This chapter contains sections titled: Forkhead transcription factors Functions of FoxO Cardiovascular forkhead effects Metabolic forkhead effects Histone acetylation and deacetylation Sirtuin deacetylases Sirtuin regulation Antiinflammatory, cardiovascular, and myocyte sirtuin effects Sirtuin effects on metabolism Sirtuins and cell longevity Forkhead deregulation and insulin resistance Paradoxical effect of nutrition versus stress on cell death suppression Conclusion Bibliography

Almost 5 million individuals in the United States are diagnosed with chronic heart failure (HF), and the prevalence is increasing. Angiotensin-converting enzyme (ACE) inhibitors and beta blockers, neurohormonal antagonists that block the renin-angiotensin system (RAS) and the sympathetic nervous system, respectively, have been shown in clinical trials to reduce morbidity and mortality in patients with HF, and these therapies are now integral components of standard HF treatment. Yet, morbidity and mortality rates in HF remain unacceptably high, and the limitations of current standard therapies are becoming increasingly apparent. About 10% of patients with HF are unable to tolerate ACE inhibitors, often because of cough. In addition, ACE inhibition may not completely block the RAS because angiotensin H, the main end product of the RAS, can be generated via non-ACE enzymatic pathways. Angiotensin R receptor blockers (ARBs) may exert more complete RAS blockade than ACE inhibitors by interfering with the binding of angiotensin II at the receptor level, regardless of the enzymatic pathway of production. They are also better tolerated than ACE inhibitors and have been shown to improve symptoms and function in clinical trials in patients with HF. These factors provide a strong rationale for the study of the clinical effects of ARBs in patients with HF.

Almost 5 million individuals in the United States have chronic heart failure (HF), which is increasing in prevalence. Angiotensin-converting enzyme (ACE) inhibitors are standard therapies for HF, although more than 10% of patients with HF are unable to tolerate these agents. Furthermore, ACE inhibitors may not provide complete blockade of the renin-angiotensin system (RAS) in the long term. Because angiotensin II receptor blockers (ARBs) may block the RAS more completely than ACE inhibitors and are better tolerated, several large-scale ARB trials have been performed exploring their potential role in treating patients with symptomatic HF and left ventricular systolic dysfunction. The Losartan Heart Failure Survival Study (ELITE II) demonstrated no significant differences in morbidity and mortality between the ARB losartan and the ACE inhibitor captopril among elderly patients with HF. The Valsartan Heart Failure Trial (Val-HeFT) demonstrated reductions in hospitalizations for HF with the ARB valsartan when added to standard HF therapy, with no effect on mortality. Both trials suggested a potential negative interaction between ARB and beta-blocker therapy. The Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program demonstrated significant reductions in morbidity and mortality with the ARB candesartan in patients withHF due to systolic dysfunction, with or without ACE inhibitors and with or without beta blockers. Thus, the addition of ARBs to the treatment regimen of patients with symptomatic HF should be strongly considered.

Almost 5 million individuals in the United States are diagnosed with chronic heart failure (HF), and the prevalence is increasing. Angiotensin‐converting enzyme (ACE) inhibitors and beta blockers, neurohormonal antagonists that block the renin‐angiotensin system (RAS) and the sympathetic nervous system, respectively, have been shown in clinical trials to reduce morbidity and mortality in patients with HF, and these therapies are now integral components of standard HF treatment. Yet, morbidity and mortality rates in HF remain unacceptably high, and the limitations of current standard therapies are becoming increasingly apparent. About 10% of patients with HF are unable to tolerate ACE inhibitors, often because of cough. In addition, ACE inhibition may not completely block the RAS because angiotensin II, the main end product of the RAS, can be generated via non‐ACE enzymatic pathways. Angiotensin II receptor blockers (ARBs) may exert more complete RAS blockade than ACE inhibitors by interfering with the binding of angiotensin II at the receptor level, regardless of the enzymatic pathway of production. They are also better tolerated than ACE inhibitors and have been shown to improve symptoms and function in clinical trials in patients with HF. These factors provide a strong rationale for the study of the clinical effects of ARBs in patients with HF.

