Loss Of Cardiac Function Research Articles

Amelioration of myocardial global ischemia/reperfusion injury with volume-regulatory chloride channel inhibitors in vivo1

Recently, the apoptotic volume decrease was suggested to be regulated by volume regulatory Cl- channels in cultured cell lines. We thus examined whether inhibition of volume-regulatory Cl- channels is cardioprotective, like caspase inhibition, by hindering the apoptosis of cardiomyocytes induced by global ischemia/reperfusion (I/R) in vivo. We performed global ischemia for 8 min at 37 degrees C or 4 degrees C in isolated rat hearts, followed by 24-hr reperfusion via heterotopic heart transplantation. The heart tissue was examined by means of the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method, genomic DNA electrophoresis, and caspase-3 activity. Two blockers of volume-regulatory Cl- channels, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), and a broad-spectrum caspase inhibitor, benzoyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-Asp-DCB), were administered intravenously. Triphenyltetrazolium chloride (TTC) staining and ultrasound cardiography were performed to examine myocardial viability. The TTC-unstained region was assessed by means of horseradish peroxidase (HRP) infiltration and the TUNEL method. The transplanted hearts showed TUNEL-positivity and DNA laddering with a peak at 24 hr during reperfusion after ischemia at 37 degrees C, but not at 4 degrees C. NPPB and DIDS were as potent as Z-Asp-DCB for recovery of cardiac function and for blocking the appearance of TUNEL-positivity, DNA laddering, caspase 3 activity, and a TTC-unstained area. TTC-unstained areas were composed of either TUNEL- and slightly HRP-positive or TUNEL-negative and strongly HRP-positive cardiomyocytes. The present results demonstrated that myocardial DNA fragmentation, caspase activation, and loss of cardiac function after global I/R were blocked by NPPB and DIDS, similar to in the case of Z-Asp-DCB. These results suggest that inhibition of volume-regulatory Cl- channels is also effective for preventing cardiac I/R injury.

Physiological insulin concentrations protect against ischemia-induced loss of cardiac function in rats

This study determined whether insulin at pre- (fasting) and post-prandial concentrations increases coronary blood flow and improves cardiac function after acute ischemia during a situation of myocardial stunning. The experiments were performed using an isolated, erythrocyte perfused, working rat heart model. To the perfusate we added erythrocytes and 1.5% bovine serum albumin to improve clinical relevance. The following protocol was used: 8 min baseline performance assessment, 10 min pre-ischemic treatment, 12 min global ischemia, 20 min post-ischemic treatment and 8 min recovery assessment. Vehicle, 10 mIU l −1 and 100 mIU l −1 human insulin were tested (all n=6). No significant vasodilator response to insulin was observed either pre- or post-ischemically. After the 12-min ischemic insult, cardiac function returned dose-dependently to pre-ischemic values (function loss with 100 mIU l −1 insulin: −0.2±0.4% vs. vehicle: 10.7±0.8%). This study clearly shows that in our clinically relevant model of moderate ischemia (stunning), insulin is highly cardioprotective at physiological concentrations. This may be explained primarily by higher glucose uptake, improving the myocardial energetic state during ischemia. Therefore, insulin should be considered for use when the myocardium is at acute risk for ischemic incidents.

Glibenclamide attenuates ischemia-induced acidosis and loss of cardiac function in rats

