoretic Pattern of DNA Fragments in Myocytes Extracted from Two Control Hearts (Top Panel, Lanes 1 and 2), from the Heart of a Patient with Idiopathic Dilated Cardiomyopathy (Top Panel, Lane 3), and from the Hearts of Three Patients with Ischemic Cardiomyopathy (Bottom Panel, Lanes 1 through 3).
A combination of DNA laddering and diffusion is apparent in the bottom panel, lane 2. MW denotes markers of molecular weight. The arrows indicate multiples of 180 bp.
Expression of BCL2 and BAX
BCL2 protein was apparent in the myocyte cytoplasm (Figure 4Aand Figure 4B), and BCL2-positive cells were more numerous indiseased hearts. BAX protein had a similar cytoplasmic localization(Figure 4C and Figure 4D), but no differences were apparentbetween control and failing hearts. The results for samplesfrom the left and right ventricles were combined. Heart failurewas characterized by a near doubling of the percentage of myocyteslabeled with BCL2 (control hearts, 36±11 percent; diseasedhearts, 66±18 percent; P<0.001). In contrast, thefraction of myocytes labeled with BAX remained roughly constant(control hearts, 75±11 percent; diseased hearts, 84±13percent).
Figure 4. Detection of the Proteins BCL2 (Panels A and B) and BAX (Panels C and D).
Panels A and C show tissue from control hearts, and Panels B and D tissue from decompensated hearts. (Panels A and B, x600; Panels C and D, x450).
The changes in the expression of BCL2 and BAX in the myocardiumwere also analyzed by Western blotting. This portion of thestudy included samples from three control hearts, three heartsfrom patients with ischemic cardiomyopathy, and three from patientswith idiopathic dilated cardiomyopathy. As Figure 5 shows, theamount of BCL2 protein was higher in decompensated hearts thanin normal hearts. Similar results were obtained in the two ventricles,and the data were therefore combined. In comparison with controlhearts, there was a significant 2.4-fold increase in BCL2 infailing hearts (optical density: control hearts, 30±10;hearts from patients with congestive heart failure, 72±18)(P<0.01). However, the expression of BAX protein was notaltered by heart failure (optical density: control hearts, 76±9;hearts from patients with congestive heart failure, 88±11)(Figure 5).
Figure 5. Western Blot Analysis of the BCL2 and BAX Proteins in Human Myocardium.
C denotes control hearts, CHF hearts from patients with congestive heart failure, and P positive control. Protein extracts from the myocardium of mice overexpressing BCL2 (kindly provided by Dr. Richard Kitsis) and from the LG12 lymphoid cell line were used as positive controls for BCL2 and BAX, respectively. Loading of proteins is illustrated by Coomassie blue staining. The upper panels show the Western blot assay for BCL2 (arrowhead) and BAX, and the lower panels show the corresponding loading of proteins.
Discussion
Heart Failure and Myocyte Death
These results demonstrate that cell death accompanies irreversiblecongestive heart failure in humans. Myocyte death occurred throughapoptosis and necrosis. Apoptosis was documented histologicallyby the TdT assay and biochemically by DNA agarose-gel electrophoresis.These methods identified double-strand cleavage of the DNA inmyocyte nuclei and DNA laddering in the myocardium, respectively.Myocyte necrosis was inferred on the basis of sites of reparativefibrosis in the ventricular wall and a diffuse pattern, resemblinga smear, of DNA. The magnitude of ongoing programmed myocytedeath was measured quantitatively and found to amount to anaverage of 2318 cells per 106 myocytes. The extent of acutenecrotic cell death was not determined in these tissue samples,but the consequences of this form of myocyte loss resulted inscarring of nearly 10 percent of the myocardium. Whether ongoingmyocyte necrosis was present in these failing hearts could notbe established morphologically.7,8,27
The degree of apoptosis in myocytes varied considerably in recentinvestigations,8,9,10,15,16,17,18,19,20 possibly reflectingtechnical limitations in the procedures used. In the currentstudy, confocal microscopy was used to address this criticalissue. With this approach, it was possible to document thatboth dUTP labeling of the DNA and alterations in the morphologicfeatures of chromatin that are typical of apoptosis28 were presentin 77 percent of myocyte nuclei. In addition, 14 percent ofmyocyte nuclei with normal-appearing chromatin were positivefor dUTP. Since the formation of DNA-strand breaks precedesstructural damage,11 the degree of dUTP labeling in cells withno apparent loss of morphologic integrity is consistent withthe progression of the apoptotic process. Nine percent of myocytenuclei had severe changes in chromatin but were dUTP-negative.This phenomenon may reflect apoptotic changes with limited digestionof the genomic DNA to 300-kb and 50-kb fragments without theformation of mononucleosomes and oligonucleosomes. Such an occurrencehas been demonstrated in hepatocytes and in endothelial andepithelial cells.21,29 Even if the 9 percent of cells with apoptoticnuclei that were not detected by dUTP labeling are includedin calculating the prevalence of apoptotic cells, the estimatedvalue increases only from 0.23 percent to 0.25 percent. Thisanalysis did not include the contribution of apoptotic bodies,because of the difficulty of recognizing the cell of originin these late stages of cell death.
Our results differ from the observations of Narula et al.,19who found that the percentage of myocytes affected by apoptosisin patients with ischemic cardiomyopathy and idiopathic dilatedcardiomyopathy was 5 to 35.5 percent. These percentages are20 and 142 times as high as those reported here, raising questionsabout the actual level of apoptosis in patients with cardiacfailure. Since this form of cell death is completed in at mosta few hours,21,22 such high values would be incompatible withlife. Moreover, the histochemical detection of apoptosis inthe study by Narula et al. did not include morphologic confirmationof chromatin abnormalities and nuclear damage, suggesting thatour estimate of the degree of this process in the decompensatedhuman heart is more reliable. The inclusion of a larger numberof samples allowed us to measure the extent of apoptosis inpatients with ischemic cardiomyopathy and idiopathic dilatedcardiomyopathy in quantitative statistical terms. We found nosignificant difference between these two pathologic conditions.
