Hemodynamics of the diastolic pressure gradients in acute heart failure: implications for the diagnosis of pre-capillary pulmonary hypertension in left heart disease.

The diastolic pressure gradient (DPG) has been proposed as the metric of choice for the diagnosis of pulmonary vascular changes in left heart disease. We tested the hypothesis that this metric is less sensitive to changes in left atrial pressure and stroke volume (SV) than the transpulmonary gradient (TPG). We studied the effect of dynamic changes in pulmonary capillary wedge pressure (PCWP), SV, and pulmonary artery capacitance (PAC) on DPG and TPG in 242 patients with acute heart failure undergoing decongestive therapy with continuous hemodynamic monitoring. There was a close impact of PCWP reduction on TPG and DPG, with a 0.13 mmHg (95% confidence interval [CI] 0.07-0.19, P < 0.0001) and 0.21 mmHg (95% CI 0.16-0.25, P < 0.0001) increase for every 1 mmHg decrease in PCWP, respectively. Changes in SV had a negligible effect on TPG and DPG (0.19 and 0.13 mmHg increase, respectively, for every 10-mL increase in SV). Heart rate was positively associated with DPG (0.41-mmHg increase per 10 BPM [95% CI 0.22-0.60, P < 0.0001]). The resistance-compliance product was positively associated with both TPG and DPG (2.65 mmHg [95% CI 2.47-2.83] and 1.94 mmHg [95% CI 1.80-2.08] for each 0.1-s increase, respectively). In conclusion, DPG is not less sensitive to changes in left atrial pressure and SV compared with TPG. Although DPG was not affected by changes in PAC, the concomitant increase in the resistance-compliance product increases DPG.

Diuretic Response: Clinical and Hemodynamic Predictors and Relation to Clinical Outcome.

OBJECTIVE: The aims of this work were to investigate the clinical and hemodynamic profile underlying the response to loop diuretics in acute decompensated heart failure (ADHF), and to compare the relative usefulness of measures of diuretic resistance for predicting mortality. METHODS AND RESULTS: We studied 475 patients with ADHF, of whom 241 underwent right heart catheterization. Linear regression models were used to identify factors that affected urine output. Loop diuretics response was estimated as (1) net fluid loss per 40 mg furosemide equivalents and (2) urine output produced per 40 mg furosemide equivalents. In a multivariable regression model, key independent predictors of urine output included diuretic dose (partial r = 0.44), baseline renal function (partial r = 0.38), systolic blood pressure (partial r = 0.26), and fluid intake (partial r = 0.31; all P < .0001). Among hemodynamic variables, elevated right atrial pressure was associated with greater urine output (partial r = 0.19; P = .002). The partial correlation attributable to diuretic dose (partial R2 = 0.19) accounted for approximately one-half of the variance in urine output explained by the model (model R2 = 0.40).Cox regression models demonstrated inverse relationships between quartiles of net fluid loss (P = .004) and quartiles of urine output (P = .04) per 40 mg furosemide and 6-month mortality. When comparing nested models, the model based on net fluid loss was better than the model based on urine output for the prediction of mortality (χ2 = 8.1; 3 df; P = .04). CONCLUSIONS: In patients with ADHF, beyond diuretic dose, other parameters including renal function, hemodynamic status, the degree of volume overload, and fluids intake also affect urine output. Measures of loop diuretic response are associated with short-term mortality.

Fluid loss, venous congestion, and worsening renal function in acute decompensated heart failure.

