HomeCirculationVol. 138, No. 11Recent Legislation, Public Policy Changes, and Women's Cardiovascular Health Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBRecent Legislation, Public Policy Changes, and Women's Cardiovascular HealthDisproportionate Burden Nanette K. Wenger, MD, Beverly H. Lorell, MD and C. Noel Bairey Merz, MD Nanette K. WengerNanette K. Wenger Nanette K. Wenger, MD, Emory University School of Medicine, Division of Cardiology, 49 Jesse Hill Jr Drive SE, Atlanta, GA 30303. Email E-mail Address: [email protected] Emory University School of Medicine, Emory Heart and Vascular Center, Emory Women's Heart Center, Atlanta, GA (N.K.W.). , Beverly H. LorellBeverly H. Lorell FDA and Life Science Group, King & Spalding LLP, Atlanta. GA (B.H.L.). and C. Noel Bairey MerzC. Noel Bairey Merz Barbra Streisand Women's Heart Center, Linda Joy Pollin Women's Health Program, Erika J. Glazer Women's Heart Research Initiative, Preventive Cardiac Center, Cedars-Sinai Medical Center, Los Angeles, CA (C.N.B.M.). Originally published10 Sep 2018https://doi.org/10.1161/CIRCULATIONAHA.118.034612Circulation. 2018;138:1082–1084Cardiovascular disease (CVD) remains the leading contributor to morbidity and mortality in women. Application of evidence-based, sex-specific information in clinical care has substantially decreased CVD mortality among US women from 1 in every 2 women in the year 2000 to 1 in 4 women at present. In this context, the guidance by the Department of Health and Human Services, which instructed the Centers for Disease Control and Prevention on December 26, 2017, not to use 7 words in its 2019 budget appropriation request—diversity, transgender, vulnerable, fetus, entitlement, evidence-based, and science-based—will undermine science and research integrity in women's health.1 Specific to women, because of the links between general and reproductive health, this guidance and related administration policy changes will disproportionately adversely affect women. Because CVD is the leading health threat for women of all ages, these recent legislation and public policy changes are particularly relevant to the cardiovascular community.As outlined in the World Health Organization (Promoting Health Through the Life-Course), among the 10 top issues for women's health, noncommunicable diseases such as CVD are inextricably linked to issues specific to women and girls, including breast and cervical cancer, reproductive health, HIV and sexually transmitted disease, violence against women, and growing older with fewer pensions and benefits. Given this interplay of sex-specific health issues for women, reductions in access to and funding for medical care disproportionately adversely affect women.CVD remains underaddressed in nonreproductive women's health care. In a nationally representative survey of US community women and physicians, CVD in women remained largely invisible with multiple barriers to care.2 Weight and breast health were ranked higher than CVD for women by primary care physicians. Social stigma concerning body weight is reported as a barrier to women discussing heart health.2 In another study, women reported 3 specific barriers to CVD diagnosis and treatment: They had to struggle to take a cholesterol test; they perceived that their risk was downplayed by doctors; and their symptoms of coronary heart disease were misinterpreted when they consulted doctors for evaluation and treatment. Combined with physician-reported barriers to CVD treatment, socioeconomic issues, the cost of care, and lack of a multidisciplinary team place women disproportionately at risk for no or suboptimal CVD health care.The Patient Protection and Affordable Care Act (ACA; Public Law No. 111-148) extended healthcare coverage to ≈20 million predominantly low-income Americans. From 2013 to 2015, the uninsured rate of US women fell from 17% to 11% among those 19 to 54 years of age. This legislation promoted women's health in a number of specific ways. Before the ACA, coverage could be denied on the basis of preexisting conditions, which included pregnancy for women. Furthermore, the ACA reversed prior sex inequities by eliminating the 10% to 50% higher premiums charged to women, including women beyond reproductive age. The ACA access to the 10 "minimal essential coverage" benefit requirements is particularly relevant to CVD by prohibiting copayment for specified preventive services, including annual