Late cardiac effects of chemotherapy in breast cancer survivors treated with adjuvant doxorubicin: 10-year follow-up.

Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent's University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index >34 mL/m(2) and/or lateral wall E prime <10 m/s, and LVSD as LVEF <50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m(2). Median Dox dose was 240 mg/m(2) [225-298]; 92 patients (59.7 %) received ≤240 mg/m(2) and 62 (40.3 %) > 240 mg/m(2). Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF <50 % and one (0.7 %) had LVDD. Dox >240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9-36.5] and 21.1 pg/ml [9.8-37.7] in those without LVD and 61.5 pg/ml [50-68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.

Getting to the heart of cardiac remodeling; how collagen subtypes may contribute to phenotype.

The objective of this study was to investigate the nature and biomechanical properties of collagen fibers within the human myocardium. Targeting cardiac interstitial abnormalities will likely become a major focus of future preventative strategies with regard to the management of cardiac dysfunction. Current knowledge regarding the component structures of myocardial collagen networks is limited, further delineation of which will require application of more innovative technologies. We applied a novel methodology involving combined confocal laser scanning and atomic force microscopy to investigate myocardial collagen within ex-vivo right atrial tissue from 10 patients undergoing elective coronary bypass surgery. Immuno-fluorescent co-staining revealed discrete collagen I and III fibers. During single fiber deformation, overall median values of stiffness recorded in collagen III were 37±16% lower than in collagen I [p<0.001]. On fiber retraction, collagen I exhibited greater degrees of elastic recoil [p<0.001; relative percentage increase in elastic recoil 7±3%] and less energy dissipation than collagen III [p<0.001; relative percentage increase in work recovered 7±2%]. In atrial biopsies taken from patients in permanent atrial fibrillation (n=5) versus sinus rhythm (n=5), stiffness of both collagen fiber subtypes was augmented (p<0.008). Myocardial fibrillar collagen fibers organize in a discrete manner and possess distinct biomechanical differences; specifically, collagen I fibers exhibit relatively higher stiffness, contrasting with higher susceptibility to plastic deformation and less energy efficiency on deformation with collagen III fibers. Augmented stiffness of both collagen fiber subtypes in tissue samples from patients with atrial fibrillation compared to those in sinus rhythm are consistent with recent published findings of increased collagen cross-linking in this setting.

Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion.

Clinical states with portal venous hypertension are frequently associated with impairment in renal hemodynamics and water excretion, as well as increased renin secretion. In the present investigation, portal venous pressure (PVP) was increased in anesthetized dogs undergoing a water diuresis. Renal arterial pressure was maintained constant in all studies. As PVP was increased from 6 to 20 mm Hg, decreases in cardiac output (2.5-2.0 liter/min, P less than 0.05) and mean arterial pressure (140-131 mm Hg, P less than 0.05) were observed. Increases in PVP were also associated with decreases in glomerular filtration rate (GFR, 40-31 ml/min, P less than 0.001), renal blood flow (RBF, 276-193 ml/min, P less than 0.001), and increases in renin secretion (232-939 U/min, P less than 0.025) in innervated kidneys. No significant change in either GFR or RBF and a decrease in renin secretion occurred with increases in PVP in denervated kidneys. To dissociate the changes in cardiac output and mean arterial pressure induced by increase PVP from the observed decreases in GFR and RBF, studies were performed on animals undergoing constriction of the thoracic inferior vena cava. In these studies, similar decreases in cardiac output and mean arterial pressure were not associated with significant changes in GFR or RBF. Increases in PVP also were associated with an antidiuresis as urine osmolality increased from 101 to 446 mosmol/kg H2O (P less than 0.001). This antidiuresis was significantly blunted but not abolished by acute hypophysectomy. In hypophysectomized animals, changes in free water clearance and urine flow were linearly correlated as PVP was increased. These studies indicate that increases in PVP result in decreases in GFR and RBF and increases in renin secretion mediated by increased renal adrenergic tone. Increased PVP is also associated with antidiuresis; this antidiuresis is mediated both by vasopressin release and by diminished tubular fluid delivery to the distal nephron.

Effect of central catecholamine depletion on the osmotic and nonosmotic stimulation of vasopressin (antidiuretic hormone) in the rat.