Previous research has shown that the sulfonylurea derivative glibenclamide may improve post-ischemic cardiac functional recovery. Although K ATP channel blockade is a possible explanation for this observation, alternative mechanisms exist. Therefore, we simultaneously recorded cardiac function and the intracellular concentration of ATP, phosphocreatine, Pi and pH before and after ischemia in the presence of glibenclamide or vehicle. 31Phophorus magnetic resonance (MS) spectroscopy on erythrocyte-perfused, isolated working rat hearts was performed. Glibenclamide 4 μmol l −1 or vehicle alone was tested (both n=5). The following protocol was used: 8 min performance assessment, 10 min drug treatment, 12 min global ischemia, 20 min reperfusion with drug treatment and 8 min functional recovery assessment. Compared with vehicle, glibenclamide significantly decreased coronary blood flow (59.5±7.0% vs. 94.3±1.3%, P=0.008), ischemia-induced cardiac functional loss (7.4±1.3% vs. 18.8±3.3%; P=0.019) as well as the ichemia-induced intracellular acidosis (6.75±0.01 vs. 6.43±0.03 for vehicle, P=0.03). In conclusion, glibenclamide is able to reduce the myocardial functional loss after ischemia while preserving pH but not ATP levels during ischemia. This suggests that the beneficial response to glibenclamide is probably not the result of myocardial K ATP channel blockade, but may be explained by inhibition of glycolysis.

Ischemic-reperfused isolated working mouse hearts: membrane damage and type IIA phospholipase A2.

For the murine heart the relationships between ischemia-reperfusion-induced loss of cardiac function, enzyme release, high-energy phosphate (HEP), and membrane phospholipid metabolism are ill-defined. Accordingly, isolated ejecting murine hearts were subjected to varying periods of ischemia, whether or not followed by reperfusion. On reperfusion, hemodynamic function was almost completely restored after 10 min of ischemia [83 +/- 14% recovery of cardiac output (CO)], but was severely depressed after 15 and 20 min of ischemia (40 +/- 24 and 31 +/- 24% recovery of CO, respectively). Reperfusion was associated with partial recovery of HEP stores and enhanced degradation of phospholipids as indicated by the accumulation of fatty acids (FA). Myocardial FA content and enzyme release during reperfusion were correlated (r = 0.70), suggesting that membrane phospholipid degradation and cellular damage are closely related phenomena. To investigate the role of type IIA secretory phospholipase A2 (sPLA2) in this process, hearts from wild-type and sPLA2-deficient mice were subjected to ischemia-reperfusion. Postischemic functional recovery, ATP depletion, enzyme release, and FA accumulation were not significantly different between wild-type and sPLA2- deficient hearts. These findings argue against a prominent role of type IIA sPLA2 in the development of irreversible cell damage in the ischemic-reperfused murine myocardium.

Passive ventricular constraint for the treatment of congestive heart failure

Progressive heart failure is characterized by loss of cardiac function associated with maladaptive changes in myocardial gene expression and neuroendocrine activity, leading to progressive increases in heart size. Elevated ventricular wall stress results from an increase in chamber size, and is thought to play a role in furthering development towards end-stage disease. Reduction of wall stress and stress mediated myocardial stretch may be an important means for mitigating heart failure progression. One possible approach to accomplish this goal is through passive support of the heart with the Cardiac Support Device. Results from preclinical and clinical evaluation give support to this premise.

Apoptosis of ventricular and atrial myocytes from pacing-induced canine heart failure.

Rapid ventricular pacing in dogs results in a low output cardiomyopathic state similar to idiopathic dilated cardiomyopathy in man. Cell death by apoptosis may play an important role in the loss of cardiac function. This study investigates the molecular pathways involved in the regulation of apoptosis in dogs with pacing-induced heart failure. Apoptosis was identified by terminal transferase nick end-labelling (TUNEL) in the ventricles and atria of dog hearts affected by rapid-ventricular pacing. Western blots were used to determine expression of the components involved in the initiation (Fas, Fas-Ligand, FADD), regulation (Bcl-2, Bax) and execution (caspase-2 and caspase-3) of apoptosis. Pacing-induced heart failure resulted in a significant increase in the number of ventricular and atrial myocyte nuclei undergoing apoptosis as measured by TUNEL. Compared to the samples from control hearts (n=6) the expression of Bcl-2, an inhibitor of apoptosis, was significantly reduced in ventricles from five dogs with pacing-induced heart failure. No change in the expression of the apoptotic inducer Bax was detected. Fas and FADD were significantly elevated in all paced ventricles, and Fas-L was only detected in the paced hearts. Both caspase-2 and caspase-3 were elevated following ventricular pacing. We have identified components of the signalling pathways along which apoptosis proceeds following the induction of heart failure in dogs. Apoptosis was also detected in the atria raising the possibility that, like human dilated cardiomyopathy, the molecular changes are global.