Measurements of the number of myocytes in humans have shownthat cell loss occurs in ischemic cardiomyopathy,30 idiopathicdilated cardiomyopathy,2 and hypertensive hypertrophy.31 Apoptosiswas not analyzed in these studies, and necrosis was consideredthe exclusive mechanism of myocyte death. Similarly, the lossof myocytes with aging has been linked to defects in the oxygenationpotential of the aging myocardium and to myocyte necrosis.5However, the contention that cardiac damage is only necroticin nature has been challenged. Studies in vitro15,32 and inanimal models of transient ischemia6,33 and coronary-arteryocclusion and myocardial infarction7 have demonstrated thatmyocyte apoptosis is an important component of ischemic myocardialinjury. Moreover, this form of cell death may involve the cardiacconduction system, promoting fatal arrhythmias.34 Embolizationof the intramural branches of the coronary vasculature in experimentalstudies10 and, most important, the infarcted human heart18,35are characterized by myocyte apoptosis and necrosis. Limitationsin coronary blood flow may exist in the failing heart4,36 incombination with heightened mechanical stress15; apoptosis triggeredby these mechanisms may increase myocyte death in the ventricle,thus contributing to cardiac dysfunction.
Expression of BCL2 and BAX
Our results indicate that alterations in the expression of membersof the BCL2 family of proteins occurred in myocytes from thehearts of patients with congestive heart failure; specifically,the level of BCL2 increased and that of BAX remained unchanged.BCL2 promotes cell survival13 by forming heterodimers with BAX,a protein that otherwise induces apoptosis.37 The formationof such heterodimers is mediated by three conserved motifs calledthe BCL2 homology 1 (BH1), BCL2 homology 2 (BH2), and BCL2 homology3 (BH3) domains.13,37,38,39 The process of heterodimerizationis dependent on these BH1 and BH2 domains, and selected mutationswithin these domains abolish the ability of BCL2 to bind toBAX. If BAX homodimers predominate, cell death will occur, whereasif BCL2–BAX heterodimers prevail, the cell will survive.37The enhanced expression of BCL2 in the failing heart in theabsence of changes in the quantity of BAX strongly suggeststhat compensatory mechanisms are activated in the overloadedmyocardium in an attempt to maintain cell survival.
Supported by grants from the National Institutes of Health (HL-38132,HL-39902, HL-40561, and PO1-HL-43023) and from the AmericanHeart Association (950321).
We are indebted to Maria Feliciano for her expert technicalassistance.
Source Information
From the Departments of Medicine (G.O., J.K., W.C., J.A.N., P.A.) and Pathology (R.A.), New York Medical College, Valhalla; the Department of Pathology, University of Parma, Parma, Italy (F.Q.); the Department of Pathology, University of Udine, Udine, Italy (C.D., C.A.B.); the De Gasperis Division of Cardiac Surgery, Milan, Italy (E.Q.); and the Burnham Institute, La Jolla, Calif. (S.K., J.C.R.).
Address reprint requests to Dr. Anversa at the Department of Medicine, Vosburgh Pavilion 302, New York Medical College, Valhalla, NY 10595.
References
Anversa P, Li P, Zhang X, Olivetti G, Capasso JM. Ischaemic myocardial injury and ventricular remodelling. Cardiovasc Res 1993;27:145-157. [Free Full Text]
Beltrami CA, Finato N, Rocco M, et al. The cellular basis of dilated cardiomyopathy in humans. J Mol Cell Cardiol 1995;27:291-305. [Medline]
Bing OHL. Hypothesis: apoptosis may be a mechanism for the transition to heart failure with chronic pressure overload. J Mol Cell Cardiol 1994;26:943-948. [CrossRef][Medline]
Parodi O, De Maria R, Oltrona L, et al. Myocardial blood flow distribution in patients with ischemic heart disease or dilated cardiomyopathy undergoing heart transplantation. Circulation 1993;88:509-522. [Free Full Text]
Rakusan K, Flanagan MF, Geva T, Southern J, Van Praagh R. Morphometry of human coronary capillaries during normal growth and the effect of age in left ventricular pressure-overload hypertrophy. Circulation 1992;86:38-46. [Free Full Text]
Kajstura J, Cheng W, Reiss K, et al. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest 1996;74:86-107. [Medline]
Kajstura J, Cheng W, Sarangarajan R, et al. Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats. Am J Physiol 1996;271:H1215-H1228. [Free Full Text]
Liu Y, Cigola E, Cheng W, et al. Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest 1995;73:771-787. [Medline]
Sharov VG, Sabbah HN, Shimoyama H, Goussev AV, Lesch M, Goldstein S. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol 1996;148:141-149. [Abstract]
Arends MJ, Morris RG, Wyllie AH. Apoptosis: the role of endonuclease. Am J Pathol 1990;136:593-608. [Abstract]
Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 1993;75:241-251. [CrossRef][Medline]
Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol 1994;124:1-6. [Free Full Text]
Krajewski S, Krajewska M, Shabaik A, Miyashita T, Wang HG, Reed JC. Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol 1994;145:1323-1336. [Abstract]
Cheng W, Li B, Kajstura J, et al. Stretch-induced programmed myocyte cell death. J Clin Invest 1995;96:2247-2259.
