Experimentally Induced Peripheral Venous Congestion Exacerbates Inflammation, Oxidative Stress, and Neurohormonal and Endothelial Cell Activation in Patients With Systolic Heart Failure.

BACKGROUND: Venous congestion (VC) is a hallmark of symptomatic heart failure (HF) requiring hospitalization; however, its role in the pathogenesis of HF progression remains unclear. We investigated whether peripheral VC exacerbates inflammation, oxidative stress and neurohormonal and endothelial cell (EC) activation in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Two matched groups of patients with HFrEF and with no peripheral VC vs without recent HF hospitalization were studied. We modeled peripheral VC by inflating a cuff around the dominant arm, targeting ∼ 30 mmHg increase in venous pressure (venous stress test [VST]). Blood and ECs were sampled before and after 90 minutes of VST. We studied 44 patients (age 53 ± 12 years, 32% female). Circulating endothelin-1, tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II (ang-2), angiopoietin-2, vascular cell adhesion molecule-1, and CD146 significantly increased after the VST. Enhanced endothelin-1 and angiopoietin-2 responses to the VST were present in patients with vs without recent hospitalization and were prospectively associated with incident HF-related events; 6698 messenger ribonucleic acid (mRNA probe sets were differentially expressed in ECs after VST. CONCLUSIONS: Experimental VC exacerbates inflammation, oxidative stress, neurohormonal and EC activation and promotes unfavorable transcriptome remodeling in ECs of patients with HFrEF. A distinct biological sensitivity to VC appears to be associated with high risk for HF progression.

Peripheral venous congestion causes inflammation, neurohormonal, and endothelial cell activation.

AIMS: Volume overload and venous congestion are typically viewed as a consequence of advanced and of acute heart failure (HF) and renal failure (RF) although it is possible that hypervolaemia itself might be a critical intermediate in the pathophysiology of these diseases. This study aimed at elucidating whether peripheral venous congestion is sufficient to promote changes in inflammatory, neurohormonal, and endothelial phenotype similar to those observed in HF and RF. METHODS: To experimentally model peripheral venous congestion, we developed a new method (so-called venous stress test) and applied the methodology on 24 healthy subjects (14 men, age 35 ± 2 years). Venous arm pressure was increased to ∼30 mmHg above the baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 min of venous congestion, using angiocatheters and endovascular wires. Magnetic beads coated with EC-specific antibodies were used for EC separation; amplified mRNA was analysed by Affymetrix HG-U133 Plus 2.0 Microarray. RESULTS: Plasma interleukin-6 (IL-6), endothelin-1 (ET-1), angiotensin II (AII), vascular cell adhesion molecule-1 (VCAM-1), and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. A total of 3437 mRNA probe sets were differentially expressed (P < 0.05) in venous ECs before vs. after testing, including ET-1, VCAM-1, and CXCL2. CONCLUSION: Peripheral venous congestion causes release of inflammatory mediators, neurohormones, and activation of ECs. Overall, venous congestion mimicked, notable aspects of the phenotype typical of advanced and of acute HF and RF.

Prognostic importance of comorbidities in heart failure with preserved left ventricular ejection fraction.

The relative impact of comorbidities and parameters of left ventricular diastolic function on clinical outcome has not been thoroughly investigated in patients who are hospitalized for heart failure decompensation and found to have preserved ejection fraction. We identified 98 HFpEF patients among 1452 patients admitted with acute heart failure. Clinical characteristics, hemoglobin levels, estimated glomerular filtration rate (eGFR), B-type natriuretic peptide (BNP) and Doppler-echocardiographic parameters were analyzed. The primary end point of the study combined death and rehospitalization for decompensated heart failure after the index hospitalization. Mean age was 76 ± 9 years. LV ejection fraction, E/E (a) ratio, and estimated systolic pulmonary artery pressure were 61 (55-67)%, 12.9 (9.4-15.1), 40 (32-46) mmHg, respectively. BNP values, hemoglobin and eGFR were 287 (164-562) pg/mL, 11.3 (10.4-12.4) g/dL and 45 (37-74) mL/min/m(2), respectively. During a mean follow-up of 17 ± 11 months, 56% reached the primary endpoint of the study: 31 died and 24 were re-hospitalised for heart failure. Diabetes [HR = 1.76 (1.03-3.00), P = 0.039], lower systolic blood pressure [HR = 0.99 (0.97-0.99), P = 0.016], hemoglobin [HR = 0.62 (0.49-0.76), P < 0.0001], and eGFR [HR = 0.98 (0.97-0.99), P = 0.004] were associated with a poor outcome. Neither BNP nor echocardiographic parameters were correlated with outcome. Comorbidities primarily correlate with outcome in patients with HFpEF.