well visits, tobacco screening/cessation, aspirin for heart disease prevention, and screening for blood pressure, diabetes mellitus, and lipids in women and men. As a result of the ACA, 55 million women benefited from preventive services without cost sharing.3CVD risk factor detection and treatment are particularly important for women because established risk prediction scores categorize most women as low risk. Significantly underappreciated is the impact of adverse pregnancy outcomes, which often occur in young, otherwise healthy women; the "stress test" of pregnancy affects near- and far-term metabolic and cardiovascular conditions such as hypertension, diabetes mellitus, and CVD events. CVD risk calculators such as the Framingham, Reynolds, and 2013 atherosclerotic CVD disease risk scores do not incorporate these adverse pregnancy conditions, leading to potential underestimation of women's lifetime CVD risk. Among the ACA's "minimal essential coverage" are benefit requirements critical for women's cardiovascular health; examples include maternity and newborn care during which gestational hypertension, preeclampsia, and heart failure may be recognized and treated. The minimal essential coverage also affects emergency care in which women with acute myocardial infarction and stroke may be rapidly diagnosed and managed in a manner consistent with current guidelines. Many benefits and reimbursements for services for women's health not included in the ACA are also at risk of losing federal support. Specifically, the Department of Health and Human Services can decrease support for health services to women through reducing funding to support the ACA in general, reducing specific women's health services, and decreasing other non-ACA programs that support health services for women. As an example, Department of Health and Human Services cuts to Planned Parenthood are anticipated to extend beyond reproductive care to include reduced preventive health and chronic CVD risk management for the women served.Although the new administration and Congress did not "remove and replace" the ACA in 2017, the Tax Cuts and Jobs Act (Public Law No. 115-97), signed into law on December 22, 2017, is anticipated to disadvantage women's CVD health care. Effective in 2019, Section 11081 of the new tax bill repeals the financial penalty of the "individual mandate," the monetary penalty for individuals who fail to comply with the ACA requirement to maintain "minimum essential coverage." (The individual mandate itself in the ACA was not repealed.) The penalty linked to the individual mandate was the underpinning of the ACA health insurance marketplaces that attempted to ensure that the pool of insured people was balanced by healthy and sick people. The repeal of the penalty in this new tax law, rather than the individual mandate itself, is consistent with the 2012 Supreme Court decision in National Federation of Independent Business (NFIB) v Sebelius that held that Congress did not have the authority to require individuals to purchase insurance under its authority to regulate interstate commerce; instead, the court upheld the validity of the individual mandate with its penalty as a tax. We predict that repeal of the individual mandate penalty, as well as subsequent sharp increases in healthcare premiums, will lead to the failure of many women who are disproportionately economically disadvantaged to purchase comprehensive healthcare insurance, including women at high risk of CVD or with active CVD who are not yet diagnosed or treated.Some policy experts have speculated that the effects of the new tax bill on health care will be even broader than a subset of Americans "opting out" of the purchase of health insurance. As an example, in the Harvard Business Review, David Blumenthal4 called attention to the overall impact of this bill on the federal deficit over the next decade, which is likely to drive efforts to reduce federal spending. By most recent estimates, including the nonpartisan Congressional Budget Office, the new tax bill will increase the federal deficit by just under $1.5 trillion in the first 10 years. Medicare and Medicaid, together with the Children's Health Insurance Program and marketplace subsidies, historically account for 26% to 28% of annual federal budget expenditures; the White House has already proposed substantial reductions to Children's Health Insurance Program funding. The tax