The central nervous system (CNS) mechanism(s) for the release of antidiuretic hormone (ADH) by various stimuli is unknown. In this study, the role of CNS catecholamines in effecting ADH release was examined in conscious rats 10-14 d after the cerebroventricular injection of 6-hydroxydopamine (6-OHDA). This dose of 6-OHDA caused a 67% depletion of brain tissue norepinephrine and only 3% depletion of heart norepinephrine, as compared with controls, which were injected with the vehicle buffer alone. Either intravenous 3% saline (osmotic stimulus) or intraperitoneal hyperoncotic dextran (nonosmotic stimulus) was administered to water-diuresing rats through indwelling catheters. Neither of these maneuvers changed arterial pressure, pulse, or inulin clearance in control or 6-OHDA rats. The 3% saline caused similar increases in plasma osmolality (15 mosmol/kg H(2)O) in control and 6-OHDA rats. The control rats, however, increased urinary osmolality (Uosm) to 586 mosmol/kg H(2)O, whereas 6-OHDA rats increased Uosm only to 335 mosmol/kg H(2)O (P < 0.005). These changes in Uosm were accompanied by an increase in plasma ADH to 7.6 muIU/ml in control animals vs. 2.9 muIU/ml in 6-OHDA rats (P < 0.005). All waterdiuresing animals had undetectable plasma ADH levels. Dextran-induced hypovolemia caused similar decrements (- 10%) in blood volume in both control and 6-OHDA animals, neither of which had significant changes in plasma osmolality. This nonosmotic hypovolemic stimulus caused an increase in Uosm to 753 mosmol/kg H(2)O in control rats, whereas Uosm in 6-OHDA rats increased to only 358 mosmol/kg H(2)O (P < 0.001). At the same time, ADH levels also were significantly greater in Cont rats (2.4 muIU/ml) than in the 6-OHDA animals (0.69 muIU/ml; P < 0.05). These results therefore suggest that CNS catecholamines may play an important role in mediating ADH release in response to both osmotic and nonosmotic (hypovolemic) stimuli.

Mechanism of effect of thoracic inferior vena cava constriction on renal water excretion.

Persistent secretion of vasopressin and/ or diminished distal fluid delivery have been proposed to explain the impaired water excretion associated with low-output cardiac failure. In the present investigation cardiac output (CO) was diminished in anesthetized dogs undergoing a water diuresis by constriction of the thoracic inferior vena cava (TIVC). In intact animals (group I) acute TIVC constriction decreased CO from 3.5 to 2.2 liters/min (P < 0.005) as urinary osmolality (U(osm)) increased from 103 to 543 mosmols/ kg (P < 0.001) and free water clearance (C(H2o)) decreased from 2.1 to -0.6 ml/min (P < 0.001). This antidiuretic effect was disassociated from changes in renal arterial and venous pressures, glomerular filtration rate, solute excretion, and renal innervation. To examine the role of vasopressin in this antidiuresis, studies (group II) were performed in acutely hypophysectomized, steroid-replaced animals. In these animals TIVC constriction decreased CO to a similar degree from 3.4 to 2.1 liters/min (P < 0.001). However, the effects on U(osm) (87-104 mosmols/kg) and C(H2o) (2.1-1.6 ml/min) were significantly less than in intact dogs. In another group of hypophysectomized animals, (group III) renal arterial and venous pressures were not controlled, and the effect of TIVC constriction on U(osm) was not significant (65-79 mosmols/kg) although C(H2o) decreased from 3.3 to 1.9 ml/min (P < 0.001). In both the group II and III studies, there were linear correlations between the changes in C(H2o) and the urine flow. Studies were also performed in baroreceptor-denervated animals with intact hypothalamo-neurohypophyseal tracts, and acute TIVC constriction altered neither U(osm) nor C(H2o) when renal arterial pressure was controlled. These results therefore indicate that the effect of TIVC constriction on U(osm) is primarily vasopressin mediated while the effect on C(H2o) is mediated both by vasopressin release and diminished distal fluid delivery. A decrease in renal arterial pressure, or some consequence thereof, seems to be an important determinant of the latter effect.