Mitochondrial Pathobiology and Metabolic Remodeling in Progression to Overt Systolic Heart Failure.

The mitochondria are mostly abundant in the heart, a beating organ of high- energy demands. Their function extends beyond being a power plant of the cell including redox balance, ion homeostasis and metabolism. They are dynamic organelles that are tethered to neighboring structures, especially the endoplasmic reticulum. Together, they constitute a functional unit implicated in complex physiological and pathophysiological processes. Their topology in the cell, the cardiac myocyte in particular, places them at the hub of signaling and calcium homeostasis, making them master regulators of cell survival or cell death. Perturbations in mitochondrial function play a central role in the pathophysiology of myocardial remodeling and progression of heart failure. In this minireview, we summarize important pathophysiological mechanisms, pertaining to mitochondrial morphology, dynamics and function, which take place in compensated hypertrophy and in progression to overt systolic heart failure. Published work in the last few years has expanded our understanding of these important mechanisms; a key prerequisite to identifying therapeutic strategies targeting mitochondrial dysfunction in heart failure.

Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea.

BACKGROUND: Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. METHODS AND RESULTS: Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP > or = 4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP > or = 4 hours daily. CONCLUSIONS: OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations.

Growth hormone resistance in severe heart failure resolves after cardiac transplantation.

AIMS: Severe heart failure (HF) is associated with cachexia; this is often reversed post cardiac transplantation (HTx) with frequent development of obesity. Growth hormone (GH) resistance is common in HF and may contribute to cachexia. Whether GH resistance resolves post HTx is unknown. We aimed to confirm that HF is associated with GH resistance and to test the hypothesis that GH resistance resolves post HTx. METHODS AND RESULTS: We measured GH, insulin-like growth factor-1 (IGF-1), and body composition in 10 HF patients awaiting HTx, in 18 patients 11 +/- 8 months post HTx, and seven controls. Body mass index was 23.5 +/- 3.2 in HF patients and 29.3 +/- 5.7 post HTx. HTx patients had gained 14 +/- 8 kg since HTx. GH was elevated in HF (control: 0.21 +/- 0.25; HF: 1.13 +/- 1.19; HTx: 0.11 +/- 0.13 ng/mL; P < 0.007), while IGF-1 was higher in HTx (control: 114 +/- 57; HF: 94 +/- 52; HTx: 190 +/- 106 ng/mL; P < 0.02). HTx had higher total body and abdominal fat %. CONCLUSION: GH resistance is present in severe HF and resolves post HTx. These findings should be confirmed through larger trials.

Exercise does not enhance the prognostic value of Doppler echocardiography in patients with left ventricular systolic dysfunction and functional mitral regurgitation at rest.

