Late Congestive Heart Failure Research Articles

Effect of standard low-dose anthracycline chemotherapy on late congestive heart failure in breast cancer survivors aged between 50 and 59 at diagnosis: A nationwide study

ObjectivesAlthough chemotherapy-induced congestive heart failure (CHF) is a well-known adverse event in cancer survivors, the long-term risk of standard low-dose anthracycline has not yet been reported. This study aimed to investigate the long-term effects of standard anthracycline on late CHF in breast cancer survivors. Materials and methodsA nationwide retrospective cohort study was conducted using the national insurance claims data for nearly 98% of Korean citizens. Between Jan 2010 and Dec 2015, a total of 56,338 newly diagnosed female breast cancer survivors were included. ResultsThe total number of person-years was 199,648 and the incidence rate of late CHF was 3.57 per 1000 person-years. In multivariate analysis according to the subject’s age at diagnosis, only in the 50–59 age group, anthracycline-based [hazard ratio (HR) 1.765, 95% confidence interval (CI) 1.206–2.583] and taxane plus anthracycline-based regimens (HR 1.816, 95% CI 1.192–2.768) significantly increased the risk of late CHF. In the 50–59 age group, standard low-dose anthracycline significantly increased the risk of late CHF (HR 1.627, 95% CI 1.080–2.451) in Cox proportional hazard regression models. In competing risk model with recurrence and in-hospital death as competing risks, standard low-dose anthracycline was a significant risk factor for late CHF [subdistribution hazard ratio (SHR) 1.553, 95% CI 1.029–2.340]. ConclusionThis nationwide study showed that standard chemotherapy with low-dose anthracycline is a risk factor for late-onset CHF in breast cancer survivors who were in their 50 s at breast cancer diagnosis. Long-term monitoring of late CHF should be considered in these younger breast cancer survivors.

Long-term risk of congestive heart failure in younger breast cancer survivors: A nationwide study by the SMARTSHIP group.

There is a controversy about late-onset congestive heart failure (CHF) among breast cancer survivors. This study investigated the incidence rate and risk factors of late-onset CHF more than 2years after the breast cancer diagnosis. A nationwide, retrospective study was conducted with the National Health Information Database. With 1:3 age- and sex-matched noncancer controls, Cox proportional hazard regression models were used to analyze the incidence and risk factors of late CHF. The cumulative incidence rate of late CHF was evaluated with a Kaplan-Meier analysis and a log-rank test. A total of 91,227 cases (286,480 person-years) and 273,681 controls (884,349 person-years) were evaluated between January 2007 and December 2013. The risks of late CHF were higher in cases than controls (hazard ratio [HR], 1.396; 95% confidence interval [CI], 1.268-1.538). Younger survivors (age≤50years) showed a higher risk of late CHF than their younger counterparts (HR, 2.903; 95% CI, 2.425-3.474). Although older age was a risk factor for late CHF, older survivors (age≥66years) showed no difference in the risk of late CHF in comparison with their counterparts (HR, 0.906; 95% CI, 0.757-1.084). Anthracyclines and taxanes were risk factors for late CHF, although trastuzumab, radiation, and endocrine therapy were not. Young breast cancer survivors have a greater risk of late CHF than the young population without cancer. More attention should be paid to young breast cancer survivors who receive taxane- or anthracycline-based regimens over the long term.

The tell-tale heart: molecular and cellular responses to childhood anthracycline exposure

Since the modern era of cancer chemotherapy that began in the mid-1940s, survival rates for children afflicted with cancer have steadily improved from 10% to current rates that approach 80% (60). Unfortunately, many long-term survivors of pediatric cancer develop chemotherapy-related health effects; 25% are afflicted with a severe or life-threatening medical condition, with cardiovascular disease being a primary risk (96). Childhood cancer survivors have markedly elevated incidences of stroke, congestive heart failure (CHF), coronary artery disease, and valvular disease (96). Their cardiac mortality is 8.2 times higher than expected (93). Anthracyclines are a key component of most curative chemotherapeutic regimens used in pediatric cancer, and approximately half of all childhood cancer patients are exposed to them (78). Numerous epidemiologic and observational studies have linked childhood anthracycline exposure to an increased risk of developing cardiomyopathy and CHF, often decades after treatment. The acute toxic effects of anthracyclines on cardiomyocytes are well described; however, myocardial tissue is comprised of additional resident cell types, and events occurring in the cardiomyocyte do not fully explain the pathological processes leading to late cardiomyopathy and CHF. This review will summarize the current literature regarding the cellular and molecular responses to anthracyclines, with an important emphasis on nonmyocyte cardiac cell types as well as those that mediate the myocardial injury response.