In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin.

In a previous study we demonstrated that indomethacin potentiated the hydro-osmotic action of vasopressin in vivo. It was hypothesized that this action of indomethacin was due to its ability to suppress renal medullary prostaglandin synthesis, since in vitro studies have suggested that prostaglandins interfere with the ability of vasopressin to stimulate production of its intracellular mediator, cyclic AMP. In the present study this hypothesis was tested in vivo. Anesthetized rats undergoing a water diuresis were studied. In a control group, bolus injections of 200 muU of vasopressin caused a rise in urinary osmolality (Uosm) from 124 +/- 6 to 253 +/- 20 mosmol/kg H2O (P less than 0.005). In a group treated with 2 mg/kg of indomethacin the same dose of vasopressin caused a significantly greater (P less than 0.001) rise in Uosm from 124 +/- 7 to 428 +/- 19 mosmol/kg H2O. Medullary tissue cyclic AMP rose from 9.4 +/- 0.9 to 13.4 +/- 1.7 (P less than 0.05) pmol/mg tissue protein after vasopressin administration in animals receiving no indomethacin, while in indomethacin-treated animals there was a significantly greater rise (P less than 0.001) in medullary cyclic AMP from 10.4 +/- 0.9 to 21.6 +/- 2.1 pmol/mg tissue protein in response to the vasopressin injections. In neither control animals nor indomethacin-treated animals were there significant changes in renal hemodynamics, as measured by clearance techniques. Indomethacin, when given alone, had no effect on Uosm or medullary tissue cyclic AMP. Indomethacin did, however, reduce medullary prostaglandin E content from 84.7 +/- 15.0 to 15.6 +/- 4.3 pg/mg tissue. This study has shown that indomethacin, in a dose which suppresses medullary prostaglandin content, potentiates the ability of vasopressin to increase the tissue content of its intracellular mediator, cyclic AMP. Indomethacin caused no demonstrable inhibition of cyclic AMP phosphodiesterase. Therefore, it seems likely that indomethacin enhanced the ability of vasopressin to increase medullary cyclic AMP levels by causing an increased production rather than decreased destruction of the nucleotide. We conclude that this action of indomethacin contributes to its ability to potentiate the hydro-osmotic action of vasopressin in vivo. A corollary to this conclusion is that endogenous medullary prostaglandin E's may be significant physiological modulators of the renal response to vasopressin.

Effect of beta adrenergic blockade on renin response to renal nerve stimulation.

The ability of d,l-propranolol to block renin secretion in response to various extrarenal stimuli, such as hemorrhage and hypoglycemia, has been interpreted to indicate the presence of an intrarenal beta receptor regulating renin release. However, two problems complicate this interpretation: (a) the stimuli have effects outside the kidney, and (b) d,l-propranolol has a local anesthetic, as well as a beta adrenergic blocking, action. In the present study, the effects of a purely intrarenal stimulus, in the form of renal nerve stimulation (RNS), on renin secretion was examined. The effects of d,l-propranolol (anesthetic and beta-blocking activity), l-propranolol (beta-blocking activity only), and d-propranolol (local anesthetic activity only) on the renin response to RNS were examined. In a control group of animals, two sequential RNS increased mean renin secretion from 401 to 1,255 U/min (P less than 0.25) and from 220 to 2,179 U/min (P less than 0.01). In a second group the first RNS increased renin secretion from 201 to 1,181 U/min (P less than 0.01), but after d,l-propranolol was given RNS did not significantly alter renin secretion (33 to 55 U/min). In a third group the initial RNS increased renin secretion from 378 to 1,802 U/min (P less than 0.025), but after l-propranolol was given RNS had no significant effect on renin secretion (84 to 51 U/min). A fourth group of dogs showed a rise in renin secretion from 205 to 880 U/min (P less than 0.001) in response to the first RNS, while the second RNS, given after an infusion of d-propranolol, caused a rise in renin secretion from 80 to 482 (P less than 0.005). The nature of the electrical stimulus was consistent in all groups and caused no detectable changes in renal or systemic hemodynamics or in urinary electrolyte excretion. The results, therefore, indicate that renin secretion can be stimulated through intrarenal beta receptors independent of changes in systemic or renal hemodynamics or in tubular sodium reabsorption. Hence the effect of beta stimulation on renin secretion would appear to result from a direct action on the renin-secreting cells of the juxtaglomerular apparatus.

