Adverse structural remodeling of the left ventricle and ventricular arrhythmias in patients with depressed ejection fraction.

BACKGROUND: The relationship of life-threatening ventricular arrhythmias to specific patterns of adverse LV remodeling has not been reported. We examined the relationship of ventricular tachycardia and/or fibrillation (VT/VF) to the pattern of left ventricular (LV) structural remodeling and to the degree of LV dysfunction in patients with a low ejection fraction (EF). METHODS AND RESULTS: Data from 127 patients with a low EF (≤0.45) and an implantable cardioverter-defibrillator (ICD) were examined and VT/VF identified by means of ICD device interrogation. Echocardiographic data were used to define LV structural remodeling (eccentric hypertrophy, concentric remodeling/hypertrophy, and normal geometry). VT/VF occurred in 26% of the 127 patients. VT/VF was more common in the 60 patients with LV hypertrophy versus the 67 with normal LV mass (40% vs 13%; P = .001) and in the 61 patients with LV enlargement versus the 66 with a normal chamber size (34% vs 18%; P = .04). When LV chamber size, wall mass, and geometry were assessed in a combinatorial fashion, a Kaplan-Meier analysis indicated that the occurrence of VT/VF was highest in the patients with eccentric hypertrophy (43%), intermediate in those with concentric remodeling/hypertrophy (30%), and lowest (12%) in those with normal geometry (all P < .02). The EFs were similar (P = ns) in these 3 groups of distinctly different patterns of remodeling. CONCLUSIONS: Life-threatening ventricular arrhythmias in patients with a low EF are related to the pattern of LV remodeling, not the degree of LV dysfunction. Risk stratification of such patients might be improved by a consideration of the pattern of LV remodeling.

Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial.

BACKGROUND: The mode of death has been well characterized in patients with heart failure and a reduced ejection fraction; however, less is known about the mode of death in patients with heart failure and a preserved ejection fraction (HFPEF). The purpose of this study was to examine the mode of death in patients with HFPEF enrolled in the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial and to determine whether irbesartan altered the distribution of mode of death in HFPEF. METHODS AND RESULTS: All deaths were reviewed by a clinical end-point committee, and the mode of death was assigned by consensus of the members. The annual mortality rate was 5.2% in the I-Preserve trial. There were no significant differences in mortality rate between the placebo and irbesartan groups. The mode of death was cardiovascular in 60% (including 26% sudden, 14% heart failure, 5% myocardial infarction, and 9% stroke), noncardiovascular in 30%, and unknown in 10%. There were no differences in the distribution of mode-specific mortality rates between placebo and irbesartan. CONCLUSIONS: Sixty percent of the deaths in patients with HFPEF were cardiovascular, with sudden death and heart failure death being the most common. Treatment with irbesartan did not affect overall mortality or the distribution of mode-specific mortality rates. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

An Appraisal of the Association of Clinical Outcomes With the Severity of Regurgitant Volume Relative to End-Diastolic Volume in Patients With Secondary Mitral Regurgitation.

Importance: Two randomized clinical trials of transcatheter edge-to-edge mitral valve repair in patients with secondary mitral regurgitation (the Multicentre Randomized Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation [MITRA-FR] and the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation [COAPT]) report clinical outcome disparities that are largely unexplained. This appraisal sought to provide insight and an explanation for the differences in clinical outcomes (survival and hospitalization rates) in the 2 clinical trials. The mean echocardiogram Doppler results (and derived volume parameters) from each of the 2 clinical trials were compared and examined relative to the clinical outcomes. Special emphasis was placed on the assessment of mitral regurgitation proportionality coefficients that were determined as the ratio of effective regurgitant orifice area (EROA) to end-diastolic volume and the ratio of mitral regurgitant volume to end-diastolic volume. Observations: In this analysis of the differences in the clinical outcomes of the MITRA-FR and COAPT clinical trials, the ratio of the EROA to the end-diastolic volume in the COAPT study was found to be twice that of the MITRA-FR study (0.002 cm-1 vs 0.001 cm-1, respectively). The finding of a larger proportional EROA in the COAPT study suggests more severe mitral regurgitation compared with the MITRA-FR study, thereby providing a potential explanation for the different outcomes in the 2 clinical trials. In contrast, the ratio of the mitral regurgitant volume to the end-diastolic volume in the COAPT study was similar to (but slightly lower than) that of the MITRA-FR study (0.15 vs 0.18, respectively), indicating that the proportional mitral regurgitant volume was comparable in the 2 clinical trials. This finding contradicts the conclusions of the EROA analysis. Conclusions and Relevance: The results of proportionality analyses based on EROA differ from those based on a volume analysis. This disparity casts doubt on the notion that an EROA analysis alone can explain the different results of the 2 randomized clinical trials.