bill includes a waiver provision that prevents $25 billion in Medicare cuts that would normally be automatically triggered by the tax bill under budget rules. However, Blumenthal4 and others5 point out that federal healthcare programs are prime targets for future deficit reduction and could include changes in eligibility age, caps on spending per beneficiary, or higher cost sharing. Because women have higher rates of chronic CVD and disability and lower mean incomes and live longer, they have a higher dependence on both Medicare and Medicaid and will be disproportionately affected by future pressures for deficit reduction.Recent legislation and policy changes will adversely affect women's general and specific CVD health while placing a disproportionate burden on women, physicians, and society. The changes in the ACA and the new tax bill will negatively affect access to the minimal essential coverage that is critical for women's general and CVD health. These and potential future restrictions in both Medicare and Medicaid benefits will disproportionately disadvantage women.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.The opinions in this editorial are those of the authors and not their institutions.https://www.ahajournals.org/journal/circNanette K. Wenger, MD, Emory University School of Medicine, Division of Cardiology, 49 Jesse Hill Jr Drive SE, Atlanta, GA 30303. Email [email protected]eduReferences1. Sun E, Ellperin J. CDC gets list of forbidden words: fetus, transgender, diversity. Washington Post.December 15, 2017. https://www.washingtonpost.com/national/health-science/cdc-gets-list-of-forbidden-words-fetus-trasgender-diversity/2017/12/15/f503837a-elcf-11e7-89e8-edec16379010_story.html?utm_term=.fd4bd587a147. Accessed June 20, 2018.Google Scholar2. Bairey Merz CN, Andersen H, Sprague E, Burns A, Keida M, Walsh MN, Greenberger P, Campbell S, Pollin I, McCullough C, Brown N, Jenkins M, Redberg R, Johnson P, Robinson B. Knowledge, attitudes, and beliefs regarding cardiovascular disease in women: the Women's Heart Alliance.J Am Coll Cardiol. 2017; 70:123–132. doi: 10.1016/j.jacc.2017.05.024CrossrefMedlineGoogle Scholar3. The White House. Office of the Press Secretary FACT SHEET: the Affordable Care Act: healthy communities six years later.March 2, 2016. http://obamawhitehouse.archieves.gov/the-press-office-affordable-care-act-healthy-communities-six-years-later. Accessed June 20, 2018.Google Scholar4. Blumenthal D. How the new U.S. tax plan will affect health care: Harvard Business Review.December 19, 2017. https://hbr.org/2017/12/how-the-new-u-s-tax-plan-will-affect-health-care. Accessed June 20, 2018.Google Scholar5. Bindman AB. JAMA Forum: Undermining health care through tax reform.November 15, 2017. https://newsatjama.jama.com/2017/11/15/jama-forum-undermining-health-care-through-tax-reform/. Accessed June 20, 2018.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetails September 11, 2018Vol 138, Issue 11 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.034612PMID: 30354386 Originally publishedSeptember 10, 2018 Keywordscardiovascular diseaseslegislationcardiologywomenPDF download Advertisement

Background Informed consent is the cornerstone for protection of human subjects in clinical trials. However, a growing body of evidence suggests that reform of the informed consent process in the United States is needed. Methods The Clinical Trials Transformation Initiative conducted interviews with 25 experienced observers of the informed consent process to identify limitations and actionable recommendations for change. Results There was broad consensus that current practices often fail to meet the ethical obligation to inform potential research participants during the informed consent process. The most frequent single recommendation, which would affect all participants in federally regulated clinical research, was reform of the informed consent document. The interviews also identified the need for reform of clinical research review by institutional review boards, including transitioning to a single institutional review board for multi-site trials. Conclusion The consensus recommendations from the interviewees provide a framework for meaningful change in the informed consent process. Although some proposed changes are feasible for rapid implementation, others such as substantive reform of the informed consent document may require change in federal regulations.