Lipotoxic heart disease in obese rats: implications for human obesity.

To determine the mechanism of the cardiac dilatation and reduced contractility of obese Zucker Diabetic Fatty rats, myocardial triacylglycerol (TG) was assayed chemically and morphologically. TG was high because of underexpression of fatty acid oxidative enzymes and their transcription factor, peroxisome proliferator-activated receptor-alpha. Levels of ceramide, a mediator of apoptosis, were 2-3 times those of controls and inducible nitric oxide synthase levels were 4 times greater than normal. Myocardial DNA laddering, an index of apoptosis, reached 20 times the normal level. Troglitazone therapy lowered myocardial TG and ceramide and completely prevented DNA laddering and loss of cardiac function. In this paper, we conclude that cardiac dysfunction in obesity is caused by lipoapoptosis and is prevented by reducing cardiac lipids.

Diastolic Suction During Acute Coronary Occlusion

To the Editor: We congratulate Bell et al on the recent publication of their study1 that presents evidence indicating a decrease in forces responsible for diastolic suction during an acute occlusion of the left anterior descending coronary artery in dogs. Their experimental preparation is elegant, and we agree with their principal interpretation of their data: the acute loss of regional cardiac contractile function due to myocardial ischemia can result in a decrease in the mechanical generation and storage of elastic forces available to induce ventricular suction during early diastole. In our view, the authors’ introductory remark that “One determinant of filling that may be altered during coronary occlusion but has not previously been studied is the ability of the LV to fill by suction” is an incomplete representation of the literature. In a previous publication,2 we described in detail the form of intraventricular pressure gradients found in the normal canine left ventricle during early diastole. In that report, we argued that the pattern of these early diastolic pressure gradients could only be present in a structure that filled by the process of mechanical suction. In a follow-up to that study, we hypothesized …

Cyclooxygenase Inhibition Aggravates Ischemia–Reperfusion Injury in the Perfused Guinea Pig Heart: Involvement of Isoprostanes

Objectives. Postischemic contractile dysfunction in the heart may be due, in part, to isoprostanes, thought to accumulate during myocardial reperfusion. This study tested whether cyclooxygenase (COX) inhibitors increase the amount of isoprostanes and, consequently, lead to deterioration of postischemic heart function.Background. Isoprostanes are bioactive prostaglandin-like compounds that are formed in vivo directly by free radical–catalyzed peroxidation of arachidonic acid. In particular, 8-iso-prostaglandin (PG) F2αis a potent vasoconstrictor.Methods. Isolated working guinea pig hearts underwent 30-min low flow ischemia followed by reperfusion, 15 min in a nonworking mode and 20 min performing pressure–volume work. Hearts were perfused with or without 100 μmol/liter acetylsalicylic acid (ASA), 3 or 10 μmol/liter indomethacin or 1 μmol/liter SQ 29548, a thromboxane-A2(TxA2) receptor antagonist able to abolish the vasoconstrictive actions of 8-iso-PGF2α. External heart work (EHW) and coronary resistance were compared before and after ischemia. Coronary release and tissue content of 8-iso-PGF2αwere also determined.Results. During reperfusion, 8-iso-PGF2αrelease increased tenfold compared with the preischemic value in all groups. However, in ASA- and indomethacin-treated hearts, 8-iso-PGF2αlevels were ∼15-fold higher than in control hearts (5.4 vs. 0.35 pg/ml, respectively). Postischemic tissue levels of 8-iso-PGF2αwere also markedly higher: 215 (indomethacin) and 301 (ASA) pg/ml g dry weight versus 43 pg/mg dry weight for control hearts (p < 0.05). Treatment of hearts with COX inhibitor led to a reduction in recovery of EHW (40% vs. 71%, p < 0.05) and seemed to be due to impaired myocardial oxygenation: Coronary venous oxygen was lower (67% of control values), whereas anaerobic metabolism (lactate release vs. pyruvate consumption) was enhanced. Coronary resistance was correspondingly elevated (164% of control values). SQ 29548 caused all variables to revert to control values.Conclusions. These data demonstrate that in the guinea pig heart, COX-inhibiting drugs exacerbate loss of cardiac function after ischemia. The enhanced production of isoprostanes favors coronary vasoconstriction and leads to myocardial oxygen deprivation.