AIMS: To investigate the relationship between decongestion, central venous pressure, and risk of worsening renal function (WRF) in patients with acute decompensated heart failure (ADHF). METHODS AND RESULTS: We studied 475 patients with ADHF, of whom 238 underwent right heart catheterization. Right atrial pressure (RAP) was measured at baseline and at 24 h. Net fluid loss was recorded in the first 24 h. WRF was defined as a >0.3 mg/dL increase in serum creatinine above baseline. WRF occurred in 84 catheterized patients (35.3%). There was a weak correlation between baseline RAP and baseline estimated glomerular filtration rate (r = -0.17, P = 0.009). The amount of fluid removed during the first 24 h did not correlate with the magnitude of RAP reduction (r = 0.06, P = 0.35). No association was observed between WRF and baseline RAP [odds ratio (OR) 1.06, 95% confidence interval (CI) 0.80-1.41, P = 0.68 per 6.6 mmHg] or the decrease in RAP (adjusted OR 1.13, 95% CI 0.85-1.49, P = 0.40 per 5.3 mmHg reduction in RAP). In contrast, smaller net fluid loss was strongly associated with increased WRF risk. Compared with the first net fluid loss tertile, the adjusted OR was 1.85 (95% CI 0.90-3.80, P = 0.10) and 2.58 (95% CI 1.27-5.25; P = 0.009) for the second and third tertile, respectively (P for trend <0.0001). CONCLUSION: Smaller early net fluid loss is associated with increased risk for WRF. RAP is not a reliable surrogate of the magnitude of decongestion and risk of WRF. Future research is necessary to determine if targeting congestion may help prevent WRF.

Hemodynamic determinants of dyspnea improvement in acute decompensated heart failure.

BACKGROUND: Dyspnea relief constitutes a major treatment goal and a key measure of treatment efficacy in decompensated heart failure. However, there are no data with regard to the relationship between hemodynamic measurements during treatment and dyspnea improvement. METHODS AND RESULTS: We studied 233 patients assigned to right heart catheterization in the Vasodilation in the Management of Acute Congestive Heart Failure trial. Dyspnea (assessed using a 7-point Likert scale) and hemodynamic parameters were measured simultaneously at 15 and 30 minutes and 1, 2, 3, 6, and 24 hours. Dyspnea relief was defined as moderate or marked improvement. There was a time-dependent association between the reductions in pulmonary capillary wedge pressure (PCWP; 25.4, 24.6, 24.0, 23.5, 23.4, 21.5, and 19.9 mm Hg) and the percentage of patients achieving dyspnea relief (17.7%, 24.6%, 32.2%, 36.2%, 37.8%, 47.4%, and 66.1%, in the respective time points). Multivariable logistic generalized estimating equations modeling demonstrated that reductions of both PCWP and mean pulmonary artery pressure were independently associated with dyspnea relief. Compared with the highest PCWP quartile, the adjusted odds ratios for dyspnea relief were 0.92 (95% confidence interval [CI], 0.67-1.29), 1.07 (95% CI, 0.75-1.55), and 1.80 (95% CI, 1.22-2.65) in the third, second, and first PCWP quartiles, respectively (P(trend)=0.003). Compared with the highest mean pulmonary artery pressure quartile, the adjusted odds ratios for dyspnea relief were 2.0 (95% CI, 1.41-2.82), 2.23 (95% CI, 1.52-3.27), and 2.98 (95% CI, 1.91-4.66) in the third, second, and first mean pulmonary artery pressure quartiles, respectively (P(trend)<0.0001). CONCLUSIONS: A clinically significant improvement in dyspnea is associated with a reduction in both PCWP and mean pulmonary artery pressure.

Crescendo in depolarization and repolarization heterogeneity heralds development of ventricular tachycardia in hospitalized patients with decompensated heart failure.

BACKGROUND: A critical need exists for reliable warning markers of in-hospital life-threatening arrhythmias. We used a new quantitative method to track interlead heterogeneity of depolarization and repolarization to detect premonitory changes before ventricular tachycardia (VT) in hospitalized patients with acute decompensated heart failure. METHODS AND RESULTS: Ambulatory ECGs (leads V(1), V(5), and aVF) recorded before initiation of drug therapy from patients enrolled in the PRECEDENT (Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Nesiritide Therapy) trial were analyzed. R-wave heterogeneity (RWH) and T-wave heterogeneity (TWH) were assessed by second central moment analysis and T-wave alternans (TWA) by modified moving average analysis. Of 44 patients studied, 22 had experienced episodes of VT (≥4 beats at heart rates >100 beats/min) following ≥120 minutes of stable sinus rhythm, and 22 were age- and sex-matched patients without VT. TWA increased from 18.6±2.1 µV (baseline, mean±SEM) to 27.9±4.6 µV in lead V(5) at 15 to 30 minutes before VT (P<0.05) and remained elevated until the arrhythmia occurred. TWA results in leads V(1) and aVF were similar. RWH and TWH were elevated from 164.1±33.1 and 134.5±20.6 µV (baseline) to 299.8±54.5 and 239.2±37.0 µV at 30 to 45 minutes before VT (P<0.05), respectively, preceding the crescendo in TWA by 15 minutes. Matched patients without VT did not display elevated RWH (185.5±29.4 µV) or TWH (157.1±27.2 µV) during the 24-hour period. CONCLUSIONS: This investigation is the first clinical demonstration of the potential utility of tracking depolarization and repolarization heterogeneity to detect crescendos in electrical instability that could forewarn of impending nonsustained VT. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00270400.