The role of the angiotensin II type 2 (AT2) receptor in cardiac hypertrophy remains controversial. We studied the effects of AT2 receptors on chronic pressure overload-induced cardiac hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes. Left ventricular (LV) hypertrophy was induced by ascending aorta banding (AS). Transgenic mice overexpressing AT2 (AT2TG-AS) and nontransgenic mice (NTG-AS) were studied after 70 days of aortic banding. Nonbanded NTG mice were used as controls. LV function was determined by catheterization via LV puncture and cardiac magnetic resonance imaging. LV myocyte diameter and interstitial collagen were determined by confocal microscopy. Atrial natriuretic polypeptide (ANP) and brain natriuretic peptide (BNP) were analyzed by Northern blot. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2, inducible nitric oxide synthase (iNOS), endothelial NOS, ERK1/2, p70S6K, Src-homology 2 domain-containing protein tyrosine phosphatase-1, and protein serine/threonine phosphatase 2A were analyzed by Western blot. LV myocyte diameter and collagen were significantly reduced in AT2TG-AS compared with NTG-AS mice. LV anterior and posterior wall thickness were not different between AT2TG-AS and NTG-AS mice. LV systolic and diastolic dimensions were significantly higher in AT2TG-AS than in NTG-AS mice. LV systolic pressure and end-diastolic pressure were lower in AT2TG-AS than in NTG-AS mice. ANP, BNP, and SERCA2 were not different between AT2TG-AS and NTG-AS mice. Phospholamban (PLB) and the PLB-to-SERCA2 ratio were significantly higher in AT2TG-AS than in NTG-AS mice. iNOS was higher in AT2TG-AS than in NTG-AS mice but not significantly different. Our results indicate that AT2 receptor overexpression modified the pathological hypertrophic response to aortic banding in transgenic mice.

OBJECTIVE To develop a model to predict stroke-free survival and mortality over a multiyear time frame for a trial-excluded population of medically managed asymptomatic patients with significant carotid artery stenosis. METHODS We calibrated, validated, and applied a Monte Carlo microsimulation model. For calibration we adjusted general-population mortality and stroke risks to capture these risks specific to asymptomatic carotid stenosis patients. For validation, we compared model-predicted and actual stroke-free survival curves and stroke counts from a population of comparable patients. For application, the validated model predicted stroke-free survival for a hypothetical medically managed arm of a recent single-arm carotid revascularization trial. RESULTS For each month in the 60-month time frame, the model-predicted and actual calibration trial stroke-free survival curves were not statistically different (P > 0.62). In validation, the calibrated model's stroke-free survival curvematched the actual curve from an independent population; beyond 24 months, the model-predicted and actual curves were not statistically different (P > 0.32). We also compared model-predicted and actual number of strokes from the independent trial. The model predicted 187.25 strokes (95% confidence interval 161.49-213.01), while the actual number was 171.6, within 1.22 standard deviations of the simulated mean. CONCLUSIONS Given the absence of medically managed populations in recent carotid stenosis trials, our model can estimate stroke-free survival and mortality data for these patients. The model may also estimate the effectiveness of novel medical and procedural therapies for stroke prevention. These effectiveness estimates can inform the development of policies, guidelines, or cost-effectiveness analyses when only single-arm trial data exist.

Public registration of clinical trials is fundamentally important to the integrity of the medical device development process. In addition to fulfilling obligations to those study volunteers, a complete record of trial results provides the general public, clinical community, and medical device manufacturers with a more accurate understanding as to how a specific therapeutic should be used. Although the issues associated with public disclosure of clinical trials are similar to the pharmaceutical industries, the iterative nature of device development introduces differences in what type of information needs to be disclosed during development and commercialization. The Second Dartmouth Device Development Symposium (3D2) held in October 2004 brought together thought leaders representing many of the stakeholders associated with medical device development. This consensus document arising from the proceedings of the 3D2 is offered to provide background to these issues and recommend pathways to implementation of device trial registration.