BACKGROUND: Functional mitral regurgitation (MR) is a powerful predictor of poor prognosis in patients with chronic heart failure (CHF) due to left ventricular systolic dysfunction (LVSD). However, severity of MR varies with dynamic exercise. Accordingly, we sought to assess the prognostic value of exercise-induced changes in functional MR in patients with LVSD and functional MR at rest. METHODS: One hundred four patients with chronic heart failure due to LVSD (ejection fraction [EF] < 45%) and functional MR at rest underwent conventional continuous 2-dimensional Doppler echocardiography at rest and during maximal symptom-limited exercise. The primary end point of the study was all-cause mortality. The median follow-up period was 20 months. RESULTS: Fifty-six patients (54%) had ischemic cardiomyopathy. When feasible, all 56 patients with ischemic cardiomyopathy had undergone revascularization procedures before enrollment into the study. In the whole patient cohort, resting LV end-diastolic volume was 205 +/- 76 mL and EF was 26% +/- 9%. Univariate predictors of death were functional class (New York Heart Association), LV EF, LV end-diastolic volume, resting mitral effective regurgitant orifice, mitral E deceleration time, tricuspid annular plane systolic excursion < or = 14 mm, systolic blood pressure, LV EF, and trans-tricuspid pressure gradient response to exercise. Exercise-induced change in mitral effective regurgitant orifice did not predict survival (HR 0.99, 95% CI 0.94-1.04, P = .63). By Cox multivariate analysis, resting LV end-diastolic volume and tricuspid annular plane systolic excursion < or = 14 mm were the independent predictors of death. CONCLUSIONS: Exercise Doppler echocardiography does not refine the predictive value of resting Doppler echocardiography in patients with LVSD and functional MR at rest.

Left ventricular abnormal response during dynamic exercise in patients with heart failure and preserved left ventricular ejection fraction at rest.

BACKGROUND: The mechanisms that contribute to limit functional capacity are incompletely understood in patients with preserved resting ejection fraction (HFpREF). We assessed left ventricular (LV) systolic response to dynamic exercise in patients with HFpREF and in patients with similar comorbidities to HFpREF patients but without history or evidence of heart failure. METHODS AND RESULTS: Twenty-five HFpREF patients in steady-state clinical condition without significant coronary artery disease and 25 hypertensive controls underwent exercise echocardiography. At rest, systolic pulmonary artery pressure, left atrial area, E/A and E/e' ratios were greater in patients with HFpREF than in control patients, whereas peak systolic mitral annular velocity was lower in HFpREF patients. The exercise-induced changes in LVEF, forward stroke volume, and cardiac output were significantly lower in HFpREF compared with control patients (-4 +/- 8 vs. +6 +/- 6 %, P = .001; -4 +/- 9 vs. +10 +/- 10 mL, P < .0001, and 1.6 +/- 1.2 vs. 3.5 +/- 1.8 L/min, P < .0001, respectively). Exercise-induced changes in effective arterial elastance significantly differed in HFpREF and control patients (0.5 +/- 0.6 vs. -0.2 +/- 0.5 mm Hg/mL, P < .0001). In addition, 7 of the 25 HFpREF patients developed functional mitral regurgitation during exercise and none in controls. CONCLUSIONS: When compared with patients with similar comorbidities but without history or evidence of heart failure, patients with HFpREF experience greater arterial stiffening and thereby a deterioration of global LV systolic performance during dynamic exercise.

Prognostic importance of tissue Doppler-derived diastolic function in patients presenting with acute coronary syndrome: a bedside echocardiographic study.

AIMS: We sought to evaluate the prognostic value of bedside tissue Doppler derived diastolic function in patients presenting with acute coronary syndrome (ACS) on top of major clinical predictors of mortality and routine laboratory testings. METHODS AND RESULTS: Bedside Doppler echocardiography and laboratory tests were prospectively performed in 239 consecutive patients (mean age 62 +/- 14, 69% men) admitted for ACS. Ratio of early transmitral flow (E) to early mitral annulus velocities (e') was calculated. The study endpoint was cardiac death. The median follow-up period was 2 years. E/e' was >15 in 39 patients. Multivariate predictors of E/e' > 15 were older age, diabetes, non-ST-segment elevation ACS, and decreased LV ejection fraction (LVEF). Survival free from cardiac death was lower in patients with E/e' ratio >15 (P = 0.01). History of coronary artery disease, lower creatinine clearance, higher glycemia on admission, decreased LVEF, and E/e' >15 were independent predictors of cardiac death. CONCLUSION: Bedside Doppler echocardiography provides prognostic information on top of major clinical predictors of mortality and routine laboratory testings in patients presenting with ACS.

Steady endothelial nitric oxide synthase expression in heart failure.