Molecular Genetics of Congestive Heart Failure

The manifestation of congestive heart failure occurs secondary to a great variety of cardiac or systemic disorders that share a temporal or permanent loss of cardiac function. In order to enhance our knowledge about the genetics of heart failure it is mandatory to analyse the aetiologic factors of these underlying disorders separately. Monogenic forms of congestive heart failure have initially been described by observant physicians in consecutive generations of affected families. Molecular genetic analyses of these families subsequently allowed us to localise and identify some of the genes that cause hypertrophic, dilative, or restrictive cardiomyopathies, congenital heart disease, as well as a number of inborn errors of metabolism. However, the great majority of patients develops heart failure as a final consequence of multifactorial conditions such as hypertension, cardiac hypertrophy, or coronary artery disease. Each of these conditions may be the product of a complex equation that includes environmental and genetic factors. Indeed, some of these factors may be harmful, others protective and for most it takes decades before a phenotype will be clinically detectable. Given this complex scenario it was not unexpected that early studies on candidate genes came up with partially controversial information. This review aims to summarize and to comment on the principal findings of this work.

The Role of the Tumor Suppressor Gene p53 in Cardiomyocyte Apoptosis

The possibility that a significant fraction of cardiac myocyte loss in various disease states occurs through apoptosis has elicited considerable attention in recent years. Evidence from human studies as well as in vitro and animal models of disease has shown that cardiac myocyte apoptosis can be induced by a variety of stimuli and in a number of disease states, including hypoxia, ischemia–reperfusion, myocardial infarction, mechanical stretch, aortic constriction, and heart failure. Because adult cardiac myocytes are terminally differentiated cells, the effects of such loss can never be fully compensated. Interest in cardiomyocyte apoptosis has been fueled by the possibility that once the proximal and distal signals were defined that initiate this pathway of cell removal, it would be possible to develop stategies to selectively interfere with such signaling and prevent the loss of cardiac function. This article examines the evidence for possible proximal stimuli of apoptosis in the heart, including ligand-dependent activation of the membrane receptors for Fas ligand and tumor necrosis factor-α, and, in particular, activation of the tumor suppressor gene p53. It relates what is known about the mechanism by which these stimuli in other cells induce apoptosis and discusses possible strategies for inhibiting apoptosis in the heart.

Patterns of Mobilization of Copper and Iron Following Myocardial Ischemia: Possible Predictive Criteria for Tissue Injury

Direct evidence for substantial iron and copper mobilization into the coronary flow immediately following prolonged, but not short, cardiac ischemia is presented. When small volumes of coronary flow fractions (CFFs) were serially collected upon reperfusion, after 25–60 min of ischemia, the copper and iron levels in the first CFF were 50-fold and 12- to 15-fold higher, respectively, than corresponding pre-ischemic values. The copper and iron levels after shorter periods (15–21 min) of ischemia were only about five-fold higher than the pre-ischemic values. This demonstrates that the resumption of coronary flow is accompanied by a burst of both metal ions. The levels of Cu/Fe in the CFFs correlated well with the loss of cardiac function following global ischemia of varying duration. After 18 min of ischemia, the residual cardiac function was less than 50%, and the damage was essentially reversible. After 25 min of ischemia, it exceeded 50% and was only partially reversible, while after 35 min, the damage exceeded 80%, and was mostly irreversible. The results are in accord with the hypothesis that copper and iron play causative roles in myocardial injury through mediation of hydroxyl radical production. Thus, the pattern of Cu/Fe mobilization from the tissue into the CFF can be used for the prediction of the severity of myocardial damage following ischemia, and could be developed into useful modalities for intervention in tissue injury.