Geng Y-J, Libby P. Evidence for apoptosis in advanced human atheroma: colocalization with interleukin-1 -converting enzyme. Am J Pathol 1995;147:251-266. [Abstract]
Cheng W, Kajstura J, Nitahara JA, et al. Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res 1996;226:316-327. [CrossRef][Medline]
Olivetti G, Quaini F, Sala R, et al. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol 1996;28:2005-2016. [CrossRef][Medline]
Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996;335:1182-1189. [Free Full Text]
Mallat Z, Tedgui A, Fontaliran F, Frank R, Durigon M, Fontaine G. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia.N Engl J Med 1996;335:1190-6.
Bursch W, Oberhammer F, Schulte-Hermann R. Cell death by apoptosis and its protective role against disease. Trends Pharmacol Sci 1992;13:245-251. [CrossRef][Medline]
Resnicoff M, Abraham D, Yutanawiboonchai W, et al. The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. Cancer Res 1995;55:2463-2469. [Free Full Text]
Colucci WS. Apoptosis in the heart. N Engl J Med 1996;335:1224-1226. [Free Full Text]
Olivetti G, Giordano G, Corradi D, et al. Gender differences and aging: effects on the human heart. J Am Coll Cardiol 1995;26:1068-1079. [Abstract]
Krajewski S, Bodrug S, Gascoyne R, Berean K, Krajewska M, Reed JC. Immunohistochemical analysis of Mcl-1 and Bcl-2 proteins in normal and neoplastic lymph nodes. Am J Pathol 1994;145:515-525. [Abstract]
Wallenstein S, Zucker CL, Fleiss JL. Some statistical methods useful in circulation research. Circ Res 1980;47:1-9. [Free Full Text]
Benjamin IJ, Jalil JE, Tan LB, Cho K, Weber KT, Clark WA. Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis. Circ Res 1989;65:657-670. [Free Full Text]
Gorczyca W, Gong J, Darzynkiewicz Z. Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays. Cancer Res 1993;53:1945-1951. [Free Full Text]
Oberhammer F, Wilson JW, Dive C, et al. Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J 1993;12:3679-3684. [Medline]
Beltrami CA, Finato N, Rocco M, et al. Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation 1994;89:151-163. [Free Full Text]
Olivetti G, Melissari M, Balbi T, et al. Myocyte cellular hypertrophy is responsible for ventricular remodelling in the hypertrophied heart of middle aged individuals in the absence of cardiac failure. Cardiovasc Res 1994;28:1199-1208. [Free Full Text]
Tanaka M, Ito H, Adachi S, et al. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res 1994;75:426-433. [Free Full Text]
Buerke M, Murohara T, Skurk C, Nuss C, Tomaselli K, Lefer AM. Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. Proc Natl Acad Sci U S A 1995;92:8031-8035. [Free Full Text]
James TN, St Martin E, Willis PW III, Lohr TO. Apoptosis as a possible cause of gradual development of complete heart block and fatal arrhythmias associated with absence of the AV node, sinus node, and internodal pathways. Circulation 1996;93:1424-1438. [Free Full Text]
Itoh G, Tamura J, Suzuki M, et al. DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis. Am J Pathol 1995;146:1325-1331. [Abstract]
Cannon PJ, Weiss MB, Sciacca RR. Myocardial blood flow in coronary artery disease: studies at rest and during stress with inert gas washout techniques. Prog Cardiovasc Dis 1977;20:95-120. [CrossRef][Medline]
Oltvai ZN, Korsmeyer SJ. Checkpoints of dueling dimers foil death wishes. Cell 1994;79:189-192. [CrossRef][Medline]
Hanada M, Aime-Sempe C, Sato T, Reed JC. Structure-function analysis of Bcl-2 protein: identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax. J Biol Chem 1995;270:11962-11969. [Free Full Text]
Zha HB, Aime-Sempe C, Sato T, Reed JC. Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2. J Biol Chem 1996;271:7440-7444. [Free Full Text]
Omland, T., de Lemos, J. A., Sabatine, M. S., Christophi, C. A., Rice, M. M., Jablonski, K. A., Tjora, S., Domanski, M. J., Gersh, B. J., Rouleau, J. L., Pfeffer, M. A., Braunwald, E., the Prevention of Events with Angiotensin Converti,
(2009). A Sensitive Cardiac Troponin T Assay in Stable Coronary Artery Disease. NEJM
0: NEJMoa0805299v1-1
[Abstract][Full Text]
Venteo, L., Bourlet, T., Renois, F., Douche-Aourik, F., Mosnier, J.-F., Lorain De la Grand Maison, G., Pluot, M., Pozzetto, B., Andreoletti, L.
(2009). Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis. Eur Heart J
0: ehp489v1-ehp489
[Abstract][Full Text]
Triposkiadis, F., Karayannis, G., Giamouzis, G., Skoularigis, J., Louridas, G., Butler, J.
(2009). The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.. J Am Coll Cardiol
54: 1747-1762
[Abstract][Full Text]
Sosnovik, D. E., Nahrendorf, M., Panizzi, P., Matsui, T., Aikawa, E., Dai, G., Li, L., Reynolds, F., Dorn, G. W. II, Weissleder, R., Josephson, L., Rosenzweig, A.
(2009). Molecular MRI Detects Low Levels of Cardiomyocyte Apoptosis in a Transgenic Model of Chronic Heart Failure. Circ Cardiovasc Imaging
2: 468-475
[Abstract][Full Text]
Chen, L., Gong, Q., Stice, J. P., Knowlton, A. A.
(2009). Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res
84: 91-99
[Abstract][Full Text]
Wang, X., Jameel, M. N., Li, Q., Mansoor, A., Qiang, X., Swingen, C., Panetta, C., Zhang, J.
(2009). Stem Cells for Myocardial Repair With Use of a Transarterial Catheter. Circulation
120: S238-S246
[Abstract][Full Text]
Johnston, R. K., Balasubramanian, S., Kasiganesan, H., Baicu, C. F., Zile, M. R., Kuppuswamy, D.