HER2 Signaling Pathway and Trastuzumab Cardiotoxicity

Trastuzumab-induced cardiotoxicity may induce reversible damage that is usually transitory and improves with trastuzumab withdrawal. In clinical trials with trastuzumab in the adjuvant setting patients with cardiac risks were not included. Subgroup analysis identified subpopulations that were most likely to experience cardiac damage upon trastuzumab exposure. Although there is a risk of cardiac toxicity with adjuvant trastuzumab, the improvement of outcome in patients treated with this drug outweighs this. It is essential, therefore, to properly assess cardiac function prior to, during and after trastuzumab therapy in all patients. The incidence of congestive heart failure in older patients treated with trastuzumab is expected to be higher than in the overall population evaluated in large clinical trials. Therefore, cardiac risk assessment, breast cancer recurrence risk, and discussion between cardiologists and oncologists should take place prior to deciding which adjuvant treatment is appropriate for a woman with early breast cancer. A longer follow-up period is recommended in order to verify whether cardiac reversibility remains and, accordingly, whether the short-term risk is exaggerated or understated. With the NSABP-B31 trial regimen, the benefit of trastuzumab definitely outweighs the risk; indeed, the occurrence of late congestive heart failure after adding trastuzumab to chemotherapy is fairly unusual. In the era of personalized medicine, efforts are needed to promote strategies for risk detection and management to avoid dangerous toxicities that may impede the development of and patient access to new agents.

Cardiovascular Risk: Analysis of Known Factors in Patients After Treosulfan-Based Conditioning for Haploidentical and HLA-Identical Stem Cell Transplantation

Abstract 4471Allogeneic stem cell transplantation (HSCT) is an emerging risk factor for cardiovascular disease. Long-term survivors seem to be at higher risk for premature arterial vascular disease compared with sex- and age-matched population. In HSCT, pre-transplant treatments and the conditioning regimen play a key role in endothelial and organ damage. The use of immunosuppressant drugs to prevent graft-versus-host disease (GvHD) influences as well the development of cardiac disease. To better understand the impact of treosulfan-based conditioning regimens in leading to the emergence of cardiovascular disease, we retrospectively evaluated 94 consecutive patients who had survived longer than 1 year, transplanted at Our Institution between 2002 and 2010 (62 males – median age 46, range 14–69). For 48 patients an HLA-identical sibling was available, 6 patients found an unrelated donor while 40 patients underwent haploidentical HSCT from family donors. Forty-six patients received in vivo T-cell depletion and 72 B-cell depletion. GvHD prophylaxis was based upon cyclosporine + methotrexate for the HLA-identical transplants (48 – median EBMT risk score 3) whereas rapamycin + MMF were used for patients undergoing transplantation from HLA-haploidentical donors (35 – median EBMT risk score 4); 9 did not receive any immunosuppression because of application of suicide gene strategy as tool to prevent GvHD (median EBMT risk score 3). We compared clinical variables (i.e. GvHD, OS, TRM, major cardiac events and comorbidities) with biochemical and functional tests (i.e. cardiac function, lipid profile and ferritin levels) both before and 1 year after transplantation. After a median follow-up of 29 months, only 3 patients experienced a major cardiovascular event; no one experienced a late congestive heart failure. In all series, we found that ferritin levels significantly decrease after 1 year of follow-up, compared to pre-transplant values (P <0.0001); viceversa, the lipid profile (total cholesterol, HDL and LDL fractions) remarkably increased (p <0.05). Interestingly, the linear regression analysis for the overall survival showed no difference for both ferritin level and cholesterol level. Moreover, no significant variations were detected comparing cyclosporine versus rapamycin-treated patients, nor comparing patients with or without GvHD. Increased rates of cardiovascular disease are commonly associated to HSCT. In our experience, no differences were found in the incidence of cardiovascular events comparing different donor source or immunosuppressants. This suggests that haploidentical transplants are feasible and have similar cardiac toxicity than standard HLA-identical ones. Our analysis was surely limited by the short time of observation. In future, the evaluation of dynamic biomarkers on a greater series and on a longer follow-up will help us to identify a tailored schedule of cardiac monitoring after HSCT to prevent major lethal events in our patients. Disclosures:No relevant conflicts of interest to declare.