BACKGROUND: Vascular nitric oxide (NO)-mediated vasodilation is reduced in the limb vasculature of patients with chronic heart failure. Depressed gene expression of vascular endothelial NO synthase has been reported in experimental models of heart failure. We sought to investigate endothelial NO synthase (eNOS) mRNA expression in the skeletal muscle vasculature of patients with chronic heart failure (CHF) and in controls. METHODS AND RESULTS: Transcript levels for eNOS were measured and normalized to von Willebrand factor gene expression level, in samples of skeletal muscle from patients with CHF (n = 20) and healthy subjects (n = 7). CHF was not associated with a decrease in eNOS expression. There was a trend towards an increased expression in NYHA class IV patients. Similar results were found when normalized to GAPDH mRNA levels. CONCLUSION: Vascular endothelial dysfunction that is observed in patients with severe heart failure does not appear to be related to a specific decrease in the expression of the gene encoding for endothelial NOS.

Peripheral venous congestion causes time- and dose-dependent release of endothelin-1 in humans.

Endothelin-1 (ET-1) is a pivotal mediator of vasoconstriction and inflammation in congestive states such as heart failure (HF) and chronic kidney disease (CKD). Whether peripheral venous congestion (VC) increases plasma ET-1 at pressures commonly seen in HF and CKD patients is unknown. We seek to characterize whether peripheral VC promotes time- and dose-dependent increases in plasma ET-1 and whether these changes are sustained after decongestion. We used a randomized, cross-over design in 20 healthy subjects (age 30 ± 7 years). To experimentally model VC, venous pressure was increased to either 15 or 30 mmHg (randomized at first visit) above baseline by inflating a cuff around the subject's dominant arm; the nondominant arm served as a noncongested control. We measured plasma ET-1 at baseline, after 20, 60 and 120 min of VC, and finally at 180 min (60 min after cuff release and decongestion). Plasma ET-1 progressively and significantly increased over 120 min in the congested arm relative to the control arm and to baseline values. This effect was dose-dependent: ET-1 increased by 45% and 100% at VC doses of 15 and 30 mmHg, respectively (P < 0.05), and declined after 60 min of decongestion though remaining significantly elevated compared to baseline. In summary, peripheral VC causes time- and dose-dependent increases in plasma ET-1. Of note, the lower dose of 15 mmHg (more clinically relevant to HF and CKD patients) was sufficient to raise ET-1. These findings support the potentially contributory, not merely consequential, role of VC in the pathophysiology of HF and CKD.

Endothelial cell activation in patients with decompensated heart failure.

BACKGROUND: Vascular endothelial functions, other than nitric oxide (NO)-mediated control of vasomotor tone, are poorly characterized in patients with chronic heart failure (CHF). Veins and arteries are exposed to the same circulating proinflammatory mediators in patients with CHF. The present study tested whether endothelial cell activation occurs in veins of patients with decompensated CHF and whether activation, if present, subsides with return to a clinically compensated state. METHODS AND RESULTS: Fifteen patients with decompensated CHF requiring transient inotropic support and 6 age-matched, healthy controls were studied. Endothelial cells and blood were collected from a forearm vein, and brachial artery flow-mediated dilation (FMD) was measured before and 24 hours after discontinuation of short-term inotropic therapy, when patients had returned to a steady compensated state. Nitrotyrosine immunoreactivity (an intracellular marker of oxidative stress), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS) expression were significantly higher in venous endothelial cells of patients in clinical decompensation when compared with healthy subjects. Return to a compensated state resulted in a significant reduction in nitrotyrosine immunoreactivity, COX-2, and iNOS expression. Concomitantly, a significant increase in FMD and a decline in plasma total 8-isoprostane and bicycloprostaglandin E2 levels were observed. Venous endothelial NOS expression was unaffected by clinical decompensation. CONCLUSIONS: Clinical decompensation in CHF is associated with activation of the venous endothelium. Return to a compensated state after short-term inotropic therapy results in a significant reduction in endothelial nitrotyrosine formation, COX-2, and iNOS expression.

Functional status and quality of life after emergency revascularization for cardiogenic shock complicating acute myocardial infarction.