Epidemiological studies suggest that women with heart failure differ from men with heart failure in that their survival is better. Therapeutic trials have not clearly demonstrated a survival benefit for women. This study was to determine the tolerance for high doses of angiotensin-converting enzyme (ACE) inhibitor-nitrates in women versus men and to compare their symptomatic response, exercise tolerance, and ventricular functional improvement over 1 year. Eighty-eight sequential patients with heart failure, 54 men and 34 women with left ventricular ejection fraction < or = 35%, were prospectively followed for 1 year. For all patients, ACE inhibitor-nitrate therapy was intensified. Each patient had three 6-monthly echocardiograms at baseline, at 6 months, and at 1 year, and metabolic stress testing. Patients were 57.3 +/- 12.3 years old, with New York Heart Association (NYHA) class severity 2.6 +/- 1.0. Lisinopril dosages were raised from 14 +/- 14 mg/day to 57 +/- 26 mg/day, isosorbide mononitrate from 15 +/- 27 mg/day to 126 +/- 72 mg/day, and carvedilol (n = 34) to 17 +/- 16 mg/day. Women and men were epidemiologically comparable, with similar baseline echocardiographic parameters (left ventricular ejection fraction 19% +/- 7% versus 17% +/- 6%, respectively). Both tolerated up-titration in medical therapy. Final 12-month ejection fractions were equivalent for women and men at 34% +/- 17% and 34% +/- 13%, respectively, with similar improvements in left ventricular diameters. At 1 year, women had higher resting heart rates and remained more symptomatic with lower exercise capacity. However, the relative changes in NYHA status and aerobic capacity were similar for women and men. Thus, both women and men tolerated uptitrated ACE inhibitor-nitrate medical therapy, with comparable reversal of heart failure remodeling. Although women continued to be more symptomatic than men, relative improvements in symptomatic status, in exercise capacity, and in hospitalization rate were equivalent.

Congestive heart failure (CHF) is a major medical problem with significant hospital costs. The authors developed an inpatient disease management program for CHF in a community hospital setting to determine if it is possible to: 1) increase implementation of Agency for Health Care Policy and Research criteria for CHF; 2) improve the quality of patient care, while lowering length of stay and treatment cost for CHF; and 3) maintain nursing staff satisfaction. The program encompassed a clinical pathway incorporating Agency for Health Care Policy and Research criteria for CHF, CHF education, and patient educational materials. When compared to "unmanaged" patients (n=197) not participating in the algorithm due to physician choice, "managed" patients (n=396) had significantly increased documentation of left ventricular dysfunction and of angiotensin-converting enzyme inhibitor use. In contrast to unmanaged patients, managed patients had a significantly lower length of stay (3.9+/-2.2 vs. 6.1+/-2.8 days; p<0.0001) with a significant reduction in cost per patient ($4404+/-$1989 vs. $6828+/-$3347; p<0.0001). These changes were sustained in follow-up over 1 year and were associated with an improvement in nursing staff education and nursing care. Thus, a disease management program for CHF can be successfully implemented in a general community hospital setting, achieving improved compliance with Agency for Health Care Policy and Research treatment criteria and enhancing patient care, while reducing length of stay and cost.

Background: Intravenous inotropic intervention in congestive heart failure is generally associated with a poor prognosis and is largely used as a "bridge" to mechanical support or heart transplantation. Hypothesis: We hypothesized that the inotropic support afforded by dobutamine may serve as a bridge to the introduction and intensification of angiotensin-converting enzyme (ACE) inhibitor-nitrate therapy.Methods: We studied the efficacy of transitioning inotrope-dependent patients in endstage heart failure from intravenous dobutamine to high-dose ACE inhibitor-nitrates, with 1-year follow-up. Forty-nine sequential dobutamine-dependent patients with left ventricular ejection fraction (LVEF) 17 +/- 17% were treated with increasing lisinopril (1.9 +/- 1.5 to 46 +/- 28 mg/day) and isosorbide dinitrate (7 +/- 6 to 229 +/- 161 mg/day). Outpatient dobutamine was continued or repeat infusions pursued, as indicated, and dobutamine was tapered when feasible.Results: During the following year, 14 of 49 patients required repeat dobutamine, with home treatment with dobutamine for 6.3 +/- 3.7 months (n = 5). At 1 year, New York Heart Association (NYHA) classification improved from 3.6 +/- 0.5 to 1.9 +/- 1.0, p < 0.0001; yearly hospitalizations fell from 2.7 +/- 2.3 to 1.2 +/- 3.0, p = 0.02; and LVEF rose from 17 +/- 7% to 24 +/- 11%, p < 0.0001. At 1 year, 14 patients who remained dobutamine dependent had significantly more severe symptoms than dobutamine-independent patients (n = 35). Transplant or death occurred in 7 of 14 patients with follow-up dobutamine, and in 5 of 35 patients free of subsequent dobutamine, p = 0.03. Patients with poor outcome (transplant n = 10, death n = 12) continued to be more limited (NYHA 2.7 +/- 0.9 vs. 1.7 +/- 0.9, p = 0.0002), with more follow-up hospitalizations (3.6 +/- 5.3 vs. 0.6 +/- 0.8, p = 0.0004), and no improvement in LVEF (17 +/- 8 vs. 28 +/- 11%, p = 0.003).Conclusions: Of the patients on dobutamine inotropic support, 70% were successfully transitioned to ACE inhibitor-nitrate therapy, with improved symptoms and LVEF and with reduced hospitalizations and follow-up dobutamine or transplant. Thirty percent of patients with continued need for dobutamine had a significantly poorer 1-year clinical outcome.