Relationship between reactive pulmonary hypertension and mortality in patients with acute decompensated heart failure.

BACKGROUND: In patients with heart failure, pulmonary hypertension (PH) predicts higher risk for morbidity and mortality. However, few data are available on the prognostic implications of reactive (precapillary) PH superimposed on passive (postcapillary) PH. METHODS AND RESULTS: We performed a subgroup analysis of 242 patients with acute decompensated heart failure assigned to pulmonary artery catheter placement in the Vasodilation in the Management of Acute Congestive Heart Failure trial. Patients were classified into 3 groups, using the final (posttreatment) hemodynamic measurements: (1) no PH (mean pulmonary artery pressure ≤ 25 mm Hg; (2) passive PH (mean pulmonary artery pressure > 25, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance ≤ [corrected] Wood units); and (3) reactive PH (mean pulmonary artery pressure > 25, [corrected] pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance > 3 Wood units). Fifty-eight patients were classified as normal mean pulmonary artery pressure, 124 with passive PH and 60 with reactive PH. During follow-up of 6 months, 5 (8.6%), 27 (21.8%), and 29 (48.3%) deaths occurred in patients without PH, patients with passive PH, and with reactive PH, respectively (P<0.0001). After multivariable adjustments, reactive PH remained an independent predictor of death, with an adjusted hazard ratio of 4.8 compared with patients without PH, and 2.8 compared with patients with passive PH (95% confidence interval, 1.7 to 4.7, P=0.0001). Similar results were obtained when reactive PH was defined on the basis of transpulmonary gradient. CONCLUSIONS: Reactive PH is common among patients with acute decompensated heart failure after initial diuretic and vasodilator therapy. The adverse outcome associated with PH is predominantly due to increased mortality rates in the subgroup of patients with reactive PH.

The relationship between transient and persistent worsening renal function and mortality in patients with acute decompensated heart failure.

BACKGROUND: Worsening renal function (WRF) is an ominous complication in patients with acute heart failure syndrome (AHFS). Few data are available with regard to the clinical implications of transient versus persistent WRF in this setting. METHODS AND RESULTS: We studied 467 patients with AHFS and creatinine measurements at baseline and on days 2, 5, 14, and 30. WRF (>/= 0.5 mg/dL increase in serum creatinine above baseline at any time point) was defined as persistent when serum creatinine remained >/= 0.5 mg/dL above baseline throughout day 30, and transient when creatinine levels subsequently decreased to < 0.5 mg/dL above baseline. WRF occurred in 115 patients, and was transient in 39 patients (33.9%). The 6-month mortality rates were 17.3%, 20.5%, and 46.1% in patients without WRF, transient WRF, and persistent WRF, respectively. In a multivariable Cox model, compared with patients with stable renal function, the adjusted hazard ratio for mortality was 0.8 (95% CI 0.4-1.7; P = .58) in patients with transient WRF and 3.2 (95% CI 2.1-5.0; P < .0001) in patients with persistent WRF. CONCLUSION: Transient WRF is frequent among patients with AHFS. Whereas persistent WRF portends increased mortality, transient WRF appears to be associated with a better outcome as compared with persistent renal failure.

The relationship between body mass index and mortality in patients with acute decompensated heart failure.

Recent studies have suggested that body mass index (BMI) may be an independent prognostic factor in patients with chronic heart failure (HF). It is unknown whether or not BMI has the same predictive value in acute decompensated heart failure. We studied 489 patients with the previous diagnosis of HF (84% NYHA class III-IV) who were admitted for decompensated HF. During follow-up of greater than 6 months, 110 patients (22.4%) died. Kaplan-Meier analysis demonstrated that patients with BMI <25 kg/m(2) were at a higher risk of death. After adjusting for other risk variables in a Cox proportional hazard regression model, BMI <25 kg/m(2) remained an independent predictor of mortality with a hazard ratio of 1.6 (95% CI 1.1-2.4, p=0.03). We conclude that BMI in the normal or cachectic range is an independent predictor of mortality in patients with acute decompensated HF.