The role of renal nerves and prostaglandins in control of renal hemodynamics and plasma renin activity during hypotensive hemorrhage in the dog.

The effects of hypotensive hemorrhage (HH) on renal hemodynamics and plasma renin activity (PRA) during prostaglandin (PG) synthesis inhibition were examined in three groups of dogs. In each group of animals arterial blood pressure was lowered by a 30% decrement. In the first group of eight control animals, HH was not associated with a significant change in glomerular filtration rate (GFR, 42-36 ml/min, NS); renal blood flow (RBF) declined significantly, from 234 to 171 ml/min, P < 0.05. In the second group of eight animals, pretreated with RO 20-5720 (RO, 2 mg/kg), a competitive inhibitor of PG synthesis, HH was associated with a significant fall in GFR (43-17 ml/min, P < 0.001) and RBF (195-89 ml/min, P < 0.001). In the third group of eight animals, pretreatment with indomethacin (IN, 10 mg/kg), a chemically dissimilar PG inhibitor, HH was also associated with a significant fall in GFR (38-8 ml/min, P < 0.001) and RBF (150-30 ml/min, P < 0.001). Renal denervation attenuated this renal ischemic effect of HH in the presence of PG inhibition. In the RO group, GFR (34 vs. 17 ml/min, P < 0.005) and RBF (145 vs. 89 ml/min, P < 0.025) were significantly greater in denervated vs. innervated kidneys during HH. Similarly, in animals treated with IN, a significantly higher GFR (28 vs. 8 ml/min, P < 0.005) and RBF (101 vs. 30 ml/min, P < 0.005) occurred in denervated as compared to innervated kidneys during HH. With HH, the increase in PRA in the control group (3.34-11.68 ng/ml per h, P < 0.005) was no different than that observed in the RO group (4.96-18.9 ng/ml per h, P < 0.001) or IN group (4.71-17.8 ng/ml per h, P < 0.001). In summary, the present results indicate that renal PG significantly attenuate the effect of HH to decrease GFR and RBF. Furthermore, renal denervation exerts a protective effect against the enhanced renal ischemic effects which occur in the presence of PG inhibition during HH. Finally, PG inhibition does not alter the effect of HH to cause an increase in PRA.

Myocardial bioenergetic abnormalities in a canine model of left ventricular dysfunction.

OBJECTIVES: The purpose of this study was to assess high energy phosphate compound metabolism in remodeled left ventricular myocardium. BACKGROUND: The development of heart failure several years after myocardial infarction is often unexplained. Certain abnormalities of remodeled myocardium suggest that structural changes occurring in viable myocardium after discrete myocardial damage may contribute to the later appearance of heart failure. Whether these abnormalities alter metabolism in the surviving muscle and thereby possibly contribute to ventricular dysfunction is unknown. METHODS: High energy phosphate compound metabolism was assessed using spatially localized phosphorus-31 nuclear magnetic resonance spectroscopy. Eleven dogs with documented left ventricular dysfunction, resulting from infarction produced by transmyocardial direct current shock, were compared with eight normal dogs. Analyses were performed at baseline and during coronary hyperperfusion induced by intravenous adenosine. Myocardial blood flow was measured with radioactive microspheres. RESULTS: The creatine phosphate/adenosine triphosphate (CP/ATP) ratio was significantly reduced in the left ventricular dysfunction group in both the subepicardium ([mean +/- SE] 1.94 +/- 0.08 vs. 2.32 +/- 0.13, p = 0.019) and the subendocardium (1.71 +/- 0.07 vs. 2.05 +/- 0.07, p = 0.004). Intravenous adenosine produced significant coronary hyperemia in both groups but was less marked in dogs with left ventricular dysfunction. The improvement in myocardial perfusion was accompanied by a significant increase in the subendocardial CP/ATP ratio (from 1.71 +/- 0.07 to 1.92 +/- 0.08, p = 0.01) in dogs with left ventricular dysfunction. CONCLUSIONS: An abnormal transmural distribution of high energy phosphate compounds is evident in remodeled myocardium. This abnormality may be related in part to mismatch of oxygen delivery and demand.