(2009). {beta}3 Integrin-mediated ubiquitination activates survival signaling during myocardial hypertrophy. FASEB J.
23: 2759-2771
[Abstract][Full Text]
Campian, M. E., Verberne, H. J., Hardziyenka, M., de Bruin, K., Selwaness, M., van den Hoff, M. J.B., Ruijter, J. M., van Eck-Smit, B. L.F., de Bakker, J. M.T., Tan, H. L.
(2009). Serial Noninvasive Assessment of Apoptosis During Right Ventricular Disease Progression in Rats. JNM
50: 1371-1377
[Abstract][Full Text]
Park, M., Shen, Y.-T., Gaussin, V., Heyndrickx, G. R., Bartunek, J., Resuello, R. R. G., Natividad, F. F., Kitsis, R. N., Vatner, D. E., Vatner, S. F.
(2009). Apoptosis predominates in nonmyocytes in heart failure. Am. J. Physiol. Heart Circ. Physiol.
297: H785-H791
[Abstract][Full Text]
Blendea, D, Blendea, M, Banker, J, McPherson, C A
(2009). Troponin T elevation after implanted defibrillator discharge predicts survival. Heart
95: 1153-1158
[Abstract][Full Text]
Choi, Y.-H., Cowan, D. B., Moran, A. M., Colan, S. D., Stamm, C., Takeuchi, K., Friehs, I., del Nido, P. J., McGowan, F. X. Jr.
(2009). Myocyte apoptosis occurs early during the development of pressure-overload hypertrophy in infant myocardium.. J. Thorac. Cardiovasc. Surg.
137: 1356-1362.e3
[Abstract][Full Text]
French, C. J., Spees, J. L., Zaman, A. K. M. T., Taatjes, D. J., Sobel, B. E.
(2009). The magnitude and temporal dependence of apoptosis early after myocardial ischemia with or without reperfusion. FASEB J.
23: 1177-1185
[Abstract][Full Text]
Bogaard, H. J., Abe, K., Vonk Noordegraaf, A., Voelkel, N. F.
(2009). The Right Ventricle Under Pressure: Cellular and Molecular Mechanisms of Right-Heart Failure in Pulmonary Hypertension. Chest
135: 794-804
[Abstract][Full Text]
Lee, B.-C., Hsu, H.-C., Tseng, W.-Y. I., Chen, C.-Y., Lin, H.-J., Ho, Y.-L., Su, M.-J., Chen, M.-F.
(2009). Cell therapy generates a favourable chemokine gradient for stem cell recruitment into the infarcted heart in rabbits. Eur J Heart Fail
11: 238-245
[Abstract][Full Text]
Dorn, G. W. II
(2009). Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc Res
81: 465-473
[Abstract][Full Text]
Mihatsch, K., Nestler, M., Saluz, H.-P., Henke, A., Munder, T.
(2009). Proapoptotic protein Siva binds to the muscle protein telethonin in cardiomyocytes during coxsackieviral infection. Cardiovasc Res
81: 108-115
[Abstract][Full Text]
Nicolaou, P., Knoll, R., Haghighi, K., Fan, G.-C., Dorn, G. W. II, Hasenfuss, G., Kranias, E. G.
(2008). Human Mutation in the Anti-apoptotic Heat Shock Protein 20 Abrogates Its Cardioprotective Effects. J. Biol. Chem.
283: 33465-33471
[Abstract][Full Text]
Davies, B., d'Udekem, Y., Ukoumunne, O. C., Algar, E. M., Newgreen, D. F., Brizard, C. P.
(2008). Differences in extra-cellular matrix and myocyte homeostasis between the neonatal right ventricle in hypoplastic left heart syndrome and truncus arteriosus. Eur. J. Cardiothorac. Surg.
34: 738-744
[Abstract][Full Text]
Cheng, A., Nguyen, T. C., Malinowski, M., Daughters, G. T., Miller, D. C., Ingels, N. B. Jr
(2008). Heterogeneity of Left Ventricular Wall Thickening Mechanisms. Circulation
118: 713-721
[Abstract][Full Text]
Qiu, H., Dai, H., Jain, K., Shah, R., Hong, C., Pain, J., Tian, B., Vatner, D. E., Vatner, S. F., Depre, C.
(2008). Characterization of a Novel Cardiac Isoform of the Cell Cycle-related Kinase That Is Regulated during Heart Failure. J. Biol. Chem.
283: 22157-22165
[Abstract][Full Text]
Daniels, L. B., Laughlin, G. A., Clopton, P., Maisel, A. S., Barrett-Connor, E.
(2008). Minimally Elevated Cardiac Troponin T and Elevated N-Terminal Pro-B-Type Natriuretic Peptide Predict Mortality in Older Adults: Results From the Rancho Bernardo Study. J Am Coll Cardiol
52: 450-459
[Abstract][Full Text]
Abel, E. D., Litwin, S. E., Sweeney, G.
(2008). Cardiac Remodeling in Obesity. Physiol. Rev.
88: 389-419
[Abstract][Full Text]
Rice, K. C., Bayles, K. W.
(2008). Molecular Control of Bacterial Death and Lysis. Microbiol. Mol. Biol. Rev.
72: 85-109
[Abstract][Full Text]
Kobara, M., Sunagawa, N., Abe, M., Tanaka, N., Toba, H., Hayashi, H., Keira, N., Tatsumi, T., Matsubara, H., Nakata, T.
(2008). Apoptotic myocytes generate monocyte chemoattractant protein-1 and mediate macrophage recruitment. J. Appl. Physiol.