A pilot study to test the effect of pulsatile insulin infusion on cardiovascular mechanisms that might contribute to attenuation of renal compromise in type 1 diabetes mellitus patients with proteinuria.

We hypothesized that correction of insulin deficiency by pulsatile intravenous insulin infusion in type 1 diabetes mellitus patients with nephropathy preserves renal function by mechanisms involving cardiac autonomic function, cardiac mass, or efficiency, or by hemostatic mechanisms. The control group (8 patients) received subcutaneous insulin (3-4 injections per day). The intravenous infusion group (10 patients) received three 1-hour courses of pulsed intravenous insulin infusion on a single day per week in addition to subcutaneous insulin. Laboratory measurements included 2-dimensional Doppler echocardiography, 24-hour ambulatory monitoring with heart rate variation analysis, platelet aggregation and adhesion, plasma fibrinogen, factor VII, von Willebrand factor, fibrinolytic activity, plasminogen activator inhibitor, and viscosity measured at baseline and 12 months. Blood pressure control was maintained preferentially with angiotensin-converting enzyme inhibitors. Ratio of carbon dioxide production to oxygen utilization was measured with each infusion and showed rapid increase from 0.8 to 0.9 (P = .005) at weekly treatments through 12 months. We observed an annualized decrease in creatinine clearance of 9.6 mL/min for controls vs 3.0 mL/min for infusion patients. Annualized fall in blood hemoglobin was 1.9 vs 0.8 g/dL, respectively (P = .013). There were no differences between the control and infusion group with respect to glycohemoglobin, advanced glycated end products, cholesterol, or triglycerides. No differences between the study groups for hemodynamic or hemostatic factors were evident. Blood pressures were not significantly different at baseline or 12 months. We conclude that although preservation of renal function with attenuation of loss of blood hemoglobin during 12 months of intravenous insulin infusion was associated with improvement in the efficiency of fuel oxidation as measured by respiratory quotient, this occurred without differences in metabolic/hemostatic factors, cardiac autonomic function, cardiac wall, or chamber size. Our hypothesis that preservation of renal function in type 1 diabetes mellitus patients with proteinuria by weekly pulsed insulin infusion involves mechanisms from the autonomic nervous system, cardiac size, and function, or elements of hemostasis was not confirmed.

Serum blood urea nitrogen as an independent marker of subsequent mortality among patients with acute coronary syndromes and normal to mildly reduced glomerular filtration rates.

OBJECTIVES: We hypothesized that elevated blood urea nitrogen (BUN) would be associated with adverse outcomes independent of serum creatinine (sCr)-based estimates of kidney function in patients with acute coronary syndromes (ACS). BACKGROUND: Although lower glomerular filtration rates (GFR) have prognostic significance among patients with ACS, estimates of GFR based on sCr may perform less accurately among patients with milder kidney dysfunction. In this population in particular, BUN, which can reflect increased proximal tubular reabsorption in addition to decreased GFR, may have independent prognostic value. METHODS: Data were drawn from 9,420 patients with unstable coronary syndromes from Orbofiban in Patients With Unstable Coronary Syndromes-Thrombolysis In Myocardial Infarction (OPUS-TIMI)-16, a trial that excluded patients with sCr >1.6 mg/dl or estimated creatinine clearance <40 ml/min. RESULTS: Patients with elevated BUN were older, had a higher prevalence of comorbidities, and had higher heart rates, lower systolic blood pressures, and an abnormal Killip class more often on admission. In univariate analyses, as well as in stratified and multivariable analyses including sCr-based estimates of GFR as a covariate, a stepwise increase in mortality occurred with increasing BUN (multivariable hazard ratio with BUN 20 to 25 mg/dl 1.9, 95% confidence interval 1.3 to 2.6; with BUN >/=25 mg/dl 3.2 [95% confidence interval 2.2 to 4.7]) compared with BUN

Prognostic impact of diabetes mellitus in patients with acute decompensated heart failure.