Troponins Do Not Predict Cardiotoxicity in a Pilot Study of Adjuvant Bevacizumab (B) Plus Dose-Dense Doxorubicin/Cyclophosphamide (AC) Followed by Nanoparticle Albumin-Bound Paclitaxel (nab-P).

Abstract Background: We previously reported that dose dense (dd) q2wk AC-nab-P with concurrent bevacizumab (B) in early stage breast cancer is safe (McArthur, SABCS 2008). Prospective randomized studies of adjuvant B-containing, anthracycline-based regimens are ongoing with stringent cardiac monitoring strategies. However, accurate predictors of cardiotoxicity, including congestive heart failure (CHF), are lacking. Currently, treatment-related CHF is monitored by measuring left ventricular ejection fraction (LVEF) changes at various time points. Cardiac troponins (cTn) are myocardial contractile proteins that are released into the circulation after cardiac injury. As highly specific biomarkers of myocardial damage, cTns may augment existing cardiac monitoring strategies by providing earlier and more reliable evidence of myocyte damage. Consequently, we investigated cTnI as a potential biomarker of cardiotoxicity in our pilot study of cardiac safety with ddAC-nab-P+B.Methods: In this phase II study, B was administered concurrently (10 mg/kg IV q2wk x 8) with pegfilgrastim-supported chemotherapy (AC at 60/600 mg/m2 q2wk x4 then nab-paclitaxel at 260 mg/m2 q2wk x4) and continued at 15 mg/kg q3wk thereafter for a total one year of B therapy. The primary endpoint was cardiac safety. A secondary endpoint was the prospective exploration of TnI as a potential predictor of cardiotoxicity. Peripheral blood for TnI was collected at baseline; weeks 2, 4, 6, 8, 10, 12, and 14; and months 6, 9, and 18. In this pre-planned analysis, TnI values over time were examined as continuous variables by institution and as categorical variables. TnI values were categorized as undetectable (UN; &amp;lt;0.06 MSKCC or &amp;lt;0.05ng/ml UCSF), minimally detectable (MD; 0.06-0.31ng/ml MSKCC or 0.05-0.16ng/ml UCSF) or elevated (EL; &amp;gt;0.31ng/ml MSKCC or &amp;gt;0.16ng/ml UCSF). Baseline and maximum TnI values were compared with the maximum change in left ventricular ejection fraction (LVEF) values for all 80 enrolled patients over the study period using ANOVA or regressionResults: Median age: 48y (range, 27–75y). Median follow-up: 24.5mo (range, 1–32mo). Median baseline LVEF: 68% (range, 53–82%). The baseline TnI was MD for 1 pt and UN for 79 pts. Overall, 57 pts developed MD TnIs and 6 pts developed EL TnIs. There was no significant association between TnI and LVEF for the 6 pts who developed protocol-defined asymptomatic LVEF declines and the 1 pt who developed CHF versus not, or for 6 pts who develop EL TnI versus not. Furthermore, there was no significant association between continuous TnIs and the maximum % LVEF change [(max-min)/min)].Conclusions: In this prospective study, TnIs do not appear to predict for LVEF changes with B + ddAC-nab-P. Long-term follow-up continues for late CHF events. Accurate biomarkers of cardiotoxicity in this setting are needed. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3087.