104: 601-609
[Abstract][Full Text]
Dhanasekaran, A., Gruenloh, S. K., Buonaccorsi, J. N., Zhang, R., Gross, G. J., Falck, J. R., Patel, P. K., Jacobs, E. R., Medhora, M.
(2008). Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia. Am. J. Physiol. Heart Circ. Physiol.
294: H724-H735
[Abstract][Full Text]
Roubille, F., Combes, S., Leal-Sanchez, J., Barrere;, C., Cransac, F., Sportouch-Dukhan, C., Gahide, G., Serre, I., Kupfer, E., Richard, S., Hueber, A.-O., Nargeot, J., Piot, C., Barrere-Lemaire, S.
(2007). Myocardial Expression of a Dominant-Negative Form of Daxx Decreases Infarct Size and Attenuates Apoptosis in an In Vivo Mouse Model of Ischemia/Reperfusion Injury. Circulation
116: 2709-2717
[Abstract][Full Text]
Hsu, C.-P., Huang, C.-Y., Wang, J.-S., Chiang, H.-I., Shih, C.-C.
(2007). Down-Regulation of Apoptosis After Left Ventricular Aneurysm Repair. Ann. Thorac. Surg.
84: 1279-1287
[Abstract][Full Text]
Wang, T. J.
(2007). Significance of Circulating Troponins in Heart Failure: If These Walls Could Talk. Circulation
116: 1217-1220
[Full Text]
Latini, R., Masson, S., Anand, I. S., Missov, E., Carlson, M., Vago, T., Angelici, L., Barlera, S., Parrinello, G., Maggioni, A. P., Tognoni, G., Cohn, J. N., for the Val-HeFT Investigators,
(2007). Prognostic Value of Very Low Plasma Concentrations of Troponin T in Patients With Stable Chronic Heart Failure. Circulation
116: 1242-1249
[Abstract][Full Text]
Shuros, A. C., Salo, R. W., Florea, V. G., Pastore, J., Kuskowski, M. A., Chandrashekhar, Y., Anand, I. S.
(2007). Ventricular Preexcitation Modulates Strain and Attenuates Cardiac Remodeling in a Swine Model of Myocardial Infarction. Circulation
116: 1162-1169
[Abstract][Full Text]
Sharma, A. K., Dhingra, S., Khaper, N., Singal, P. K.
(2007). Activation of apoptotic processes during transition from hypertrophy to heart failure in guinea pigs. Am. J. Physiol. Heart Circ. Physiol.
293: H1384-H1390
[Abstract][Full Text]
Sipido, K. R., Janssens, S. P.
(2007). How Old Is Your Heart?. Circ. Res.
101: 323-325
[Full Text]
Shen, T., Zheng, M., Cao, C., Chen, C., Tang, J., Zhang, W., Cheng, H., Chen, K.-H., Xiao, R.-P.
(2007). Mitofusin-2 Is a Major Determinant of Oxidative Stress-mediated Heart Muscle Cell Apoptosis. J. Biol. Chem.
282: 23354-23361
[Abstract][Full Text]
Jane-wit, D., Altuntas, C. Z., Johnson, J. M., Yong, S., Wickley, P. J., Clark, P., Wang, Q., Popovic, Z. B., Penn, M. S., Damron, D. S., Perez, D. M., Tuohy, V. K.
(2007). {beta}1-Adrenergic Receptor Autoantibodies Mediate Dilated Cardiomyopathy by Agonistically Inducing Cardiomyocyte Apoptosis. Circulation
116: 399-410
[Abstract][Full Text]
Chowdhry, M. F., Vohra, H. A., Galinanes, M.
(2007). Diabetes increases apoptosis and necrosis in both ischemic and nonischemic human myocardium: Role of caspases and poly-adenosine diphosphate-ribose polymerase. J. Thorac. Cardiovasc. Surg.
134: 124-131
[Abstract][Full Text]
Jia, Y., Hikim, A. P. S., Lue, Y.-H., Swerdloff, R. S., Vera, Y., Zhang, X.-S., Hu, Z.-Y., Li, Y.-C., Liu, Y.-X., Wang, C.
(2007). Signaling Pathways for Germ Cell Death in Adult Cynomolgus Monkeys (Macaca fascicularis) Induced by Mild Testicular Hyperthermia and Exogenous Testosterone Treatment. Biol. Reprod.
77: 83-92
[Abstract][Full Text]
Satoh, M., Matter, C. M., Ogita, H., Takeshita, K., Wang, C.-Y., Dorn, G. W. II, Liao, J. K.
(2007). Inhibition of Apoptosis-Regulated Signaling Kinase-1 and Prevention of Congestive Heart Failure by Estrogen. Circulation
115: 3197-3204
[Abstract][Full Text]
Nithipongvanitch, R., Ittarat, W., Velez, J. M., Zhao, R., St. Clair, D. K., Oberley, T. D.
(2007). Evidence for p53 as Guardian of the Cardiomyocyte Mitochondrial Genome Following Acute Adriamycin Treatment. J. Histochem. Cytochem.
55: 629-639
[Abstract][Full Text]
Clarke, M., Bennett, M., Littlewood, T.
(2007). Cell death in the cardiovascular system. Heart
93: 659-664
[Abstract][Full Text]
Kietselaer, B. L.J.H., Reutelingsperger, C. P.M., Boersma, H. H., Heidendal, G. A.K., Liem, I. H., Crijns, H. J.G.M., Narula, J., Hofstra, L.
(2007). Noninvasive Detection of Programmed Cell Loss with 99mTc-Labeled Annexin A5 in Heart Failure. JNM
48: 562-567
[Abstract][Full Text]
Suzuki, R., Li, T.-S., Mikamo, A., Takahashi, M., Ohshima, M., Kubo, M., Ito, H., Hamano, K.