Long-term oral nitrate therapy prevents chronic ventricular remodeling in the dog.

OBJECTIVES: The purpose of this experiment was to assess the long-term effects of oral nitrate therapy on ventricular remodeling in a canine model of discrete myocardial damage. BACKGROUND: A progressive increase in left ventricular mass and volume has been documented after experimental and clinical myocardial infarction. This ventricular remodeling has been associated with the development of congestive heart failure. Nitrate therapy, especially when combined with hydralazine, is effective in the management of clinical heart failure. Moreover, nitrates inhibit infarct expansion, one of the earliest manifestations of ventricular remodeling. Whether nitrates can attenuate chronic left ventricular remodeling is unknown. METHODS: Dogs with discrete myocardial necrosis produced 24 h earlier by transmyocardial direct current shock were randomized to receive isosorbide mononitrate, 30 mg twice daily (n = 10), or no treatment (n = 4); the latter group was augmented by 13 control dogs from a prior study in which an identical protocol was used. Ventricular structure was assessed with nuclear magnetic resonance imaging at baseline and at 1 and 16 weeks after myocardial damage. RESULTS: Left ventricular mass increased at 1 week in the control group (mean +/- SD 68.1 +/- 10.7 g to 80.1 +/- 12.1 g, p = 0.0001) but not in the nitrate-treated group (70.2 +/- 7.7 g to 69.6 +/- 7.3 g, p = NS). No change in left ventricular volume was observed in either group during the 1st week after myocardial damage. After 16 weeks of follow-up left ventricular mass had increased by 12.7 +/- 7.1 g (p = 0.001) in the control group and had decreased by 1.2 +/- 7.7 g in the nitrate group. Left ventricular volume was increased at 16 weeks by 14.2 +/- 10.3 ml in the control group but was decreased by 3.7 +/- 7.5 ml in the nitrate group. Isosorbide mononitrate produced transient hemodynamic effects with a return of most measured variables toward baseline within 2 h after administration of the drug. At 1 week there was no intergroup difference in rest hemodynamic variables assessed 12 h after drug administration. At 16 weeks, pulmonary capillary wedge pressure (15 +/- 4 vs. 8 +/- 3 mm Hg, p = 0.0001), pulmonary artery pressure (24 +/- 5 vs. 16 +/- 3 mm Hg, p = 0.0001) and right atrial pressure (10 +/- 3 vs. 6 +/- 3 mm Hg, p = 0.008) were all higher in the control group. CONCLUSIONS: Long-term oral nitrate therapy attenuates the early and late manifestations of ventricular remodeling after myocardial damage in the dog. Hemodynamic observations suggest the possibility that drug-induced preload or afterload reduction does not completely explain this effect.

Angiotensin-converting enzyme inhibition and beta-adrenoceptor blockade regress established ventricular remodeling in a canine model of discrete myocardial damage.

OBJECTIVES: This study was designed to assess the effect of angiotensin-converting enzyme inhibition and beta-adrenoreceptor blockade on established ventricular remodeling. BACKGROUND: Angiotensin-converting enzyme inhibitor therapy attenuates the development of ventricular remodeling when given shortly after myocardial infarction. However, regression of established ventricular remodeling after infarction has received little attention. METHODS: The relative effects of angiotensin-converting enzyme inhibitor therapy and beta-adrenoceptor blockade on established ventricular remodeling were assessed in a canine model characterized by increased left ventricular mass and chamber dilation as a result of localized myocardial necrosis produced by transmyocardial direct current shock. Dogs were randomly assigned to 3 months of therapy with captopril (25 mg twice daily, n = 7) or metoprolol (100 mg twice daily, n = 7) or to a control group with no intervention (n = 6), 11 +/- 4 (mean +/- SD) months after acute myocardial damage. RESULTS: Compared with the control group, dogs in both the captopril and metoprolol groups had reduced left ventricular mass as measured by magnetic resonance imaging (-8.1 +/- 3.8 vs. 1.7 +/- 2.8 g, p = 0.003 and -9.6 +/- 5.6 vs. 1.7 +/- 2.8 g, p = 0.001), respectively. Captopril and metoprolol also produced a reduction in left ventricular end-diastolic volume (-7.6 +/- 6.0 and -6.0 +/- 5.8 ml, respectively) compared with the control value (-1.6 +/- 3.8 ml) (p = 0.14 [NS]). Both agents reduced mean arterial pressure but had disparate effects on pulmonary wedge pressure and right atrial pressure. There was no significant correlation between change in ventricular mass or volume and change in any measured hemodynamic or neurohormonal variable. CONCLUSIONS: These data suggest that pharmacologic intervention with angiotensin-converting enzyme inhibition or beta-adrenoceptor blockade can result in regression of established ventricular remodeling. The mechanism of this response will require further study, but these data did not support a close association between regression of remodeling and hemodynamic unloading of the ventricle or systemic neuroendocrine factors.