Focus on Alternative and Complementary TherapiesVolume 10, Issue 1 p. 50-51 Heart failure patients improve quality of life and exercise capacity with tai chi First published: 14 June 2010 https://doi.org/10.1211/fact.10.1.0027Read the full textAbout ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume10, Issue1March 2005Pages 50-51 RelatedInformation

Background We tested the hypotheses that long-term administration of the angiotensin-converting enzyme (ACE) inhibitor fosinopril will regress hypertrophy, modify the transition to heart failure, and prolong survival in rats with chronic left ventricular (LV) pressure overload due to ascending aortic stenosis. Methods and Results Aortic stenosis was created in weanling male Wistar rats by a stainless steel clip placed on the ascending aorta. Age-matched control animals underwent a sham operation (Sham group, n=57). Six weeks after surgery, rats with aortic stenosis were randomized to receive either oral fosinopril 50 mg * kg 1̀ d-1 (Fos/LVH group, n=38) or no drug (LVH group, n=36) for 15 weeks. Pilot studies confirmed that this dosage produced significant inhibition of LV tissue ACE in vivo. Animals were monitored daily, and survival during the 15-week treatment period was assessed by actuarial analysis. At 15 weeks, in vivo LV systolic and diastolic pressures and heart rate were measured. To assess contractile function, the force-calcium relation was evaluated by use of the isovolumic buffer-perfused, balloon-in-LV heart preparation at comparable coronary flow rates per gram LV weight. Quantitative morphometry was performed. Mortality during the 15-week trial was significantly less in the Fos/LVH group than in the LVH group (3% versus 31%, P<.005). No deaths occurred in the Sham group. In vivo LV systolic pressure was similar between Fos/LVH and LVH hearts (223+10 versus 232±9 mm Hg) and significantly higher than the Sham group (99±3 mm Hg, P<.05). In vivo LV diastolic pressure was significantly

PURPOSE: To examine the effects of a 12-week tai chi program on quality of life and exercise capacity in patients with heart failure.METHODS: Thirty patients with chronic stable heart failure and left ventricular ejection fraction less than or equal to 40% (mean [ +/- SD] age, 64 +/- 13 years; mean baseline ejection fraction, 23% +/- 7%; median New York Heart Association class, 2 [range, 1 to 4]) were randomly assigned to receive usual care (n = 15), which included pharmacologic therapy and dietary and exercise counseling, or 12 weeks of tai chi training (n = 15) in addition to usual care. Tai chi training consisted of a 1-hour class held twice weekly. Primary outcomes included quality of life and exercise capacity. Secondary outcomes included serum B-type natriuretic peptide and plasma catecholamine levels. For 3 control patients with missing data items at 12 weeks, previous values were carried forward.RESULTS: At 12 weeks, patients in the tai chi group showed improved quality-of-life scores (mean between-group difference in change, -25 points, P = 0.001), increased distance walked in 6 minutes (135 meters, P = 0.001), and decreased serum B-type natriuretic peptide levels (-138 pg/mL, P = 0.03) compared with patients in the control group. A trend towards improvement was seen in peak oxygen uptake. No differences were detected in catecholamine levels.CONCLUSION: Tai chi maybe a beneficial adjunctive treatment that enhances quality of life and functional capacity in patients with chronic heart failure who are already receiving standard medical therapy. (C) 2004 by Elsevier Inc.

The biochemical basis of the mechanism of vasodilatation by nitroglycerin (NTG) has not been previously investigated in man. However, evidence from in vitro studies suggests that NTG induces activation of guanylate cyclase via a series of enzymatic reactions that are modulated by the availability of sulfhydryl groups. Cysteine appears to be particularly effective in potentiating guanylate cyclase activation by NTG. To determine whether hemodynamic responsiveness to NTG in man might be modulated by sulfhydryl availability, concentration-response curves for effects of intravenously infused NTG on mean arterial pressure (MAP) and mean pulmonary capillary wedge pressure (PCW) were obtained in 10 patients undergoing cardiac catheterization for investigation of chest pain. NTG infusion was repeated 10 min after the intravenous infusion of 100 mg/kg of the cysteine source Nacetylcysteine (NAC). NAC induced no significant hemodynamic effect, but after NAC infusion there was a significant reduction both in the NTG infusion rate associated with a 10% fall from control values in MAP (25.8 ± 8.3 to 9.3 ± 2.7 ,g/min; p < .01) and in the infusion rate inducing a 30% reduction in PCW (13.6 + 4.6 to 4.2 + 1.6 Ag/min; p < .02). In a control group of five patients who received no NAC, there was no significant change in responsiveness to NTG between infusions. It is concluded that NAC potentiates the vasodilator effects of NTG in man. This suggests that sulfhydryl availability and/ or redox state may be determinants of in vivo responsiveness to NTG. Circulation 68, No. 6, 1247-1253, 1983. NITROGLYCERIN (NTG) has been used as an antianginal agent for over 100 years.1 Although the efficacy ofNTG in the treatment of myocardial ischemia and in some clinical settings of congestive heart failure is now well established, controversy remains concerning its mechanism of action at both the hemodynamic and cellular levels.2 Furthermore, the fundamental biochemical mechanisms of action of NTG are not well understood. Needleman et al.3 observed that incubation of rabbit aortic strips with the sulfhydryl alkylating agent ethacrynic acid led to a reduction in sensitivity to NTG. It was further suggested that tolerance to NTG could be induced by oxidation of sulfhydryl groups.4 These observations have led to the suggestion that the vasodilator action of NTG is closely linked to the availability of critical SH groups in vascular smooth muscle. From the Cardiovascular Division and the Department of Medicine, Brigham and Women's Hospital, and Department of Medicine. Harvard Medical School, Boston. Address for correspondence: Elliott M. Antman, M.D.. Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. Received May 4. 1983; revision accepted Aug. 18. 1983. *Present address: Departments of Cardiology and Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia. Vol. 68, No. 6, December 1983 More recent studies using isolated tissues have tended to support this postulated role of sulfhydryl groups in modulating responses to NTG. There is now evidence consistent with the view that NTG indirectly activates guanylate cyclase and that the vasodilator effects of NTG are mediated by increased intracellular concentrations of guanosine 3', 5'-monophosphate (cyclic GMP).5. 6 Although possible modulation of this process by sulfhydryl availability may occur at several points, available data suggest that S-nitrosothiol compounds, formed by interaction ofNTG with tissue sulfhydryl, activate guanylate cyclase.7' 8 Of a number of S-nitrosothiols tested, S-nitroso-cysteine was most effective in stimulating guanylate cyclase activation.7 Thus production of S-nitrosothiols by interaction of NTG with tissue sulfhydryl groups may be an essential step in the development of NTG-induced vasodilation. Variability in tissue sulfhydryl availability might also offer an explanation for the wide disparity in hemodynamic responsiveness to NTG at any particular plasma NTG concentration.9 However, to date no studies have been carried out to determine whether availability of sulfhydryl, or particularly cysteine, modulate responsiveness to NTG in intact animals or man. The current-

An increase in left ventricular diastolic pressure has been repeatedly observed during angina in patients with coronary artery stenoses and regional demand ischemia, but the role of relaxation abnormalities versus left ventricular segmental dyssynchrony is controversial. In contrast, patients with angina due to aortic stenosis are likely to have diffuse rather than segmental ischemia and thus may provide an alternative model for examining the diastolic physiology of angina in man. Accordingly, we examined the hemodynamic manifestations of angina in eight patients with aortic stenosis without significant coronary artery disease. Angina was induced by pacing tachycardia, and hemodynamic and echocardiographic variables were measured in the control period and during angina in the beats immediately after cessation of pacing. Heart rate (control vs angina, 69 + 12 vs 70 + 11 beats/min, p = NS) and left ventricular peak systolic pressure (207 39 vs 222 22 mm Hg, p = NS) were similar in the control and postpacing angina periods. Left ventricular end-diastolic pressure, on the other hand, was significantly higher during postpacing angina (15 ± 7 vs 28 8 mm Hg, p < .01). The time constant of left ventricular pressure decline during isovolumetric relaxation (TL), calculated as the slope of a linear fit of the natural log of pressure vs time, increased from 44 + 5 to 51 + 7 msec (p < .05); the time constant TD, derived from the slope of a linear fit of dP/dt vs pressure, also increased slightly, although the change was not statistically significant (69 + 5 vs 75 + 5 msec, p = .06). High-quality two-dimensional targeted M mode echocardiograms