It is estimated that approximately 50% of the heart failure population has a normal left ventricular ejection fraction, a complex broadly referred to as heart failure with normal left ventricular ...ejection fraction (HFNEF). While these patients have been considered in epidemiologic studies and clinical trials to represent a single pool of patients, limited more detailed studies indicate that HFNEF patients are a very heterogeneous group, with a number of key pathophysiologic mechanisms. This review summarizes and critically analyzes available data on the pathophysiology of HFNEF, placing it into context with a recently developed diagnostic algorithm. We evaluate the utility of commonly applied echocardiographic measures and biomarkers and integrate mechanistic observations into potential future therapeutic directions.
Objectives The purpose of this study was to invasively investigate the hemodynamic response to exercise in patients with heart failure with normal ejection fraction (HFNEF) and to evaluate the ...ability of the peak early diastolic transmitral velocity to peak early diastolic annular velocity ratio (E/e′) to reflect exercise hemodynamics. Background There is little information regarding the hemodynamic response to exercise in HFNEF. Methods Patients with HFNEF (n = 14) and asymptomatic controls (n = 8) underwent right-side heart catheterization at rest and during supine cycle ergometer exercise and echocardiography with measurement of resting and peak exercise E/e′. Results Resting pulmonary capillary wedge pressure (PCWP) (10 ± 4 mm Hg vs. 10 ± 4 mm Hg; p = 0.94) was similar in HFNEF patients and controls, but stroke volume index (SVI) (p = 0.02) was lower, and systemic vascular resistance index (SVRI) (p = 0.01) was higher in patients. Patients stopped exercise at lower work rate (0.63 ± 0.29 W/kg vs. 1.13 ± 0.49 W/kg; p = 0.006). Although peak exercise PCWP was similar in both groups (23 ± 6 mm Hg vs. 20 ± 7 mm Hg; p = 0.31), the peak PCWP/work rate ratio was higher in patients compared with controls (46 ± 31 mm Hg/W/kg vs. 20 ± 9 mm Hg/W/kg; p = 0.03). Peak exercise SVI (p = 0.001) was lower and SVRI was higher (p = 0.01) in patients. Resting E/e′ was modestly elevated in patients (13.2 ± 4.1 vs. 9.5 ± 3.4; p = 0.04). Peak exercise E/e′ did not differ between the groups (11.1 ± 3.4 vs. 9.4 ± 3.4; p = 0.28). Conclusions The HFNEF patients achieved a similar peak exercise PCWP to that of asymptomatic controls, at a much lower workload. This occurs at a lower SVI and in the setting of higher SVRI. The E/e′ does not reflect the hemodynamic changes during exercise in HFNEF patients.
The ratio of tricuspid regurgitation velocity (TRV) to the time-velocity integral of the right ventricular outflow tract (TVIRVOT) has been studied as a reliable measure to distinguish elevated from ...normal pulmonary vascular resistance (PVR). The equation TRV/TVIRVOT × 10 + 0.16 (PVRecho) has been shown to provide a good noninvasive estimate of PVR. However, its role in patients with significantly elevated PVR (> 6 Wood units WU) has not been conclusively evaluated. The aim of this study was to establish the validity of the TRV/TVIRVOT ratio as a correlate of PVR. The role of TRV/TVIRVOT was also compared with that of a new ratio, TRV(2)/TVIRVOT, in patients with markedly elevated PVR (>6 WU).
Data from five validation studies using TRV/TVIRVOT as an estimate of PVR were compared with invasive PVR measurements (PVRcath). Multiple linear regression analyses were generated between PVRcath and both TRV/TVIRVOT and TRV(2)/TVIRVOT. Both PVRecho and a new derived regression equation based on TRV(2)/TVIRVOT: 5.19 × TRV(2)/TVIRVOT - 0.4 (PVRecho2) were compared with PVRcath using Bland-Altman analysis. Logistic models were generated, and cutoff values for both TRV/TVIRVOT and TRV(2)/TVIRVOT were obtained to predict PVR > 6 WU.
One hundred fifty patients remained in the final analysis. Linear regression analysis between PVRcath and TRV/TVIRVOT revealed a good correlation (r = 0.76, P < .0001, Z = 0.92). There was a better correlation between PVRcath and TRV(2)/TVIRVOT (r = 0.79, P < .0001, Z = -0.01) in the entire cohort as well as in patients with PVR > 6 WU. Moreover, PVRecho2 compared better with PVRcath than PVRecho using Bland-Altman analysis in the entire cohort and in patients with PVR > 6 WU. TRV(2)/TVIRVOT and TRV/TVIRVOT both predicted PVR > 6 WU with good sensitivity and specificity.
TRV/TVIRVOT is a reliable method to identify patients with elevated PVR. In patients with TRV/TVIRVOT > 0.275, PVR is likely > 6 WU, and PVRecho2 derived from TRV(2)/TVIRVOT provides an improved noninvasive estimate of PVR compared with PVRecho.