Development and validation of the Ontario acute myocardial infarction mortality prediction rules.

OBJECTIVES: To develop and validate simple statistical models that can be used with hospital discharge administrative databases to predict 30-day and one-year mortality after an acute myocardial infarction (AMI). BACKGROUND: There is increasing interest in developing AMI "report cards" using population-based hospital discharge databases. However, there is a lack of simple statistical models that can be used to adjust for regional and interinstitutional differences in patient case-mix. METHODS: We used linked administrative databases on 52,616 patients having an AMI in Ontario, Canada, between 1994 and 1997 to develop logistic regression statistical models to predict 30-day and one-year mortality after an AMI. These models were subsequently validated in two external cohorts of AMI patients derived from administrative datasets from Manitoba, Canada, and California, U.S. RESULTS: The 11-variable Ontario AMI mortality prediction rules accurately predicted mortality with an area under the receiver operating characteristic (ROC) curve of 0.78 for 30-day mortality and 0.79 for one-year mortality in the Ontario dataset from which they were derived. In an independent validation dataset of 4,836 AMI patients from Manitoba, the ROC areas were 0.77 and 0.78, respectively. In a second validation dataset of 112,234 AMI patients from California, the ROC areas were 0.77 and 0.78 respectively. CONCLUSIONS: The Ontario AMI mortality prediction rules predict quite accurately 30-day and one-year mortality after an AMI in linked hospital discharge databases of AMI patients from Ontario, Manitoba and California. These models may also be useful to outcomes and quality measurement researchers in other jurisdictions.

The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a meta-analysis.

OBJECTIVES: This study was designed to compare the prognostic value of an abnormal troponin level derived from studies of patients with non-ST elevation acute coronary syndromes (ACS). BACKGROUND: Risk stratification for patients with suspected ACS is important for determining need for hospitalization and intensity of treatment. METHODS: We identified clinical trials and cohort studies of consecutive patients with suspected ACS without ST-elevation from 1966 through 1999. We excluded studies limited to patients with acute myocardial infarction and studies not reporting mortality or troponin results. RESULTS: Seven clinical trials and 19 cohort studies reported data for 5,360 patients with a troponin T test and 6,603 with a troponin I test. Patients with positive troponin (I or T) had significantly higher mortality than those with a negative test (5.2% vs. 1.6%, odds ratio [OR] 3.1). Cohort studies demonstrated a greater difference in mortality between patients with a positive versus negative troponin I (8.4% vs. 0.7%, OR 8.5) than clinical trials (4.8% if positive, 2.1% if negative, OR 2.6, p = 0.01). Prognostic value of a positive troponin T was also slightly greater for cohort studies (11.6% mortality if positive, 1.7% if negative, OR 5.1) than for clinical trials (3.8% if positive, 1.3% if negative, OR 3.0, p = 0.2) CONCLUSIONS: In patients with non-ST elevation ACS, the short-term odds of death are increased three- to eightfold for patients with an abnormal troponin test. Data from clinical trials suggest a lower prognostic value for troponin than do data from cohort studies.

Rapid, accurate and simultaneous noninvasive assessment of right and left ventricular mass with nuclear magnetic resonance imaging using the snapshot gradient method.