(2007). The reduction of hemodynamic loading assists self-regeneration of the injured heart by increasing cell proliferation, inhibiting cell apoptosis, and inducing stem-cell recruitment. J. Thorac. Cardiovasc. Surg.
133: 1051-1058
[Abstract][Full Text]
Angelini, A., Maiolino, G., La Canna, G., Ceconi, C., Calabrese, F., Pettenazzo, E., Valente, M., Alfieri, O., Thiene, G., Ferrari, R.
(2007). Relevance of apoptosis in influencing recovery of hibernating myocardium. Eur J Heart Fail
9: 377-383
[Abstract][Full Text]
Merkle, S., Frantz, S., Schon, M. P., Bauersachs, J., Buitrago, M., Frost, R. J.A., Schmitteckert, E. M., Lohse, M. J., Engelhardt, S.
(2007). A Role for Caspase-1 in Heart Failure. Circ. Res.
100: 645-653
[Abstract][Full Text]
Yan, C., Miller, C. L., Abe, J.-i.
(2007). Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart. Circ. Res.
100: 489-501
[Abstract][Full Text]
Yan, C., Ding, B., Shishido, T., Woo, C.-H., Itoh, S., Jeon, K.-I., Liu, W., Xu, H., McClain, C., Molina, C. A., Blaxall, B. C., Abe, J.-i.
(2007). Activation of Extracellular Signal-Regulated Kinase 5 Reduces Cardiac Apoptosis and Dysfunction via Inhibition of a Phosphodiesterase 3A/Inducible cAMP Early Repressor Feedback Loop. Circ. Res.
100: 510-519
[Abstract][Full Text]
Nguyen, T. C., Cheng, A., Tibayan, F. A., Liang, D., Daughters, G. T., Ingels, N. B. Jr., Miller, D. C.
(2007). Septal-lateral annnular cinching perturbs basal left ventricular transmural strains. Eur. J. Cardiothorac. Surg.
31: 423-429
[Abstract][Full Text]
Huang, Y., Wright, C. D., Merkwan, C. L., Baye, N. L., Liang, Q., Simpson, P. C., O'Connell, T. D.
(2007). An {alpha}1A-Adrenergic-Extracellular Signal-Regulated Kinase Survival Signaling Pathway in Cardiac Myocytes. Circulation
115: 763-772
[Abstract][Full Text]
Diwan, A., Dorn, G. W. II
(2007). Decompensation of Cardiac Hypertrophy: Cellular Mechanisms and Novel Therapeutic Targets. Physiology
22: 56-64
[Abstract][Full Text]
Khoynezhad, A.
(2007). Promising aspects and caveats of studies on anti-apoptotic therapies in patients with heart failure. Eur J Heart Fail
9: 120-123
[Full Text]
Ibe, W., Saraste, A., Lindemann, S., Bruder, S., Buerke, M., Darius, H., Pulkki, K., Voipio-Pulkki, L.-M.
(2007). Cardiomyocyte apoptosis is related to left ventricular dysfunction and remodelling in dilated cardiomyopathy, but is not affected by growth hormone treatment. Eur J Heart Fail
9: 160-167
[Abstract][Full Text]
Nguyen, T. C., Cheng, A., Langer, F., Rodriguez, F., Oakes, R. A., Itoh, A., Ennis, D. B., Liang, D., Daughters, G. T., Ingels, N. B. Jr, Miller, D. C.
(2007). Altered Myocardial Shear Strains Are Associated With Chronic Ischemic Mitral Regurgitation. Ann. Thorac. Surg.
83: 47-54
[Abstract][Full Text]
Xiang, M., Wang, J., Kaplan, E., Oettgen, P., Lipsitz, L., Morgan, J. P., Min, J.-Y.
(2006). Antiapoptotic Effect of Implanted Embryonic Stem Cell-Derived Early-Differentiated Cells in Aging Rats After Myocardial Infarction. Journals of Gerontology Series A: Biological Sciences and Medical Sciences
61: 1219-1227
[Abstract][Full Text]
Moorjani, N., Ahmad, M., Catarino, P., Brittin, R., Trabzuni, D., Al-Mohanna, F., Narula, N., Narula, J., Westaby, S.
(2006). Activation of Apoptotic Caspase Cascade During the Transition to Pressure Overload-Induced Heart Failure. J Am Coll Cardiol
48: 1451-1458
[Abstract][Full Text]
Chang, J., Xie, M., Shah, V. R., Schneider, M. D., Entman, M. L., Wei, L., Schwartz, R. J.
(2006). Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis. Proc. Natl. Acad. Sci. USA
103: 14495-14500
[Abstract][Full Text]
Malmberg, M., Vahasilta, T., Saraste, A., Kyto, V., Kiss, J., Kentala, E., Kallajoki, M., Savunen, T.
(2006). Cardiomyocyte apoptosis and duration of aortic clamping in pig model of open heart surgery.. Eur. J. Cardiothorac. Surg.
30: 480-484
[Abstract][Full Text]
Pfeiffer, P., Muller, P., Kazakov, A., Kindermann, I., Bohm, M.
(2006). Time-Dependent Cardiac Chimerism in Gender-Mismatched Heart Transplantation Patients. J Am Coll Cardiol
48: 843-845
[Full Text]
Bahi, N., Zhang, J., Llovera, M., Ballester, M., Comella, J. X., Sanchis, D.
(2006). Switch from Caspase-dependent to Caspase-independent Death during Heart Development: ESSENTIAL ROLE OF ENDONUCLEASE G IN ISCHEMIA-INDUCED DNA PROCESSING OF DIFFERENTIATED CARDIOMYOCYTES. J. Biol. Chem.
281: 22943-22952
[Abstract][Full Text]
Spencer, C. T., Bryant, R. M., Day, J., Gonzalez, I. L., Colan, S. D., Thompson, W. R., Berthy, J., Redfearn, S. P., Byrne, B. J.