Late Congestive Heart Failure After Hematopoietic Cell Transplantation

To examine the independent roles of pre-hematopoietic cell transplantation (HCT) therapeutic exposures, transplantation-related conditioning, and comorbidities (pre- and post-HCT) in the development of late congestive heart failure (CHF) after HCT. This was a nested case-control design. Individuals with late CHF (diagnosed >or= 1 year after HCT) were identified from a cohort of 2,938 1+ year survivors who underwent transplantation at City of Hope National Medical Center, Duarte, CA. This cohort formed the sampling frame for selecting controls (without CHF) matched for age and year of HCT, donor source (allogeneic v autologous), and length of follow-up. Sixty patients with late CHF were identified; median age at HCT was 45.3 years (range, 16.6 to 68.6 years); median time to CHF was 3.0 years (range, 1.03 to 18.9 years); 68% received autologous HCT. Median ejection fraction was 36.9% (range, 15% to 53%). Compared with matched controls (n = 166), patients with late CHF received more cycles of pre-HCT chemotherapy (8.6 v 4.9 cycles; P < .01), had greater body mass index at HCT (28.4 v 26.2 kg/m(2); P = .01), greater lifetime anthracycline exposure (285.3 v 175.6 mg/m(2); P < .01), and were more likely to have multiple chronic comorbidities (30.0% v 13.9%; P < .01). Multivariable analysis revealed number of pre-HCT chemotherapy cycles (odds ratio [OR] = 1.2; P < .01), anthracycline dose >/= 250 mg/m(2) (OR = 3.2; P = .05), and two or more chronic comorbidities (OR = 4.3; P = .01) to be independently associated with late CHF. Pre-HCT exposure to anthracyclines and presence of comorbidities are primarily responsible for the risk associated with late CHF after HCT. Conditioning-related therapeutic exposure does not contribute significantly to the risk. These results form the basis for identifying high-risk individuals for targeted surveillance, as well as developing preventive strategies in the form of aggressive management of comorbidities.

Enlargement of the Small Aortic Root During Aortic Valve Replacement: Is There a Benefit?

Aortic root enlargement (ARE) at the time of aortic valve replacement (AVR) is an often proposed but still unproven technique to prevent prosthesis-patient mismatch. To evaluate the risks and benefits of ARE, we examined the outcomes of patients with small aortic roots who underwent AVR with or without the use of ARE. Patients (n = 712) with small aortic roots who underwent AVR were prospectively followed (follow-up, 3,730 patient-years; mean, 5.2 +/- 4.1 years). All patients had a small aortic annulus that would have led to the insertion of an aortic prosthesis of 21 or less in size. Multivariate techniques were used to compare outcomes between patients who underwent AVR alone (n = 540) versus AVR plus ARE (n = 172). Aortic cross-clamp times were 9.9 minutes longer in the AVR+ARE group (p = 0.0002). There were no differences in reopening or stroke rates or perioperative mortality (all p = not significant). All patients in the AVR-alone group received size 19 to 21 prostheses, whereas 51% of the AVR+ARE patients received size 23 prostheses. Postoperative gradients were reduced (p < 0.01) and indexed effective orifice areas were larger (p < 0.0001) in the AVR+ARE group. While the incidence of postoperative prosthesis-patient mismatch (indexed effective orifice area < or = 0.85 cm2/m2) was lower in the AVR+ARE group (p < 0.0001), the presence of mismatch did not significantly impact long-term outcomes after surgery. The ARE was associated with a trend toward better freedom from late congestive heart failure (p = 0.19), but not an improvement in long-term survival (p = 0.81). For patients with small aortic roots, ARE at the time of AVR is a safe procedure that reduces postoperative gradients and the incidence of prosthesis-patient mismatch. However, ARE does not appreciably improve long-term clinical outcomes.

Matrix Metalloproteinase-9 Is a Marker of Heart Failure After Acute Myocardial Infarction

Background Matrix metalloproteinases (MMPs) have been associated with the development of left ventricular remodeling after myocardial infarction (MI). We sought to determine whether peripheral levels of MMPs can be used as a risk marker for the development of congestive heart failure (CHF) after acute MI. Methods and Results Plasma levels of MMP-2, MMP-9, C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and pro-brain natriuretic peptide (pro-BNP) were measured in 109 consecutive patients with acute MI treated with primary mechanical reperfusion. Echocardiographic assessment of left ventricular wall motion index was performed during admission. Patients were followed for the development of CHF. Left ventricular function and volumes were determined after 2 years with radionuclide ventriculography. During 2-year follow-up, 15 patients developed congestive heart failure (CHF). Using multivariate analysis, MMP-9 levels were the only circulating factor predictive of late onset CHF. Patients who had high MMP-9 levels had a significant risk of late onset CHF (OR of 6.5, P ≤ .006) and left ventricular remodeling (ΔEF = −9%, P = .03, and Δend-diastolic volume = +13 mL, P = .03). MMP-2, TNF-α, hs-CRP, creatine kinase, and pro-BNP were not predictive of late onset CHF. Conclusion MMP-9 levels may hold prognostic significance in MI patients.