Left ventricular, and possibly also right ventricular, mass is an important determinant of prognosis in cardiovascular disease. Consequently, noninvasive estimation of ventricular mass may be an important clinical investigation. The ideal technique for this purpose would be widely available and accurate, employ short study times and avoid exposure to contrast agents and radiation. Conventional nuclear magnetic resonance (NMR) imaging fulfills most of these criteria, but it is time-consuming and expensive. Moreover, its accuracy in estimating right ventricular mass has yet to be assessed. Accordingly, high speed NMR imaging using the snapshot gradient echo technique was used to assess right and left ventricular mass in 10 dogs and the results were compared with values obtained at autopsy, which ranged from 26.1 to 52.9 and 61 to 119.8 g, respectively. The mean absolute difference between the NMR imaging estimates and autopsy findings was 2 +/- 1.2 g (range 0.4 to 4.2) for right ventricular mass and 4.4 +/- 1.7 g (range 1.8 to 6.6) for left ventricular mass. Total NMR imaging time was less than or equal to 5 min. These data demonstrate that high speed NMR imaging can be used to accurately estimate right as well as left ventricular mass.

Hemodynamic, left ventricular structural and hormonal changes after discrete myocardial damage in the dog.

Transmyocardial direct-current (DC) shock produces localized left ventricular myocardial necrosis without obstruction to coronary blood flow. In 43 dogs sequential measurements of hemodynamic, neuroendocrine and myocardial structural changes were made at baseline and for 16 weeks after DC shock. Six dogs (14%) died in the peri-shock period. By 1 week after shock, left ventricular mass, as measured by nuclear magnetic resonance imaging, had increased from a mean value +/- SD of 67.9 +/- 10.1 to 82.5 +/- 12.9 g (p = 0.0001). Left ventricular end-diastolic volume was unchanged at 1 week but increased at 16 weeks from 56.1 +/- 10.3 to 70.3 +/- 10.7 ml (p = 0.0003). Left ventricular mass demonstrated a further increase at 12 months (107.8 +/- 14.8 g). Rest cardiac output was significantly decreased at 4 months (3.67 +/- 1.23 to 3.18 +/- 0.81 liters/min, p less than 0.01) as was stroke volume (43 +/- 9 to 37 +/- 7 ml, p less than or equal to 0.01). Left ventricular ejection fraction decreased progressively from 73% to 38% at 1 year. At 4 months there were increases in mean pulmonary artery pressure (18 +/- 4 to 23 +/- 4 mm Hg, p less than 0.01), pulmonary capillary wedge pressure (9 +/- 3 to 15 +/- 3 mm Hg, p less than 0.01) and right atrial pressure (5 +/- 4 to 9 +/- 3 mm Hg, p less than 0.01). Plasma norepinephrine was increased at 4 months (318 +/- 190 to 523 +/- 221 pg/ml, p = 0.0003), whereas plasma renin activity was not significantly changed (4.3 +/- 2.6 vs. 5.2 +/- 3.4 ng/ml per h). Microsphere regional blood flow studies demonstrated a 50% reduction in skeletal muscle blood flow at 4 months (0.06 +/- 0.06 ml/min per g compared with 0.12 +/- 0.09 in normal dogs, p = 0.05), and a reduction in the endocardial/epicardial blood flow ratio (1.11 +/- 0.13 compared with 1.24 +/- 0.13 in normal dogs, p = 0.02). Therefore, in this model of acute left ventricular damage, left ventricular hypertrophy precedes progressive left ventricular dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular hypertrophy: an initial response to myocardial injury.

The prevailing wisdom generally has been that the failing heart hypertrophies in response to increased wall stress. The increase in myocardial mass observed in heart failure is therefore a relatively late compensatory event geared to normalize wall stress. Although this is undoubtedly true, especially for heart failure resulting from a large anterior myocardial infarction accompanied by rapid left ventricular expansion, it is possible that an important form of hypertrophy occurs much earlier as an initial response to myocardial injury. One can hypothesize that the initial response to injury is a nonspecific phenotypic alteration of the cardiac myocyte to one of growth and development. Such changes may be driven by both trophic and mechanical forces and may be important in altering the architecture of the myocardial cell and surrounding cardiac interstitium. Preliminary data from a variety of models support the concept that neuroendocrine activity is an important component in the ventricular remodeling process, and that pharmacologic interventions designed to block systemic and tissue neuroendocrine activity may prevent excessive cardiac enlargement and its ultimate consequences. Because this concept has important implications for preventive cardiology, the results of several prevention trials, including the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), Studies of Left Ventricular Dysfunction (SOLVD), and Survival and Ventricular Enlargement (SAVE) are awaited eagerly.