(2006). Cardiac and Clinical Phenotype in Barth Syndrome. Pediatrics
118: e337-e346
[Abstract][Full Text]
Cheng, A., Nguyen, T. C., Malinowski, M., Langer, F., Liang, D., Daughters, G. T., Ingels, N. B. Jr, Miller, D. C.
(2006). Passive Ventricular Constraint Prevents Transmural Shear Strain Progression in Left Ventricle Remodeling. Circulation
114: I-79-I-86
[Abstract][Full Text]
Cheng, A., Nguyen, T. C., Malinowski, M., Liang, D., Daughters, G. T., Ingels, N. B. Jr, Miller, D. C.
(2006). Effects of Undersized Mitral Annuloplasty on Regional Transmural Left Ventricular Wall Strains and Wall Thickening Mechanisms. Circulation
114: I-600-I-609
[Abstract][Full Text]
Tsibiribi, P, Bui-Xuan, C, Bui-Xuan, B, Lombard-Bohas, C, Duperret, S, Belkhiria, M, Tabib, A, Maujean, G, Descotes, J, Timour, Q
(2006). Cardiac lesions induced by 5-fluorouracil in the rabbit. Hum Exp Toxicol
25: 305-309
[Abstract]
Di Mauro, M., Di Giammarco, G., Vitolla, G., Contini, M., Iaco, A. L., Bivona, A., Weltert, L., Calafiore, A. M.
(2006). Impact of No-to-Moderate Mitral Regurgitation on Late Results After Isolated Coronary Artery Bypass Grafting in Patients With Ischemic Cardiomyopathy. Ann. Thorac. Surg.
81: 2128-2134
[Abstract][Full Text]
Dyntar, D., Sergeev, P., Klisic, J., Ambuhl, P., Schaub, M. C., Donath, M. Y.
(2006). High Glucose Alters Cardiomyocyte Contacts and Inhibits Myofibrillar Formation. J. Clin. Endocrinol. Metab.
91: 1961-1967
[Abstract][Full Text]
Ge, J., Zhao, G., Chen, R., Li, S., Wang, S., Zhang, X., Zhuang, Y., Du, J., Yu, X., Li, G., Yang, Y.
(2006). Enhanced myocardial cathepsin B expression in patients with dilated cardiomyopathy. Eur J Heart Fail
8: 284-289
[Abstract][Full Text]
Anversa, P., Kajstura, J., Leri, A., Bolli, R.
(2006). Life and Death of Cardiac Stem Cells: A Paradigm Shift in Cardiac Biology. Circulation
113: 1451-1463
[Full Text]
Donath, S., Li, P., Willenbockel, C., Al-Saadi, N., Gross, V., Willnow, T., Bader, M., Martin, U., Bauersachs, J., Wollert, K. C., Dietz, R., von Harsdorf, R., on behalf of the German Heart Failure Network,
(2006). Apoptosis Repressor With Caspase Recruitment Domain Is Required for Cardioprotection in Response to Biomechanical and Ischemic Stress. Circulation
113: 1203-1212
[Abstract][Full Text]
Konhilas, J. P., Watson, P. A., Maass, A., Boucek, D. M., Horn, T., Stauffer, B. L., Luckey, S. W., Rosenberg, P., Leinwand, L. A.
(2006). Exercise Can Prevent and Reverse the Severity of Hypertrophic Cardiomyopathy. Circ. Res.
98: 540-548
[Abstract][Full Text]
Zethelius, B., Johnston, N., Venge, P.
(2006). Troponin I as a Predictor of Coronary Heart Disease and Mortality in 70-Year-Old Men: A Community-Based Cohort Study. Circulation
113: 1071-1078
[Abstract][Full Text]
Pachori, A. S., Melo, L. G., Zhang, L., Solomon, S. D., Dzau, V. J.
(2006). Chronic Recurrent Myocardial Ischemic Injury Is Significantly Attenuated by Pre-Emptive Adeno-Associated Virus Heme Oxygenase-1 Gene Delivery. J Am Coll Cardiol
47: 635-643
[Abstract][Full Text]
Sliwa, K., Forster, O., Libhaber, E., Fett, J. D., Sundstrom, J. B., Hilfiker-Kleiner, D., Ansari, A. A.
(2006). Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. Eur Heart J
27: 441-446
[Abstract][Full Text]
Miyata, S., Takemura, G., Kawase, Y., Li, Y., Okada, H., Maruyama, R., Ushikoshi, H., Esaki, M., Kanamori, H., Li, L., Misao, Y., Tezuka, A., Toyo-Oka, T., Minatoguchi, S., Fujiwara, T., Fujiwara, H.
(2006). Autophagic Cardiomyocyte Death in Cardiomyopathic Hamsters and Its Prevention by Granulocyte Colony-Stimulating Factor. Am. J. Pathol.
168: 386-397
[Abstract][Full Text]
Galvez, A. S., Brunskill, E. W., Marreez, Y., Benner, B. J., Regula, K. M., Kirschenbaum, L. A., Dorn, G. W. II
(2006). Distinct Pathways Regulate Proapoptotic Nix and BNip3 in Cardiac Stress. J. Biol. Chem.
281: 1442-1448
[Abstract][Full Text]
Shaw, J., Kirshenbaum, L. A.
(2006). Prime Time for JNK-Mediated Akt Reactivation in Hypoxia-Reoxygenation. Circ. Res.
98: 7-9
[Full Text]
D'Ascia, C., Cittadini, A., Monti, M. G., Riccio, G., Sacca, L.