Patterns of structural and functional remodeling of the left ventricle in chronic heart failure.

Patients with heart failure show a wide variety of alterations in left ventricular (LV) volume, mass, and function. The purpose of this study was to define the common patterns of LV structural and functional remodeling and consider their clinical implications in patients with chronic heart failure. Two-dimensional echocardiograms obtained during the screening phase of a study involving patients (n = 315) with chronic heart failure were used to calculate LV volume, mass, geometry, and ejection fraction (EF). Inclusion required the diagnosis of heart failure in symptomatic patients on medical therapy. Measures of LV size or function were not used as inclusion or exclusion criteria. Plots of EF against LV end-diastolic volume (EDV) showing an inverse curvilinear relation allowed a description of 4 remodeling patterns. Pattern A (n = 66) was defined as normal EDV (<91 ml/m(2)) and normal EF (> or =50%); 65% of these patients showed LV hypertrophy or concentric remodeling. Pattern B (n = 65) was defined as normal EDV and depressed EF; hypertrophy or concentric remodeling was present in 63%. Pattern C (n = 175) was defined as increased EDV and depressed EF; eccentric hypertrophy was present in 94%. Pattern D (n = 9) was defined as increased EDV and normal EF; eccentric hypertrophy was present in 88%. In conclusion, these patterns of remodeling encompass a wide spectrum of geometric changes with different clinical and pathophysiologic features and possibly different management strategies.

Cardiopulmonary exercise variables in diastolic versus systolic heart failure.

The response to cardiopulmonary exercise (CPX) in patients with heart failure (HF) with normal left ventricular (LV) ejection fractions (EFs) is not well characterized. To determine if CPX testing could distinguish between patients with HF with normal EFs (>50%; i.e., diastolic HF) and those with decreased EFs (> or =50%; i.e., systolic HF), CPX responses were compared between 185 patients with systolic HF (79% men, mean age 62.6 +/- 10.9 years) and 43 with diastolic HF (54% men, mean age 67.4 +/- 9.8 years) enrolled in a phase II multicenter clinical trial. All patients were evaluated with echocardiography and a standardized CPX test as part of the trial. CPX variables, including oxygen uptake at peak exercise (peak VO(2)) and the slope of the ventilation/carbon dioxide production ratio (VE/VCO(2)), were determined and analyzed by core laboratory personnel. Echocardiographic measurements included the LV EF, the E/A ratio, filling time, cavity volumes, right ventricular function, and mitral regurgitation. Patients in the diastolic HF group tended to be older (p <0.08), with more women (p <0.006) and with greater body mass indexes (p <0.02), than those in the systolic HF group. There was no significant difference in the use of beta blockers or the incidence of coronary artery disease. Patients with diastolic HF had decreased E/A ratios (0.9 +/- 0.4 vs 1.4 +/- 1.1, p <0.02, diastolic HF vs systolic HF) and increased filling times (30.4 +/- 3.2 vs 26.5 +/- 4.7 ms, p <0.01, diastolic HF vs systolic HF). No significant differences in peak VO(2) (14.4 +/- 1.9 vs 15.6 +/- 3.2 ml/kg/min, p = 0.06, diastolic HF vs systolic HF) were observed. The VE/VCO(2) ratios for the 2 groups were abnormal and comparable (32 2 +/- 7.5 vs 34.0 +/- 8.3, p = 0.3, diastolic HF vs systolic HF). In conclusion, the CPX response in patients with diastolic HF and systolic HF is markedly abnormal and indistinguishable with regard to peak VO(2) and ventilation despite marked differences in the LV EF.

Secondary mitral regurgitation (part 1): volumetric quantification and analysis.

Secondary mitral regurgitation (MR) develops as a consequence of left ventricular (LV) dilatation and dysfunction, which complicates its evaluation and management. The goal of this article is to review the assessment of secondary MR with special emphasis on quantification and analysis of LV volume data. At the present time, the optimal method for making these measurements appears to be cardiac MRI. In severe MR (both primary and secondary), the regurgitant fraction (RF) exceeds 50%, and as a result, the LV end diastolic volume (EDV) is increased. In secondary MR, the ejection fraction is depressed (generally <40%) and despite an RF >50%, the regurgitant volume (RegV) rarely meets the current published criteria for severe MR (>60 mL). The ratio of the RegV to EDV, which is very low in secondary MR, reflects the effect of the RegV on the ventricle and it may be predictive of the fractional change in LV size that can be expected after correction of MR. Accurate measurement of the volumetric parameters is essential to proper management of patients with secondary MR.