Wilms’ tumor management

The management of Wilms' tumor continues to evolve with two different approaches being taken by the National Wilms Tumor Study in North America and the International Society of Pediatric Oncology in Europe in regards to preoperative chemotherapy. Limiting the duration, dosage, and number of chemotherapeutic agents and the dosage of radiotherapy are common goals in both trials. Contralateral exploration of unilateral tumors will no longer be recommended in future National Wilms Tumor Studies. Percutaneous biopsy for tissue diagnosis is quite accurate, but there are concerning complications with its use. Partial nephrectomy is successful for low risk unilateral Wilms tumor, but its indications remain controversial. The surgical complication rate was similar between the National Wilms Tumor Study and the International Society of Pediatric Oncology, but intraoperative tumor spill was higher in the North American trials. Doxorubicin decreased the risk of recurrence in stage III tumors by 50%, and its current dose is not associated with late congestive heart failure. For selected patients, shorter courses of vincristine/dactinomycin or vincristine alone show equivalent results compared to current regimens. A longer course of chemotherapy (including doxorubicin) for clear cell sarcoma improves recurrence-free survival. Patients with Wilms' tumor, aniridia, major genitourinary malformations, and mental retardation, the WAGR syndrome, have a 50% chance of unexplained end-stage renal disease 20 years after treatment. Less aggressive means of diagnosis and treatment for Wilms' tumor are continuing to achieve very good cure rates while lowering long term morbidity for low risk patients. High-risk patients with unfavorable histology or the WAGR syndrome benefit from more intensive treatment and long-term follow-up.

Prediction of heart failure post myocardial infarction: comparison of ejection fraction, transmitral filling parameters, and the index of myocardial performance.

Following an acute myocardial infarction (MI), the development of congestive heart failure (CHF) has been associated with a reduced ejection fraction (EF), pseudonormal or restrictive diastolic filling, and an increased index of myocardial performance (IMP). To determine the comparative predictive value of EF, transmitral filling parameters, and IMP for the development of CHF following a first MI. A retrospective analysis of consecutive echocardiographic and Doppler studies in patients admitted for their first acute MI from the years 1988 through 1992. We studied 109 patients following their first MI with two-dimensional and Doppler within 24 hours of MI. We divided patients into those who developed CHF within 15 days (43 patients) and without CHF (66 patients). Patients who developed CHF had greater LV dilatation, lower EF (27.7%+/- 10.2% vs 45.6%+/- 13.2%, P < 0.001), higher E/A, shorter deceleration times (DCT; 157 +/- 69 msec vs 248 +/- 105 msec, P < 0.001), and increased IMP. Utilizing multiple logistic regression, EF (strongest predictor), DCT, and IMP were predictive of CHF. Nineteen patients in the no CHF group developed late CHF and had lower EFs (30.5%+/- 13.1% vs 50.5%+/- 9.8%, P < 0.001), higher E/A and shorter DCTs (161 +/- 39 msec vs 283 +/- 103 msec, P < 0.001). EF, DCT, and E/A were predictive of late CHF in patients without initial CHF. For patients admitted with a first MI, the EF, DCT, and to a lesser extent IMP predicted who would ultimately develop CHF. An EF < 40% or a DCT < 200 msec correctly predicted CHF in 60 of 62 patients. We conclude that the early and ultimate development of CHF following a first MI were associated with an moderately reduced EF < 40%, pseudonormal diastolic filling indices, and an increased IMP.

Clinical features of Staphylococcus aureus endocarditis: a 10-year experience in Denmark.