OBJECTIVES: Our goal was to describe the functional status of cardiogenic shock survivors, identify the correlates of cardiogenic shock, and compare global quality of life and functional status of patients randomly assigned to treatment with emergency revascularization (ERV) versus initial medical stabilization (IMS). BACKGROUND: Historically, the hospital survival rate of patients with cardiogenic shock complicating acute myocardial infarction (MI) has been very low. Shock survivors are salvaged from a critically ill state, and their later functional status is not well documented. The SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK (SHOCK) trial showed significantly improved one-year survival after ERV compared with IMS. METHODS: The SHOCK trial survivors completed interviews at 2 weeks after discharge and at 6 and 12 months after MI. Functional status assessment included the Multidimensional Index of Life Quality and New York Heart Association (NYHA) congestive heart failure functional class. RESULTS: Eighty-seven percent of one-year survivors of the SHOCK trial were in NYHA functional class I or II. Between two weeks after discharge and one year after MI, improvement was similar in the two treatment groups (18% overall), but fewer patients remained stable (44% vs. 71%), and more patients worsened or died (34% vs. 15%) in the IMS group compared with those assigned to ERV. Assignment to ERV was the only independent predictor of outcome at one year. CONCLUSIONS: Although one-year mortality after ERV is still high (54%), most survivors have good functional status. The ERV patients have a lower rate of deterioration than IMS patients. The level of recovery for shock patients undergoing ERV is similar to that of historical controls not in cardiogenic shock undergoing elective revascularization.

In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE).

OBJECTIVES: We sought to compare the in-hospital mortality of patients with acute decompensated heart failure (ADHF) who were receiving parenteral treatment with one of four intravenous vasoactive medications. BACKGROUND: There are limited data regarding the effects of the choice of intravenous vasoactive medication on in-hospital mortality in patients hospitalized with ADHF. METHODS: This was a retrospective analysis of observational patient data from the Acute Decompensated Heart Failure National Registry (ADHERE), a multicenter registry designed to prospectively collect data on each episode of hospitalization for ADHF and its clinical outcomes. Data from the first 65,180 patient episodes (October 2001 to July 2003) were included in this analysis. Cases in which patients received nitroglycerin, nesiritide, milrinone, or dobutamine were identified and reviewed (n = 15,230). Risk factor and propensity score-adjusted odds ratios (ORs) for in-hospital mortality were calculated. RESULTS: Patients who received intravenous nitroglycerin or nesiritide had lower in-hospital mortality than those treated with dobutamine or milrinone. The risk factor and propensity score-adjusted ORs for nitroglycerin were 0.69 (95% confidence interval [CI] 0.53 to 0.89, p < or = 0.005) and 0.46 (94% CI 0.37 to 0.57, p < or = 0.005) compared with milrinone and dobutamine, respectively. The corresponding values for nesiritide compared with milrinone and dobutamine were 0.59 (95% CI 0.48 to 0.73, p < or = 0.005) and 0.47 (95% CI 0.39 to 0.56, p < or = 0.005), respectively. The adjusted OR for nesiritide compared with nitroglycerin was 0.94 (95% CI 0.77 to 1.16, p = 0.58). CONCLUSIONS: Therapy with either a natriuretic peptide or vasodilator was associated with significantly lower in-hospital mortality than positive inotropic therapy in patients hospitalized with ADHF. The risk of in-hospital mortality was similar for nesiritide and nitroglycerin.

Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry.