BACKGROUND AND HYPOTHESIS:Although medical therapy may normalize echocardiographic left ventricular (LV) systolic function in selected patients with cardiomyopathy, other patients experience no change or a further deterioration in heart failure remodeling. Our aim was to determine what clinical or echocardiographic parameters predict a beneficial therapeutic response.METHODS:We prospectively followed biannual clinical and echocardiographic assessments in 215 patients. Forty-six of these patients ("Nonresponders") experienced no change or a decline in LV ejection fraction at 6 months. Of the 148 patients who improved LV function, 21 ("Responders") normalized LV systolic function at 6 months. Only Responders (n = 21) and Nonresponders (n = 46) were compared.RESULTS:On average, these 67 patients were 54 +/- 12 years old with 4.5 +/- 3.3 years of heart failure. At 6 months, following up-titration of angiotensin-converting enzyme inhibitors and nitrates, Responder LV ejection fraction rose from 22 +/- 6 to 50 +/- 5% with improvement in New York Heart Association classification (2.6 +/- 0.8 to 1.5 +/- 0.8, p = 0.001). These patients had significantly more favorable clinical and echocardiographic outcomes versus Nonresponders despite comparable medical therapy. All baseline demographic, clinical, and echocardiographic variables were equivalent, except for initial LV end-diastolic diameter which differentiated Nonresponders (7.1 +/- 0.7 cm) from Responders (6.1 +/- 0.8 cm), p = 0.007.CONCLUSION:Thus, although heart failure therapy improves LV systolic function in a majority of patients, with normalization in up to 10% of patients, significant LV enlargement may render remodeling unresponsive to pharmacologic intervention, with a potential future need for alternative mechanical or surgical intervention.

Objective To describe the effects of exercise training on chronotropic incompetence in patients with stable heart failure, as measured by their inability to achieve a peak exercise heart rate greater than 85% of maximum.Background Exercise intolerance and chronotropic incompetence are characteristic of patients with heart failure. Exercise training improves exercise capacity in these patients; however, to what extent reversal of chronotropic incompetence contributes to such a response remains uncertain.Methods Fifty-one patients undergoing standard medical therapy were randomly assigned to a 24-week exercise training program or a no exercise control group. Twenty-one of 26 patients assigned to the exercise group and 22 of 25 control patients completed the study. Peak oxygen consumption, resting and exercise plasma norepinephrine level, and quality of life (Living With Heart Failure Questionnaire) were assessed.Results A significant (P <.05) increase in peak heart rate was observed in the exercise group (9 +/- 3 beats/min) when compared with the central group (1 +/- 3 beats/min). Among exercise-trained patients with chronotropic incompetence at baseline (n = 14), the increase in peak heart rate at week 24 was 12 +/- 3 beats/min. Peak oxygen consumption was significantly (P <.05) increased in the exercise group (204 +/- 57 mL/min) versus the control group (72 +/- 33 mL/min). Health-related quality of life was not significantly changed with exercise training. Twenty-four weeks of exercise training induced a greater (P <.05) reduction in plasma norepinephrine at rest and during exercise in patients with a nonischemic cardiomyopathy versus those with ischemic cardiomyopathy.Conclusions Exercise training results in on increase in peak heart rate and partial reversal of chronotropic incompetence among patients with stable heart failure. These responses contribute, in part, to the exercise training-induced increase in exercise capacity that occurs in these patients.