Background Incidence, predictors, and prognostic impact of worsening renal function (WRF) in elderly patients with chronic heart failure (HF) undergoing intensive contemporary medical therapy are ...unknown. Methods and Results In 566 patients (age 77 ± 8 years) included in the TIME-CHF, serum creatinine (sCr) was repeatedly measured up to 6 months. Worsening renal function was classified as increase in sCr by 0.2 to 0.3 (WRFI), 0.3 to 0.5 (WRFII), or ≥0.5 mg/dL (WRFIII) within the first 6 months. Outcome events were assessed for 18 months. Results The incidence of WRF I, II, and III was 12%, 19%, and 22%, respectively. Worsening renal function III was associated with increased mortality (hazard ratio 1.98 95% CI 1.27-3.07, P = .002 vs no WRF), whereas WRF I/II was not. History of renal failure, spironolactone treatment, higher baseline dose, and higher maximal increase in loop diuretic dose were independently associated with the occurrence of WRF III, whereas angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and β-blocker use and allocation to N-terminal pro–B-type natriuretic peptide–guided management were not. Worsening renal function III was an independent predictor of death, death or hospitalization, and death or HF hospitalization also after adjusting for baseline characteristics. Conclusions One fifth of elderly patients with chronic HF experienced WRF III on 6-month intensive HF treatment. These patients had higher mortality, whereas patients with smaller sCr rises did not. Occurrence of WRF III was associated with high doses of loop diuretics and spironolactone use but not with other treatments.
Background Contemporary heart failure (HF) patients are elderly and have a high rate of early rehospitalization or death, resulting in a high burden for both the patients and the health care system. ...Prior studies were focused on younger and less well-characterized patients. We aimed to identify predictors of early hospital readmission and death in elderly patients with HF. Methods Patients with chronic HF taking part in the TIME-CHF study (n = 614, age 77 ± 8 years, 41% female, left ventricular ejection fraction 35% ± 13%) were evaluated with respect to predictors of hospital readmission or death 30 and 90 days after inclusion. Demographic, clinical, laboratory, echocardiographic, and social variables were obtained at baseline and included in a multivariable logistic regression analysis to identify predictors of early events. Results The rate of hospital readmission or death was high at 30 (11%) and 90 days (26%). The reason for hospitalization was HF in 33%, other cardiovascular in 32%, and noncardiovascular in 45% of the cases, respectively. Predictors of readmission or death at 30 days were angina, lower systolic blood pressure, anemia, more extensive edema, higher creatinine levels, and dry cough; and at 90 days were coronary artery disease, prior pacemaker implantation, high jugular venous pressure, pulmonary rales, prior abdominal surgery, older age, and depressive symptoms. Conclusions Early hospital readmission or death was frequent among elderly HF patients. A very large proportion of readmissions were due to noncardiovascular causes. In addition to clinical signs of HF, comorbidities are important predictors of early events in elderly HF patients.
Abstract Background In heart failure (HF), renal dysfunction is associated with an adverse prognosis. Impaired renal perfusion from left ventricular dysfunction is thought to be a principal ...underlying mechanism. Less is known about the influence of venous congestion, including the potential contribution of tricuspid regurgitation (TR). Methods and Results Echocardiograms and a simultaneous (±1 day) blood sample from 196 HF patients were analyzed. Patients with at least moderate TR (n = 78) had larger right-sided cardiac cavities, higher right ventricular systolic pressure, lower estimated glomerular filtration rate (eGFR), higher serum urea nitrogen (SUN), and SUN/creatinine ratio than patients with less than moderate TR (n = 118). In multivariate linear regression analysis, TR severity ( P = .003), older age ( P < .001), and loop diuretic use ( P = .008) were independently associated with lower eGFR, and use of inhibitors of the renin-angiotensin-aldosterone system was associated with higher eGFR ( P = .001). TR severity ( P < .001) and older age ( P < .001) were independently associated with higher SUN. TR severity ( P = .004) and smaller left ventricular end-diastolic diameter ( P = .048) were independent predictors of a higher SUN/creatinine ratio ( P = .004). Conclusions Although a causal relationship cannot be proven, we suggest that significant TR contributes to renal dysfunction in HF patients, probably by elevation of central and renal venous pressure.
Abstract Background Prediction of events in chronic heart failure (CHF) patients is still difficult and available scores are often complex to calculate. Therefore, we developed and validated a ...simple-to-use, multidimensional prognostic index for such patients. Methods A theoretical model was developed based on known prognostic factors of CHF that are easily obtainable: Body mass index (B), Age (A), Resting systolic blood pressure (R), Dyspnea (D), N-termInal pro brain natriuretic peptide (NT-proBNP) (I), Cockroft-Gault equation to estimate glomerular filtration rate (C), resting Heart rate (H), and Exercise performance using the 6-min walk test (E) (the BARDICHE-index). Scores were given for all components and added, the sum ranging from 1 (lowest value) to 25 points (maximal value), with estimated risk being highest in patients with highest scores. Scores were categorized into three groups: a low (≤ 8 points); medium (9–16 points), or high (> 16 points) BARDICHE-score. The model was validated in a data set of 1811 patients from two prospective CHF-cohorts (median follow-up 887 days). The primary outcome was 5-year all-cause survival. Secondary outcomes were 5-year survival without all-cause hospitalization and 5-year survival without CHF-related hospitalization. Results There were significant differences between BARDICHE-risk groups for mortality (hazard ratio = 3.63 per BARDICHE-group, 95%-CI 3.10–4.25), mortality or all-cause hospitalization (HR = 2.00 per BARDICHE-group, 95%-CI 1.83–2.19), and mortality or CHF-related hospitalization (HR = 3.43 per BARDICHE-group, 95%-CI 3.01–3.92; all P < 10–50). Outcome was predicted independently of left ventricular ejection fraction (LVEF) and gender. Conclusions The BARDICHE-index is a simple multidimensional prognostic tool for patients with CHF, independently of LVEF.