(2006). Effects of biventricular pacing on interstitial remodelling, tumor necrosis factor-{alpha} expression, and apoptotic death in failing human myocardium. Eur Heart J
27: 201-206
[Abstract][Full Text]
Ding, B., Abe, J.-i., Wei, H., Xu, H., Che, W., Aizawa, T., Liu, W., Molina, C. A., Sadoshima, J., Blaxall, B. C., Berk, B. C., Yan, C.
(2005). A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Proc. Natl. Acad. Sci. USA
102: 14771-14776
[Abstract][Full Text]
Leri, A., Kajstura, J., Anversa, P.
(2005). Cardiac Stem Cells and Mechanisms of Myocardial Regeneration. Physiol. Rev.
85: 1373-1416
[Abstract][Full Text]
Castro, P., Vukasovic, J. L., Chiong, M., Diaz-Araya, G., Alcaino, H., Copaja, M., Valenzuela, R., Greig, D., Perez, O., Corbalan, R., Lavandero, S.
(2005). Effects of carvedilol on oxidative stress and chronotropic response to exercise in patients with chronic heart failure. Eur J Heart Fail
7: 1033-1039
[Abstract][Full Text]
Xu, X.-B., Pang, J.-J., Cao, J.-M., Ni, C., Xu, R.-K., Peng, X.-Z., Yu, X.-X., Guo, S., Chen, M.-C., Chen, C.
(2005). GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure. Am. J. Physiol. Heart Circ. Physiol.
289: H1643-H1651
[Abstract][Full Text]
Sheppard, R., Bedi, M., Kubota, T., Semigran, M. J., Dec, W., Holubkov, R., Feldman, A. M., Rosenblum, W. D., McTiernan, C. F., McNamara, D. M., for the IMAC Investigators,
(2005). Myocardial Expression of Fas and Recovery of Left Ventricular Function in Patients With Recent-Onset Cardiomyopathy. J Am Coll Cardiol
46: 1036-1042
[Abstract][Full Text]
Okada, H., Takemura, G., Koda, M., Kanoh, M., Kawase, Y., Minatoguchi, S., Fujiwara, H.
(2005). Myocardial Apoptotic Index Based on In Situ DNA Nick End-Labeling of Endomyocardial Biopsies Does Not Predict Prognosis of Dilated Cardiomyopathy. Chest
128: 1060-1062
[Abstract][Full Text]
Pfister, O., Mouquet, F., Jain, M., Summer, R., Helmes, M., Fine, A., Colucci, W. S., Liao, R.
(2005). CD31- but Not CD31+ Cardiac Side Population Cells Exhibit Functional Cardiomyogenic Differentiation. Circ. Res.
97: 52-61
[Abstract][Full Text]
van Empel, V. P.M., Bertrand, A. T.A., Hofstra, L., Crijns, H. J., Doevendans, P. A., De Windt, L. J.
(2005). Myocyte apoptosis in heart failure. Cardiovasc Res
67: 21-29
[Abstract][Full Text]
Urbanek, K., Torella, D., Sheikh, F., De Angelis, A., Nurzynska, D., Silvestri, F., Beltrami, C. A., Bussani, R., Beltrami, A. P., Quaini, F., Bolli, R., Leri, A., Kajstura, J., Anversa, P.
(2005). Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc. Natl. Acad. Sci. USA
102: 8692-8697
[Abstract][Full Text]
Mann, D. L., Bristow, M. R.
(2005). Mechanisms and Models in Heart Failure: The Biomechanical Model and Beyond. Circulation
111: 2837-2849
[Full Text]
Syed, F. M., Hahn, H. S., Odley, A., Guo, Y., Vallejo, J. G., Lynch, R. A., Mann, D. L., Bolli, R., Dorn, G. W. II
(2005). Proapoptotic Effects of Caspase-1/Interleukin-Converting Enzyme Dominate in Myocardial Ischemia. Circ. Res.
96: 1103-1109
[Abstract][Full Text]
Ding, B., Abe, J.-i., Wei, H., Huang, Q., Walsh, R. A., Molina, C. A., Zhao, A., Sadoshima, J., Blaxall, B. C., Berk, B. C., Yan, C.
(2005). Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis: Implication in Heart Failure. Circulation
111: 2469-2476
[Abstract][Full Text]
Rodriguez, F., Langer, F., Harrington, K. B., Cheng, A., Daughters, G. T., Criscione, J. C., Ingels, N. B., Miller, D. C.
(2005). Alterations in transmural strains adjacent to ischemic myocardium during acute midcircumflex occlusion. J. Thorac. Cardiovasc. Surg.
129: 791-803
[Abstract][Full Text]
Narula, N., Narula, J., Zhang, P. J., Haider, N., Raghunath, P. N., Brittin, R., Gorman, J. H. III, Gorman, R. C., Tomaszewski, J. E.
(2005). Is the Myofibrillarlytic Myocyte a Forme Fruste Apoptotic Myocyte?. Ann. Thorac. Surg.
79: 1333-1337
[Abstract][Full Text]
Dallabrida, S. M., Ismail, N., Oberle, J. R., Himes, B. E., Rupnick, M. A.
(2005). Angiopoietin-1 Promotes Cardiac and Skeletal Myocyte Survival Through Integrins. Circ. Res.
96: e8-e24
[Abstract][Full Text]
Sarkar, S., Chawla-Sarkar, M., Young, D., Nishiyama, K., Rayborn, M. E., Hollyfield, J. G., Sen, S.
(2004). Myocardial Cell Death and Regeneration during Progression of Cardiac Hypertrophy to Heart Failure. J. Biol. Chem.
279: 52630-52642
[Abstract][Full Text]
-sarcomeric actin antibody (clone 5C5, Sigma), and the nuclei were visualized with bisbenzimide.7,8,9,15,17 
-converting enzyme. Am J Pathol 1995;147:251-266. [Abstract]
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