BACKGROUND:Angioedema in association with angiotensin converting enzyme inhibitor (ACEI) use is rare, but serious. Which patients are predisposed to the reaction and whether it involves an immune mechanism remain unclear.OBJECTIVES:To determine the frequency of ACEI angioedema in immunosuppressed cardiac and renal transplant patients.METHODS:This was a retrospective chart review of all adult cardiac (n = 156) and renal (n = 341) transplant patients followed at our hospital (years 1985 to 1995).RESULTS:Of 105 cardiac and 91 renal transplant patients on a combination of immunosuppressive and ACEI therapy, 5 (4.8%) cardiac and 1 (1%) renal patients developed angioedema. This prevalence of ACEI angioedema among cardiac and renal transplant patients is 24 times and 5 times higher, respectively, than that observed in the general population (0.1% to 0.2%). Reactions often appeared after prolonged ACEI use (average 19 months; range 3 days to 6.3 years). African-Americans were significantly more likely to experience ACEI-associated angioedema (P = .034), especially among the cardiac patients where 4 of 5 reactors were African-American.CONCLUSIONS:For unclear reasons, ACEI-induced angioedema (often late-onset) is more prevalent among immunosuppressed cardiac and renal transplant patients. Additionally, African-Americans are over-represented among those developing the reaction.

BACKGROUND:The natural history of heart failure is one of continued worsening of cardiac function. Beta-receptor blocker therapy has been effective in improving clinical status and left ventricular function in patients with heart failure. Similarly, high doses of angiotensin-converting enzyme (ACE) inhibitors with nitrates partially reverse the ventricular remodeling of heart failure.HYPOTHESIS:We tested the hypothesis that beta-blocker therapy added to high-dose ACE inhibitor-nitrates would potentiate the reversal of heart failure.METHODS:Thirteen patients, aged 52 +/- 8 years, with moderate to severe heart failure, 12 of whom were referred for transplant consideration, with heart failure duration of 4.8 +/- 2.2 years, were prospectively followed for 12 months. Baseline echocardiographic ejection fraction was 19 +/- 8%, and presenting New York Heart Association class was 2.9 +/- 0.7. Angiotensin-converting enzyme inhibitors and nitrates were uptitrated over 6 months to a final dose of lisinopril 53 +/- 31 mg/day, and isosorbide dinitrate 217 +/- 213 mg/day. At 6 months, beta-blocker therapy with atenolol was initiated and titrated to a final dose of 46 +/- 23 mg/day. Two-dimensional Doppler echocardiography and metabolic stress testing were performed at baseline, at 6 months on lisinopril-nitrates only, and at 12 months on combined ACE inhibitor-nitrate and beta-blocker therapy.RESULTS:New York Heart Association classification improved from 2.9 +/- 0.7 to 1.8 +/- 0.8 on lisinopril-nitrates (p < 0.05), and to 1.5 +/- 0.5 with the addition of beta blockade (p = NS). On follow-up, peak oxygen consumption rose from 17 +/- 7 ml O2/kg/min at baseline to 21 +/- 5 ml O2/kg/min at 6 months on lisinopril-nitrates (p = 0.06) without further change on beta blockade. Ejection fraction rose from 19 +/- 8 to 33 +/- 14% on lisinopril-nitrates at 6 months (p = 0.005) and to 36 +/- 18% on beta blockade at 12 months (p = NS).CONCLUSION:High-dose ACE inhibitor-nitrate therapy significantly improved patient clinical status and left ventricular systolic function in heart failure. The addition of beta-receptor blockade over and above high-dose ACE inhibitor-nitrates was well tolerated but had no further impact on symptomatic status, exercise tolerance, or left ventricular systolic function. The potential for pharmacologic reversal of heart failure remodeling may be finite despite the use of complementary therapies. Larger placebo-controlled and randomized trials of beta-receptor blockade added to high-dose ACE inhibitor-nitrate therapy are needed to confirm these observations.