Abstract Background The cardiopulmonary exercise testing (CPET) response in heart failure with preserved left ventricular ejection fraction (HFPEF) is incompletely understood. We aimed to describe ...the CPET response in HFPEF and to assess its invasive hemodynamic determinants. Methods and Results Ten patients with HFPEF and 8 asymptomatic controls underwent resting and exercise right heart catheterization and maximal symptom-limited CPET. The slope of the minute ventilation/carbon dioxide production relationship (VE/VCO2 slope; 34.3 ± 5.4 vs. 28.4 ± 3.4; P = .02) was steeper, peak oxygen consumption (peak VO2 ; 15.1 ± 4.9 vs. 26.6 ± 12.5 mL∗kg-1 ∗min-1 ; P = .02) was lower, and heart rate recovery 1 minute after exercise termination (HRR-1; 10 ± 5 vs. 27 ± 10 beats/min; P < .001) was slower in HFPEF compared to controls. A steeper VE/VCO2 slope ( r = 0.67, P = .002), lower peak VO2 ( r = −0.48, P = .04), and slower HRR-1 ( r = −0.58, P = .02) were significantly related to a higher ratio of the change in pulmonary capillary wedge pressure per change in work rate as a measure of the left ventricular pressure volume relationship. Conclusions In HFPEF patients, fundamental alterations in the CPET profile occur and these may, in part, result from the rapid rise in left ventricular filling pressures which accompanies exercise in these patients.
The relationship between chest radiograph (CXR) findings of pulmonary congestion and invasive hemodynamics and clinical outcomes in patients with cardiac diseases is unclear. We assessed the ...correlation between a CXR-based congestion score (RxCS) and the mean pulmonary artery wedge pressure (mPAWP) and the prognostic impact of RxCS and mPAWP in severe aortic stenosis (AS).
In 471 patients with severe AS undergoing right heart catheterization and upright CXR, the RxCS was calculated (6 items, maximum score: 10 points) independently by 2 radiologists (average value taken) blinded to clinical data. Congestion was defined as an RxCS > 1. Four patterns were defined based on the presence or absence of congestion (C+ or C-) and elevated (> 15 mm Hg) or normal mPAWP (P+ or P-).
The median (interquartile range) RxCS was 1 (0-2). Patients with an RxCS > 1 (n = 207) had a higher mean right atrial pressure, mean pulmonary artery pressure, mPAWP, and pulmonary vascular resistance than patients with an RxCS ≤ 1 (n = 264). However, the correlation between the RxCS and the mPAWP was moderate only (
= 0.45). Patients with a C+/P+ pattern had the worst hemodynamics, whereas C-/P- patients had the most favourable constellation. After a median post-valve replacement follow-up of 1361 days, mortality was higher in patients with RxCs > 1 vs ≤ 1 as well as mPAWP > 15 mm Hg vs ≤15 mm Hg. Mortality was highest in C+/P+ patients and lowest in C-/P- patients, whereas it was intermediate in C-/P+ and C+/P- patients.
In AS patients, RxCS and mPAWP have a significant but moderate correlation. Both RxCS and mPAWP provide prognostic information.
Abstract Background There is little information regarding the prognostic role of resting heart rate (HR) in older compared with younger patients with chronic heart failure (HF). Methods and Results ...In patients enrolled in the Trial of Intensified Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) with sinus rhythm, effects of baseline HR (≥70 vs <70 beats/min bpm) on 18-month outcomes were compared between older (≥75 years; n = 186) and younger (<75 years; n = 141) patients. Older patients with lower (61 ± 6 bpm) and higher (83 ± 9 bpm) HR had similar left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and survival and HF hospitalization–free survival. In contrast, younger patients with higher HR (81 ± 7 bpm) had higher NT-proBNP and NYHA functional class, lower LVEF, and a higher risk of death (hazard ratio 4.01 95% confidence interval (CI) 1.17 −13.69; P = .02) and death or HF hospitalization (hazard ratio 2.35 95% CI 1.01–5.50; P = .04) than those with lower HR (62 ± 5 bpm), with the association between higher HR and survival remaining significant after adjustment for NYHA functional class, LVEF, and NT-proBNP. Conclusions In contrast to HF patients aged <75 years, we found no association between HR and worse outcomes in HF patients aged ≥75 years.
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