in the control and postpacing periods were available in four patients; left ventricular end-diastolic and end-systolic dimensions and percent fractional shortening were unchanged. The left ventricular diastolic pressure-volume relationship and pressure-wall thickness relationship were shifted upward during angina in these patients. We conclude that angina in patients with aortic stenosis is accompanied by a substantial and reversible increase in left ventricular end-diastolic pressure; this increase appears to be due in part to an impairment of diastolic distensibility of the left ventricle and left ventricular relaxation. These findings, which are similar to those observed during pacing-induced angina in patients with coronary stenoses, suggest that the increase in left ventricular end-diastolic pressure that occurs during angina is a manifestation of demand ischemia per se, and does not depend on the presence of dyssynergistic contraction of ischemic and nonischemic regions. Circulation 74, No. 4, 675-683, 1986. ANGINA is a common symptom in patients with aortic stenosis, and is frequently the presenting complaint.' In patients with coronary artery disease, angina provoked by exercise or pacing tachycardia is often acFrom the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory of Beth Israel Hospital, and the Department of Medicine (Cardiovascular Divisions) of Beth Israel Hospital and the Brigham and Women's Hospital and Harvard Medical School, Boston. Address for correspondence: Beverly H. Lorell, M.D., Cardiovascular Division, Beth Israel Hospital, 330 Brookline Ave., Boston, MA 02215. Received Dec. 20, 1985; revision accepted June 26, 1986. Dr. Lorell was supported in part by grant HL31371-OlA1 from the National Heart, Lung, and Blood Institute. Dr. Bourdillon was supported by a British-American Research Fellowship of the British Heart Foundation, and the American Heart Association. *Current address: Cardiac Unit, Massachusetts General Hospital, Boston, MA 02114. **Current address: Cardiology Division, University of Michigan Hospital, Ann Arbor, MI 48109. Vol. 74, No. 4, October 1986 companied by a rise in the left ventricular end-diastolic pressure, associated with a decrease in diastolic distensibility.2` The mechanisms that are responsible for this transient impairment in left ventricular diastolic function during demand ischemia are unclear. Abnormalities of the isovolumetric relaxation period have been repeatedly observed during demand ischemia in patients with coronary stenoses3 6 8. 9 and in experimental animal preparations of coronary stenoses.' ` These observations suggest that the increase in left ventricular diastolic pressure during angina may be related to impaired inactivation of the myosin-actin interaction in ischemic myocardium.2' 13 On the other hand, regional dyssynchrony of ischemic and nonischemic segments is an alternate mechanism that has been proposed. 1-16

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Neuregulins and their erbB receptors are essential for cardiac development and postulated to be cardioprotective in the presence of injury in the postnatal heart. We tested the hypothesis that the development of doxorubicin-induced cardiotoxicity in vivo is more severe in mice with heterozygous knockout of the neuregulin-1 gene (NRG-1(+/-)) compared with wild-type mice (WT). Three-month old NRG-1(+/-) and WT mice were injected with a single dose of doxorubicin (20 mg/kg ip). Survival was analyzed by the Kaplan-Meier approach. Left ventricular (LV) function and signaling pathways were analyzed 4 days after treatment. Fifteen days after treatment, survival was significantly lower in doxorubicin-treated NRG-1(+/-) mice (NRG-1(+/-)-Dox) compared with doxorubicin-treated WT mice (WT-Dox) (15% vs. 33%, P < 0.01). LV mass was significantly lower in NRG-1(+/-)-Dox but not in WT-Dox compared with nontreated animals. LV systolic pressure and LV midwall fractional shortening were significantly lower in NRG-1(+/-)-Dox compared with WT-Dox mice. LV protein levels of NRG-1, erbB2, and erbB4 receptors were similar in WT-Dox and NRG-1(+/-)-Dox mice. However, levels of phosphorylated erbB2, Akt, and ERK-1/2 were significantly decreased in NRG-1(+/-)-Dox compared with WT-Dox mice. A significant decrease in phosphorylated P70S6K levels was also observed in NRG-1(+/-)-Dox compared with nontreated NRG-1(+/-) mice. These results demonstrate that heterozygous knockout of the neuregulin-1 gene worsens survival and LV function in the presence of doxorubicin-induced cardiac injury in vivo. This is associated with the depression of activation of the erbB2 receptor as well as Akt, p70S6K, and ERK-1/2 pathways.