The presence of diabetes mellitus (DM) adversely affects the natural history of heart failure (HF), but its prognostic significance is unknown in acute decompensated HF. Of the 498 patients enrolled with decompensated HF requiring intravenous vasoactive therapy, 236 (47.4%) had a previous diagnosis of DM. After 6 months, 113 patients (22.7%) had died. A Cox proportional-hazards model showed a significant association between DM and worse survival after hospital discharge. DM is common among patients admitted with decompensated HF, and diabetes-related biologic differences contribute to the progression of HF.

A review of the renal and neurohormonal effects of B-type natriuretic peptide.

Adverse neurohormonal activation is an essential component in the pathogenesis of acute decompensated congestive heart failure (CHF). Consequently, blunting this activation is an important therapeutic goal. B-type natriuretic peptide (BNP) is a counterregulatory hormone produced by the ventricles in response to pressure and volume load. Endogenous BNP levels are significantly elevated in patients with acute CHF, but these levels are frequently inadequate to overcome the excess neurohormonal activation present in this condition. Infusion of nesiritide, a recombinant form of endogenous human BNP, increases circulating BNP levels by several-fold, augmenting the counterregulatory effects of this hormone. Clinical trials demonstrate that in patients with acute decompensated CHF, nesiritide produces arterial and venous vasodilation, reducing both preload and afterload; blunts adverse neurohormones, including renin, aldosterone, norepinephrine, and endothelin-1; and improves renal hemodynamics and tubular function. As a result, nesiritide quickly reduces clinical symptoms and improves mortality in patients with acute CHF.

Effect of nesiritide (human b-type natriuretic peptide) and dobutamine on heart rate variability in decompensated heart failure.

BACKGROUND: Previous studies have suggested that natriuretic peptides may have direct sympathoinhibitory effects. Nesiritide (recombinant human B-type natriuretic peptide) has been recently approved for treatment of decompensated congestive heart failure (CHF). We sought to assess the effects of nesiritide compared with dobutamine on time-domain indices of heart rate variability (HRV) in patients with decompensated CHF. METHODS: The study population consisted of 185 patients, who were randomized to intravenous nesiritide at a low (0.015 microg/kg/min, n = 56) or high (0.03 microg/kg/min, n = 58) dose, or to dobutamine (> or = 5 microg/kg/min, n = 58). Time-domain HRV indices were obtained from 24-hour Holter recordings immediately before and during study drug therapy. RESULTS: Dobutamine therapy resulted in a decrease in standard deviation of the R-R intervals over a 24-hour period (SDNN), standard deviation of all 5-minute mean R-R intervals (SDANN), and the percentage of R-R intervals with >50 ms variation (pNN50) (all P < .05). Low-dose nesiritide induced an increase in SDNN (P < .05), and high-dose nesiritide resulted in a nonsignificant decrease in all measures of HRV. A significant interaction was noted between baseline HRV and the effect of vasoactive therapy on HRV (P = .028). Therefore, the effect of nesiritide and dobutamine was analyzed in relation to baseline HRV. In the dobutamine group, patients with moderately depressed HRV at baseline displayed a reduction in SDNN (P = .01), SDANN (P = .01), pNN50 (P = .04), and the square root of mean squared differences of successive R-R intervals (RMSSD) (P = .05), whereas no significant changes occurred in patients with severely depressed HRV. In the low-dose nesiritide group, patients with severely depressed HRV displayed an increase in SDNN (P = .001), SDANN (P = .02), and RMSSD (P = .01), with no significant changes in patients with moderately depressed HRV. HRV response to high-dose nesiritide was similar to that of dobutamine. CONCLUSIONS: Low-dose nesiritide therapy in patients with decompensated CHF improves indices of overall HRV and parasympathetic modulation, particularly if HRV is severely depressed at baseline. Dobutamine and possibly high-dose nesiritide can potentially lead to further deterioration of autonomic dysregulation.

Effect of elevated admission serum creatinine and its worsening on outcome in hospitalized patients with decompensated heart failure.