Both morbidity and mortality resulting from Staphylococcus aureus endocarditis are known to be high, and the incidence of this disease seems to increase. The Statens Serum Institut, Copenhagen, Denmark, made it possible for us to analyze the clinical features of S aureus endocarditis in a nation-wide population of non-drug addicts. Almost all Danish cases of bacteremia due to S aureus are reported to the Staphylococcus laboratory, Statens Serum Institut. The medical records were reviewed in cases reported from 1982 to 1991 in which the diagnosis of endocarditis was reported or suspected. A total of 260 patients, 145 males and 115 females, fulfilled the diagnostic criteria. The median age was 67.5 years. In 83 patients, the diagnosis of endocarditis was not suspected clinically. The overall mortality rate among those patients whose disease was diagnosed clinically was 46%. Among the subset of patients who received medical therapy only and appropriate antistaphylococcal treatment, mortality was significantly associated with late congestive heart failure, age, and involvement of the central nervous system. A raised awareness of the paucity of clinical findings and a more frequent use of echocardiography as a screening method seem essential to improve the prognosis of patients with S aureus endocarditis. Involvement of the central nervous system constitutes a relative indication of early valve replacement.

Coexistence of mitochondrial DNA and β myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure

ObjectiveTo investigate the possible coexistence of mitochondrial DNA (mtDNA) mutations in patients with β myosin heavy chain (βMHC) linked hypertrophic cardiomyopathy (HCM) who develop congestive heart failure.DesignMolecular analysis of βMHC...

Prognosis after hospitalization for acute myocardial infarction not accompanied by typical ischemic chest pain

Although ischemic-type chest pain generally identifies acute myocardial infarction (AMI), some patients are hospitalized for AMI without this symptom. Long-term mortality and morbidity after AMI presenting with alternative warning symptoms have not been examined previously. We therefore assessed the prognostic implications of the absence of typical chest pain as well as other recognized risk predictors in patients hospitalized with AMI. Data were obtained during the Multicenter Diltiazem Postinfarction Trial. Pain status and other baseline characteristics were determined prospectively by study coordinators according to simple, prespecified criteria. Patients were then examined every 3 to 4 months until trial completion. We applied chi-square methods, life-table analysis, and multivariate analysis to assess the strength and independence of prognostic power associated with each baseline variable. Of 2,464 patients enrolled 3 to 15 days after enzyme-documented AMI, 115 patients lacked typical ischemic-type chest in on presentation (the "nonpainful" group). After 25 months' mean follow-up, cardiac mortality was 20% for nonpainful patients and 10% for 2,349 patients with typical pain (the "painful" group), P < 0.001. Similar increments were seen in total deaths (27% nonpainful versus 13% painful, P < 0.001) and cardiac events, namely, cardiac death or nonfatal reinfarction (24% nonpainful versus 17% painful, P = 0.001). Late congestive heart failure was more frequent (17% nonpainful versus 7% painful, P < 0.001), but unstable angina was less (6% nonpainful versus 16% painful, P = 0.005). At outset, nonpainful patients had more left ventricular dysfunction and diabetes mellitus. However, nonpainful AMI predicted worse outcome even when these problems were absent. Logistic regression confirmed greater cardiac death risk in the nonpainful group (hazard ratio = 2.05) and showed that predictive power of nonpainful status was independent of baseline ejection fraction, Holter data, concomitant diabetes mellitus, and other covariates. Patients hospitalized with nonpainful AMI are much more likely to experience late cardiac death or congestive heart failure than are patients with painful AMI. In part, this probably reflects more ventricular damage with alternative warning symptoms such as dyspnea. However, our data suggest that defective perception of warning pain also provides a long-term risk to life that is independent of previously known predictors of poor outcome.

Early versus late congestive heart failure after initially uncomplicated anterior wall acute myocardial infarction