Massive nitrogen loss in critical surgical illness: effect on cardiac mass and function.

The authors measured cardiac mass and function to determine whether these changed in patients who were critically ill who were losing large amounts of nitrogen from the body. The large losses of body nitrogen that occur in patients with protein-energy malnutrition are associated with a loss of cardiac mass and function. It is not known if this also occurs in patients who were critically ill who are losing massive amounts of nitrogen. Once hemodynamically stable, 13 patients who were critically ill underwent sequential measurements of left ventricular mass (LVM) and function, total body nitrogen (TBN), total body potassium, body weight, fat-free mass, and limb muscle mass. Over a 21-day study period, there was no change in LVM or function despite falls of 14% and 21% in TBN and total body potassium, respectively, a 21% fall in limb muscle mass, and a deterioration in skeletal muscle function by approximately 40%. In patients who were critically ill, cardiac mass does not decrease and function does not deteriorate after hemodynamic stability has been achieved despite massive losses of protein from the body.

Analysis of beta-adrenergic receptor mRNA levels in human ventricular biopsy specimens by quantitative polymerase chain reactions: Progressive reduction of beta1-adrenergic receptor mRNA in heart failure

This study investigated the relation between the severity of heart failure and the extent of the reduction of beta 1-adrenergic receptor messenger ribonucleic acid (mRNA) levels in biopsy specimens from the ventricular septum obtained during cardiac catheterization of patients with various degrees of heart failure. Heart failure is accompanied by desensitization of the beta-adrenergic receptor system, which is in part due to downregulation of beta 1-adrenergic receptors. Downregulation of beta 1-adrenergic receptors has been suggested to be caused by reductions in mRNA levels. Because biopsy specimens were small and receptor mRNAs not abundant, mRNA levels were determined by quantitative reverse transcription/polymerase chain reactions. This method was validated by measuring synthetic ribonucleic acid (RNA) standards and samples from explanted hearts by solution hybridization assays. Both methods yielded similar results, but the polymerase chain reaction method was approximately 1,000-fold more sensitive. Sources of variations in the polymerase chain reaction were quantitated and found to be best controlled for by determination of the glyceraldehyde phosphate dehydrogenase mRNA as an endogenous control. Beta 1-adrenergic receptor mRNA levels in the biopsy specimens were decreased by 7% in mild (New York Heart Association functional class II), 26% in moderate (functional class III) and > 50% in severe heart failure (functional class IV). There was a good correlation between hemodynamic indicators of heart failure and beta 1-adrenergic receptor mRNA levels. In contrast, beta 2-adrenergic receptor mRNA levels were apparently unaffected by heart failure. Reduced beta 1-adrenergic receptor mRNA levels occur early in heart failure and can be detected in septal biopsy specimens during right heart catheterization. The reduction in beta 1-adrenergic receptor expression may contribute to further loss of cardiac function.

Copper and iron are mobilized following myocardial ischemia: possible predictive criteria for tissue injury.

Direct evidence for substantial mobilization of copper in the coronary flow immediately following prolonged, but not short, cardiac ischemia is presented. In the first coronary flow fraction (CFF) of reperfusion (0.15 ml), after 35 min of ischemia, the level of copper (as well as of iron) was 8- to 9-fold higher than the preischemic value. The levels in subsequent CFFs decreased and reached the preischemic value, indicating that both metals appear in a burst at the resumption of coronary flow. When the first CFF was used in a reaction mixture containing ascorbate and salicylate, the latter underwent chemical hydroxylation and was converted to its dihydroxybenzoate derivatives. Likewise, this CFF promoted the ascorbate-driven DNA degradation. Subsequent 150 CFFs were serially collected and demonstrated low activities. Following 18 min of ischemia, the copper level in the first CFF of reperfusion was only 15% over the preischemic value. In contrast, the mobilization of iron into coronary flow was significant but markedly lower than after 35 min. The levels of copper and the redox activity of the first CFF correlated well with the degree of loss of cardiac function, after 18 and 35 min of ischemia, respectively. After 18 min of ischemia, cardiac function was about 50% and the damage is considered reversible, whereas after 35 min the functional loss exceeded 80% and is considered irreversible. These results are in accord with the causative role that copper and iron can play in heart injury following ischemia, by virtue of their capacity to catalyze the production of hydroxyl radicals, and could lead to the development of new modalities for intervention in tissue injury.