Estimating the proportion of post-myocardial infarction patients who may benefit from prophylactic implantable defibrillator placement from analysis of the CAST registry. Cardiac Arrhythmia Suppression Trial.

We defined the proportion of post-myocardial infarction patients who would have been eligible for the Multicenter Automatic Defibrillator Implantation Trial (MADIT) from a population of 94,797 patients with myocardial infarction entered into the Cardiac Arrhythmia Suppression Trial Registry. From this large population, only between 0.3% to 1.7% would have met strict eligibility criteria for MADIT.

The basics of heart failure management: are they being ignored?

BACKGROUND: Advances have been made in the medical management of congestive heart failure. However, there is concern that these changes may not be transmitted to the heart failure population in the community. Other impediments to improved prognosis, such as failure to apply non-pharmacological strategies and poor patient comprehension may also be prevalent in the community. AIMS: The purpose of this study was to assess physician practice and patient knowledge in a heart failure population admitted to a University Hospital in Ireland. METHODS: Patients admitted with a primary diagnosis of heart failure were studied. Estimation of ejection fraction was used to subdivide the population into heart failure with impaired and normal systolic function. Patients' course in hospital was noted with reference to management by cardiology or internal medicine, use of angiotensin-converting enzyme inhibition therapy and digoxin and application of dietary and rehabilitative services. Patient knowledge was assessed by questionnaire. RESULTS: Eighty patients were included in this study. Two-thirds of the population had impaired systolic function. The majority of patients were managed by internal medicine physicians, and this population was older and more likely to have normal systolic function. Prescription of converting enzyme inhibitor therapy was more frequently used in cardiology-managed patients (96 vs. 70%, P<0.05). Neither group applied dietary or rehabilitative advice to a significant level. Patient comprehension was poor, especially with regard to understanding of medicine and the value of weight measurement. CONCLUSION: The above data demonstrate a lack of use of rehabilitative and dietary services and poor patient knowledge. These deficiencies may play a role in determining outlook and may impede the expected improvement in prognosis that has been witnessed in large randomised studies.

Primary cardiac lymphoma treated with orthotopic heart transplantation: a case report.

Primary lymphoma of the heart is an extremely rare tumor. It is associated with a high mortality rate because of the advanced stage of myocardial involvement at initial presentation. Conventional surgical and medical treatments have not met with much success. This article reports the first case of primary cardiac lymphoma treated with orthotopic heart transplantation. The patient had hemodynamically significant severe acute rejection, neutropenic sepsis, and tumor recurrence during the late postoperative period, illustrating the difficulties associated with concomitant immunosuppression and tumor chemotherapy. Unfortunately, the patient died after a period of remission. Our approach to the integration of immunosuppression with chemotherapy, posttransplantation follow-up, and complications is discussed.

Reduced vascular compliance as a marker for essential hypertension.

In 38 patients with established essential hypertension and 32 age-matched normotensive control subjects proximal and distal arterial compliance were determined by computer-based assessment of the diastolic decay of a brachial arterial tracing and a modified Windkessel model of the circulation. In the hypertensive subjects compared to the normotensive subjects mean arterial pressure was 25% higher (P less than .001), systemic vascular resistance 23% higher (P less than .01), proximal compliance 19% lower (P less than .01), and distal compliance 72% lower (P less than .001). The reduction in distal compliance was highly age-dependent. In the youngest age range (45 to 54 years) little overlap appeared between hypertensive and normotensive groups, whereas in the oldest subjects studied (65 to 75 years) distal compliance was comparably low in the two groups. Thus, distal vascular compliance provides a sensitive and specific marker for the abnormal vasculature associated with hypertension and may be particularly useful in identifying the disease in young individuals with borderline blood pressure.