OBJECTIVES: We sought to analyze clinical, angiographic, and outcome correlates of hemodynamic parameters in cardiogenic shock. BACKGROUND: The significance of right heart catheterization in critically ill patients is controversial, despite the prognostic importance of the derived measurements. Cardiac power is a novel hemodynamic parameter. METHODS: A total of 541 patients with cardiogenic shock who were enrolled in the SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK (SHOCK) trial registry were included. Cardiac power output (CPO) (W) was calculated as mean arterial pressure x cardiac output/451. RESULTS: On univariate analysis, CPO, cardiac power index (CPI), cardiac output, cardiac index, stroke volume, left ventricular work, left ventricular work index, stroke work, mean arterial pressure, systolic and diastolic blood pressure (all p < 0.001), coronary perfusion pressure (p = 0.002), ejection fraction (p = 0.013), and pulmonary artery systolic pressure (p = 0.047) were associated with in-hospital mortality. In separate multivariate analyses, CPO (odds ratio per 0.20 W: 0.60 [95% confidence interval, 0.44 to 0.83], p = 0.002; n = 181) and CPI (odds ratio per 0.10 W/m(2): 0.65 [95% confidence interval, 0.48 to 0.87], p = 0.004; n = 178) remained the strongest independent hemodynamic correlates of in-hospital mortality after adjusting for age and history of hypertension. There was an inverse correlation between CPI and age (correlation coefficient: -0.334, p < 0.001). Women had a lower CPI than men (0.29 +/- 0.11 vs. 0.35 +/- 0.15 W/m(2), p = 0.005). After adjusting for age, female gender remained associated with CPI (p = 0.032). CONCLUSIONS: Cardiac power is the strongest independent hemodynamic correlate of in-hospital mortality in patients with cardiogenic shock. Increasing age and female gender are independently associated with lower cardiac power.

Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE).

BACKGROUND: The ADHERE is designed to study characteristics, management, and outcomes in a broad sample of patients hospitalized with acute decompensated heart failure. Heart failure is a leading cause of hospitalization for adults older than 65 years in the United States. Most available data on these patients are limited by patient selection criteria and study design of clinical trials and single-center studies. METHODS: Participating hospitals identify patients with a primary or secondary discharge diagnosis of heart failure. Medical history, management, treatments, and health outcomes data are collected through review of medical records and entered into a database via secure web browser technology. RESULTS: As of January 2004, data on 107 362 patients have been received from 282 participating hospitals. Of enrollees with available analyzable data (N = 105 388 from 274 hospitals), the mean age was 72.4 (+/-14.0), and 52% were women. The most common comorbid conditions were hypertension (73%), coronary artery disease (57%), and diabetes (44%). Evidence of mild or no impairment of systolic function was found in 46% of patients. Inhospital mortality was 4.0% and the median hospital length of stay was 4.3 days. CONCLUSIONS: The ADHERE demonstrates both the feasibility and significant implications of gathering representative data on large numbers of patients hospitalized with heart failure. Initial data provided important insights into the clinical characteristics and patterns of care of these patients. Ongoing registry work will provide the framework for improved treatment strategies for patients hospitalized with decompensated heart failure.

Evolving rationale for angiotensin-converting enzyme inhibition in chronic heart failure.

The rationale behind the use of angiotensin-converting enzyme (ACE) inhibitors has evolved considerably since their approval for the treatment of hypertension. The initial rationale behind their use for the treatment of chronic heart failure was to duplicate with one agent the hemodynamic effects produced by the hydralazine-isosorbide dinitrate combination, i.e., increasing cardiac output while reducing ventricular filling pressures. The observation that the acute hemodynamic effects of ACE inhibitors did not predict long-term clinical benefits led to the search for mechanisms other than hemodynamic improvement. Attenuation or even reversal of left ventricular dilatation after myocardial infarction, which was first reported with ACE inhibition in an experimental model of myocardial infarction and subsequently in patients with recent myocardial infarction, provided a new rationale for the use of these inhibitors for chronic heart failure. However, this apparent prevention of left ventricular dilatation by ACE inhibitors is less apparent in patients with congestive heart failure due to left ventricular systolic dysfunction (decreased ejection fraction) than in patients with recent myocardial infarction. Furthermore, the unexpected finding that long-term ACE inhibition decreases the incidence of recurrent myocardial infarction in patients with coronary artery disease and an already reduced systolic function, suggested the hypothesis that vascular protection may provide most of the clinical benefits of ACE inhibitors. This hypothesis was successfully tested by demonstrating a lower incidence of cardiovascular events in high-risk vascular patients randomized to long-term ACE inhibition with ramipril. Accordingly, the current rationale behind the use of ACE inhibitors in patients with chronic heart failure is largely that of vascular protection.