Renal insufficiency (RI), as represented by elevated serum creatinine (>1.5 mg/dl) on admission, is common and found in almost half of patients hospitalized with decompensated heart failure. This finding is associated with prolongation of length of stay and rate of rehospitalizations after discharge and also has an independent unfavorable effect on 6-month mortality. Similarly, an increase in serum creatinine (>0.5 mg/dl) in the hospital results in a significantly longer length of stay and has an independent effect on long-term mortality.

Elevated blood urea nitrogen level as a predictor of mortality in patients admitted for decompensated heart failure.

BACKGROUND: Hospitalization for decompensated heart failure is associated with high mortality after discharge. In heart failure, renal function involves both cardiovascular and hemodynamic properties. We studied the relation between renal dysfunction and mortality in patients admitted for decompensated heart failure. METHODS: The prognostic importance of four measures of renal function-blood urea nitrogen, serum creatinine, blood urea nitrogen/creatinine ratio, and estimated creatinine clearance-was evaluated in 541 patients (mean [+/- SD] age, 63 +/- 14 years; 377 men [70%]) with a previous diagnosis of heart failure (96% with New York Heart Association class III or IV symptoms) who were admitted for clinical decompensation. RESULTS: During a mean follow-up of 343 +/- 185 days, 177 patients (33%) died. In multivariable Cox regression models, the risk of all-cause mortality increased with each quartile of blood urea nitrogen, with an adjusted relative risk of 2.3 in patients in the upper compared with the lower quartiles (95% confidence interval [CI]: 1.3 to 4.1; P = 0.005). Creatinine and estimated creatinine clearance were not significant predictors of mortality after adjustment for other covariates. Blood urea nitrogen/creatinine ratio yielded similar prognostic information as blood urea nitrogen (adjusted relative risk = 2.3; 95% CI: 1.4 to 3.8; P = 0.0007 for patients in the upper compared with the lower quartiles). CONCLUSION: Blood urea nitrogen is a simple clinical variable that provides useful prognostic information in patients admitted for decompensated heart failure. In this setting, elevated blood urea nitrogen levels probably reflect the cumulative effects of hemodynamic and neurohormonal alterations that result in renal hypoperfusion.

Improved glycemic control induces regression of left ventricular mass in patients with type 1 diabetes mellitus.

BACKGROUND: Diabetes mellitus has been associated with abnormalities of cardiac function and left ventricular hypertrophy. We sought to determine whether improved glycemic control in patients with type 1 diabetes mellitus will induce reversal of those abnormalities. METHODS: We prospectively studied 19 patients (mean age 40+/-9 years) with longstanding type 1 diabetes mellitus (28+/-4 years), who participated in a program of stringent glycemic control. Glycemic control was monitored with hemoglobin A1c levels, and improvement was defined as >1% (absolute) decrease of hemoglobin A1c. Two-dimensional and Doppler echocardiograms and ambulatory 24-h blood pressures were obtained at baseline and after 1 year. Left ventricular mass was determined using the area-length method. RESULTS: In the patients with improved glycemic control (n=12), hemoglobin A1c decreased from 9.8% to 7.8% (p< or =0.0001), interventricular septal thickness decreased from 10.3 to 9.4 mm (p< or =0.05), and left ventricular mass regressed from 205 to 182 g (p< or =0.05). Septal thickness and left ventricular mass remained unchanged in the patients who did not achieve improvement of glycemic control. Left ventricular internal diameters, posterior wall thickness, fractional shortening, E/A ratio of mitral inflow, E-wave deceleration time (DT), and ambulatory 24-h blood pressures did not change significantly after 1 year in either group. CONCLUSIONS: Improved glycemic control in patients with type 1 diabetes mellitus is associated with regression of septal thickness and left ventricular mass without significant effect on systolic or diastolic function, in the absence of significant alterations in ambulatory 24-h blood pressures.

Relation between pulse pressure and survival in patients with decompensated heart failure.

Elevated pulse pressure (PP), an indicator of increased arterial stiffness, has been shown to predict adverse outcome in patients with stable heart failure. However, the dependence of PP on hemodynamic factors, such as stroke volume and peak aortic blood flow, suggests that the relation between PP and outcome may depend on the clinical setting. We evaluated the relation between PP and all-cause mortality in 489 patients with decompensated heart failure. We found that the association of PP with outcome in this setting is reversed, with low PP being an independent predictor of mortality.