Mediatory role of copper in reactive oxygen intermediate-induced cardiac injury

In this report the mediatory role of copper in cardiac injury produced by reactive oxygen intermediates was examined. Isolated rat hearts were perfused with Krebs-Henseleit buffer containing 0.25 m m ascorbate plus varying concentrations of copper-bis-histidial for up to 60 min. Using salicylate as a probe, OH generation by this system was demonstrated. Copper or ascorbate alone had minimal effect on cardiac function as determined by heart rate, coronary flow, left ventricular systolic pressure development, end diastolic pressure and ± dP dt max . Copper, from 0.5 μ m to 20 μ m, and ascorbate, 0.25 m m, resulted in concentration-dependent decreases in all of the experimental variables. Treatment with 5 or 20 μ m copper resulted in complete loss of cardiac function within 40 and 30 min, respectively. By 30 min, 5 μ m copper had resulted in increased end diastolic pressure to greater than 40 mmHg. By 60 min, perfusion with 1 μ m copper resulted in almost 100% loss of function and end diastolic pressure greater than 25 mmHg. Copper, 0.5 μ m, also decreased cardiac function, but to a lesser degree. Catalase, 100 units/ml, was effective in preventing the copper-ascorbate induced cardiac damage while superoxide dismutase, 25 units/ml, was ineffective. Observations by light and electron microscopy demonstrated patchy regions with vacuolization corresponding to swollen mitochondria. These results clearly demonstrate that copper-catalyzed redox reactions can induce cardiac injury via a mechanism which appears to be related to the production of OH.

The nucleotide metabolism in lactate perfused hearts under ischaemic and reperfused conditions.

It was examined whether lactate influences postischaemic hemodynamic recovery as a function of the duration of ischaemia and whether changes in high-energy phosphate metabolism under ischaemic and reperfused conditions could be held responsible for impairment of cardiac function. To this end, isolated working rat hearts were perfused with either glucose (11 mM), glucose (11 mM) plus lactate (5 mM) or glucose (11 mM) plus pyruvate (5 mM). The extent of ischaemic injury was varied by changing the intervals of ischaemia, i.e. 15, 30 and 45 min. Perfusion by lactate evoked marked depression of functional recovery after 30 min of ischaemia. Perfusion by pyruvate resulted in marked decline of cardiac function after 45 min of ischaemia, while in glucose perfused hearts hemodynamic performance was still recovered to some extent after 45 min of ischaemia. Hence, lactate accelerates postischaemic hemodynamic impairment compared to glucose and pyruvate. The marked decline in functional recovery of the lactate perfused hearts cannot be ascribed to the extent of degradation of high-energy phosphates during ischaemia as compared to glucose and pyruvate perfused hearts. Glycolytic ATP formation (evaluated by the rate of lactate production) can neither be responsible for loss of cardiac function in the lactate perfused hearts. Moreover, failure of reenergization during reperfusion, the amount of nucleosides and oxypurines lost or the level of high-energy phosphates at the end of reperfusion cannot explain lactate-induced impairment. Alternatively, the accumulation of endogenous lactate may have contributed to ischaemic damage in the lactate perfused hearts after 30 min of ischaemia as it was higher in the lactate than in the glucose or pyruvate perfused hearts. It cannot be excluded that possible beneficial effects of the elevated glycolytic ATP formation during 15 to 30 min of ischaemia in the lactate perfused hearts are counterbalanced by the detrimental effects of lactate accumulation.