We determined the incidence and clinical, noninvasive, and angiographic variables contributing to postdischarge early (< or = 3 months) and late (> 3 months) congestive heart failure (CHF) after anterior wall acute myocardial infarction. The patient cohort consisted of 94 consecutive patients < 65 years of age who underwent predischarge exercise thallium-201 planar scintigraphy, rest radionuclide angiography, and coronary arteriography. At a mean of 49 months of follow-up, 10 of the 68 medically managed patients developed early CHF, and 10 had late CHF. The 10 patients with early CHF had significantly higher peak creatine kinase values (2,494 vs 1,032 IU/L, p = 0.01), and at discharge, a lower left ventricular (LV) ejection fraction (28 +/- 11% vs 41 +/- 11%, p < 0.02), more persistent thallium-201 defects (3.4 +/- 1.2 vs 2.1 +/- 1.2, p < 0.02), and fewer stress-induced redistribution defects (1.4 +/- 1.1 vs 0.4 +/- 1.1, p < or = 0.05) than those with late CHF. The early group had less multivessel disease (40% vs 90%, p < or = 0.03). Fifty percent (5 of 10) of patients who developed late CHF did so after a recurrent infarction compared with 10% (1 of 10) in the early CHF group (p < 0.07) and 8% in the group without CHF (p < 0.003). The 26 patients who underwent bypass surgery within 3 months had an LV ejection fraction and extent of ischemia and extent of angiographic stenoses comparable to patients with late CHF. None required hospitalization for CHF or had sustained a recurrent infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

904-53 Left Ventricular Structure and Function Eleven Years After Doxorubicin Treatment for Childhood Leukemia: Is this a Restrictive Cardiomyopathic Process?

We previously characterized the progressive abnormalities of left ventricular (LV) structure and function in 115 survivors of childhood acute lymphoblastic leukemia 6.4 years (mean) after completion of doxorubicin therapy. 65% of patients having received &gt;228 mg/m 2 of doxorubicin had either increased afterload or decreased contractility, or both. Progressive increases in afterload due to a thin LV wall appeared related to an inability to increase LV mass in response to somatic growth. Of these 115 patients, 36 have died, relapsed, or are no longer followed at our institution. 8 patients had both early and late congestive heart failure. Findings noted in patients with late heart failure included normal LV size in the setting of a mean LV fractional shortening &lt;10%, as well as frequent pulmonary hypertension, increased pulmonary resistance, and left atrial dilation. We wished to characterize the late outcome of doxorubicin cardiotoxicity by reviewing the long-term echocardiographic findings of this cohort. The remaining 79 of the original 115 patients have had echocardiographic follow-up 11.1 years (mean) after completing doxorubicin. Changes in LV structure and function adjusted for age or body surface area at 3 time points were compared: prior to doxorubicin (A), 6.4 years after doxorubicin (B), and 11.1 years after doxorubicin (C). LV fractional shortening fell from normal at A to significantly depressed at B, and remained stable but depressed at C. LV mass was normal for body surface area at A, below normal at B, and continued to become more abnormal at C (p = 0.001). LV wall thickness was normal for body surface area at A below normal at B, and continued to become more abnormal at C(p = 0.03). LV end-diastolic dimension was normal for body surface area at A and B, but during the subsequent 4.7 years, a significant fall in LV end-diastolic dimension for body surface area occurred (p = 0.03). LV afterload increased significantly from A to B, but remained elevated without further increase at C. LV contractility remained normal at all 3 times. In conclusion, the fall in LV dimension to subnormal levels with increasing follow-up, in spite of a reduced mass:volume ratio, is the pattern seen in restrictive cardiomyopathy with a loss of the capacity of the LV to dilate. Both the echocardiographic and clinical findings suggest that the moderate to long term course of children treated with boluses of doxorubicin may follow the clinical findings of a restrictive cardiomyopathic process with decreased LV compliance and a small thin-walled LV.

Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group.

The Multicenter Diltiazem Postinfarction Trial (MDPIT) reported no consistent diltiazem effect on new or worsened congestive heart failure (CHF) during 12-52 months' follow-up after acute myocardial infarction. This was puzzling in light of the observation that patients with findings suggesting left ventricular dysfunction (LVD) at baseline on diltiazem had more cardiac events (cardiac mortality or recurrent nonfatal infarction) than such patients on placebo. We hypothesized that diltiazem increased the frequency of late CHF as well as of cardiac events, but only in patients predisposed by LVD. Using the same characterizing variables as the primary MDPIT analysis, we found that patients with pulmonary congestion, anterolateral Q wave infarction, or reduced ejection fraction (EF) at baseline were more likely to have CHF during follow-up than those without these markers of LVD. CHF was particularly frequent in the patients with LVD who were randomized to diltiazem. Among those with a baseline EF of less than 0.40, late CHF appeared in 12% (39/326) receiving placebo and 21% (61/297) receiving diltiazem (p = 0.004). Life table analysis in patients with an EF of less than 0.40 confirmed more frequent late CHF in those taking diltiazem (p = 0.0017). In addition, the diltiazem-associated rise in the frequency of late CHF was progressively greater with increasingly severe decrements in baseline EF. This diltiazem effect was absent in patients with pulmonary congestion at baseline but an EF of 0.40 or more, suggesting a unique association between diltiazem-related late CHF and systolic LVD.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular dilatation and failure post-myocardial infarction: Pathophysiology and possible pharmacologic interventions