Polymorphonuclear leukocytes reduce cardiac function in vitro by release of H2O2

Polymorphonuclear leukocytes (PMNs) have been implicated in postischemic myocardial injury and associated derangements in contractile function. To examine the direct effects of PMNs on cardiac function, isolated right ventricular papillary muscles of the rabbit were exposed to increasing concentrations of purified rabbit PMNs in the presence of cimetidine. PMNs induced a significant concentration-dependent decrease in contractile function, where 5 x 10(5) PMNs/ml reduced contractile force to 75 +/- 2.1% of control (vs. 95 +/- 5% for time control; P less than 0.005). Similar decreases were also observed for peak positive and negative first derivatives of contractile force. The degree of PMN-induced contractile dysfunction correlated with the activity of the PMNs in an aggregation assay (r = 0.82, P less than 0.01). The loss of contractile function in response to PMNs was attenuated by catalase, which metabolizes H2O2, but not by superoxide dismutase, a scavenger of the superoxide anion. PMNs can convert H2O2 to either the hypochlorite anion or the hydroxyl radical, which are removed by methionine or mannitol, respectively. However, these scavengers did not ameliorate the PMN-induced loss of cardiac function. Exposure of papillary muscles to H2O2 resulted in a concentration-dependent decrease in contractile function where 100 microM reduced contractile force to 78 +/- 4%, an effect prevented by catalase. Thus PMNs reduce the contractile function of isolated papillary muscles probably by the release of H2O2.

Peripartum myocarditis and cardiomyopathy.

The clinical and pathologic features of 18 consecutive patients with peripartum cardiomyopathy at The Johns Hopkins Hospital were examined in an attempt to define the incidence of myocarditis and to determine its response to immunosuppressive agents. In addition to routine studies, patients were evaluated with echocardiography, nuclear ventriculography, right heart catheterization, and myocardial biopsy. Fourteen of the 18 patients (78%) showed evidence of myocarditis. Of these, 10 were treated with immunosuppressive therapy. Nine of the 10 treated patients with myocarditis had subjective and objective improvement. Follow-up endomyocardial biopsies in these patients showed resolution or substantial improvement in myocarditis. Four patients with myocarditis not treated with immunosuppressives also improved. All patients improving spontaneously presented with congestive heart failure within 1 month of delivery and improved dramatically within days of presentation. Four of the 18 patients showed no evidence of myocarditis. Of these, two improved, and two deteriorated (both requiring cardiac transplantation). None of these four patients were treated with immunosuppressive therapy. We conclude that in patients with peripartum cardiomyopathy, 1) the etiology remains unclear although myocarditis was present in 78% of those with this condition, 2) resolution of myocarditis is associated with significant improvement in left ventricular function, 3) myocarditis may resolve spontaneously without detectable loss of cardiac function, and 4) immunosuppressive therapy in patients with myocarditis and persistent left ventricular dysfunction may improve left ventricular function and prognosis.

Cocaine‐Induced Arrhythmia in Human Foetal Myocardium in Vitro: Possible Mechanism for Foetal Death in Utero

We examined the acute in vitro effects of cocaine on cell membrane potentials and contractility of 12-16 week old human foetal heart, to better assess the potential for the induction of serious arrhythmia, in utero, by this abused substance. Ventricular preparations were maintained in a tissue bath, and continuously provided with oxygen and glucose during the measurement of membrane potentials with microelectrodes, and developed force of contractions with microforce transducers. Cocaine (600 ng/ml) had a significant effect on the ability of the heart to produce action potentials of normal rising velocity, amplitude, and duration. Within 90 min., all electromechanical activity had ceased. Under the conditions of our study, the effects of cocaine were reversible, however, reversibility in vitro may have no counterpart in utero, and irreversible loss of cardiac function may result.