An important antecedent to the development of late congestive heart failure is left ventricular dilatation and remodeling following myocardial infarction, which occurs in 30-40% of acute anterior transmural infarcts. Dilatation and remodeling commence within the first 24 hours following myocardial infarction and may be steadily progressive over months to years. Both the infarcted and uninfarcted regions of the myocardium are equally involved in the process. The remodeling process comprises left ventricular wall thinning (mainly due to cell slippage), chamber dilatation, and compensatory hypertrophy of the uninfarcted segment of the myocardium. The hypertrophy may initially be physiologic but may ultimately become a pathologic process, and thereby contribute to pump dysfunction. The possible reasons why the ventricular hypertrophy may ultimately be dysfunctional include alterations in local architecture and their sequelae alone or in concert with local changes in the beta-adrenergic, alpha-adrenergic, or renin angiotensin systems. At the present time, there are encouraging data to suggest that nitroglycerin, or the angiotensin converting enzyme inhibitor captopril, may ameliorate this process.

Southwestern Internal Medicine Conference: The Prevention of Congestive Heart Failure: Left Ventricular Dilation and its Management

Left ventricular dilation and remodelling occur in 35-40% of anterior transmural myocardial infarcts and these events are important antecedents to the development of late congestive heart failure. This process commences within the first 24 hours following myocardial infarction and may be steadily progressive over months to years. Both the infarcted and the uninfarcted regions of myocardium are equally involved in the process. Thinning of the left ventricular wall occurs mainly as a result of cell slippage. In addition, compensatory hypertrophy occurs in the uninfarcted segment of the myocardium. While this hypertrophy may initially be physiological, it ultimately appears to become a pathological process and thereby contributes to pump dysfunction. At the present time there are encouraging data to suggest that nitroglycerin, administered in the setting of the acute infarction, or the angiotensin converting enzyme inhibitor captopril, may ameliorate this process. Whether a patent infarct related artery further limits dilation is uncertain and is currently under investigation.

Preoperative exercise capacity in symptomatic patients with aortic regurgitation as a predictor of postoperative left ventricular function and long-term prognosis.

Forty-five symptomatic patients with aortic regurgitation underwent graded treadmill exercise testing before operation. Twenty-seven patients (group A) could not complete stage I of the National Institutes of Health exercise protocol because of limiting symptoms (exercise duration less than or equal to 22.5 minutes); 18 patients (group B) completed this stage without limiting symptoms (exercise duration > 22.5 minutes). Patients in group A had higher resting pulmonary capillary wedge pressures (mean 19 vs 13 mm Hg, p < 0.05) and left ventricular (LV) end-diastolic pressures (mean 24 vs 16 mm Hg, p < 0.05) than those in group B, but did not differ with respect to LV systolic dimension or fractional shortening by echocardiography or LV ejection fraction at rest or during exercise by radionuclide cineangiography. Among 32 patients with subnormal preoperative LV fractional shortening on echo, nine of 17 in group A and 0 of 15 in group B have died (p < 0.01); seven of the nine deaths were from late congestive heart failure. Group A patients also had less decrease postoperatively in LV diastolic size by echocardiography (mean decrease 8 vs 23 mm, p < 0.001) and less increase postoperatively in LV ejection fraction during exercise by radionuclide cineangiography (mean increase 11% vs 23%, p 0.05) than group B patients. No group A patient and 60% of group B patients had normal exercise ejection fractions postoperatively (p < 0.01). The differences in postoperative mortality and function were not predicted by the differences in preoperative hemodynamics between the two groups. Thus, exercise capacity is imprecise in assessing preoperative LV function in symptomatic patients with aortic regurgitation, but is useful in predicting long-term survival after operation and reversibility of LV dilatation and systolic dysfunction.