Secondary mitral regurgitation (part 2): deliberations on mitral surgery and transcatheter repair.

Secondary mitral regurgitation (MR) develops as a consequence of postinfarction remodelling of the ventricle or other causes of left ventricular (LV) dilatation and dysfunction. The presence of MR amplifies the poor prognosis of the failing ventricle, but it has not been established whether the adverse outcomes stem from the MR or whether the MR is simply a marker of progressive LV dysfunction. In this article, an attempt will be made to clarify the clinical impact of mitral surgery and transcatheter repair in patients with secondary MR. Observational studies indicate symptomatic improvement, but the results of randomised trials are mixed. Furthermore, neither mitral surgery nor transcatheter repair consistently leads to reversal of the adverse LV remodelling. There is, however, general agreement that these procedures do not have a salutary effect on survival. Certainly mitral surgery and transcatheter repair can substantially reduce the mitral regurgitant flow, but inconsistencies and uncertainties regarding clinical outcomes persist in the published literature. Some such problems could be resolved by utilisation of more accurate and reproducible imaging modalities in randomised studies of patients who are most likely to benefit from a reduction in the regurgitant volume-namely those with the most severe MR.

Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the left ventricle.

BACKGROUND: Patients with signs and symptoms of heart failure and a normal left ventricular ejection fraction are said to have diastolic heart failure. It has traditionally been thought that the pathophysiological cause of heart failure in these patients is an abnormality in the diastolic properties of the left ventricle; however, this hypothesis remains largely unproven. METHODS: We prospectively identified 47 patients who met the diagnostic criteria for definite diastolic heart failure; all the patients had signs and symptoms of heart failure, a normal ejection fraction, and an increased left ventricular end-diastolic pressure. Ten patients who had no evidence of cardiovascular disease served as controls. Left ventricular diastolic function was assessed by means of cardiac catheterization and echocardiography. RESULTS: The patients with diastolic heart failure had abnormal left ventricular relaxation and increased left ventricular chamber stiffness. The mean (+/-SD) time constant for the isovolumic-pressure decline (tau) was longer in the group with diastolic heart failure than in the control group (59+/-14 msec vs. 35+/-10 msec, P=0.01). The diastolic pressure-volume relation was shifted up and to the left in the patients with diastolic heart failure as compared with the controls. The corrected left ventricular passive-stiffness constant was significantly higher in the group with diastolic heart failure than in the control group (0.03+/-0.01 vs. 0.01+/-0.01, P<0.001). CONCLUSIONS: Patients with heart failure and a normal ejection fraction have significant abnormalities in active relaxation and passive stiffness. In these patients, the pathophysiological cause of elevated diastolic pressures and heart failure is abnormal diastolic function.

Deliberations on Diastolic Heart Failure.

Studies of left ventricular diastolic dysfunction and diastolic heart failure (DHF), published during the past 4 decades, include a prodigious number and wide variety of research efforts. This review report considers some of the historical literature and incorporates more recent information supporting the idea that patients with DHF constitute a subgroup of the heterogeneous population of patients with heart failure and a preserved ejection fraction. Clinical investigation, particularly therapeutic trials, should be directed at specific targets within the population of interest, not at the broad heart failure with preserved ejection fraction population. To accomplish this, it is important to stipulate criteria for the diagnosis of DHF and to limit our attention to specific subgroups or phenotypes.

Impedance to retrograde and forward flow in chronic mitral regurgitation and the physiology of a double outlet ventricle.

OBJECTIVE: Mitral regurgitation (MR) is generally characterised as exhibiting a 'low impedance leak into the left atrium'. This notion is widely accepted without measured impedance data. The aim of this study was to define the impedance to retrograde and forward blood flow and to examine hydraulic (pressure-volume) and mechanical (stress-shortening) function in chronic severe MR. METHODS: A mathematical model of a double outlet ventricle was developed and the ratio of retrograde to forward impedance was plotted over a wide range of regurgitant fraction (RF). The model predicts that an impedance ratio >1 indicates that the impedance to retrograde flow exceeds that of forward flow. Left ventricular (LV) systolic pressure/flow rate was used as an index of impedance (mm Hg/mL/s). Data from 10 patients with severe MR were used to assess the clinical applicability of the model. All patients had degenerative valve disease with partial flail leaflet, an RF >50% and an ejection fraction (EF) >0.60. There were seven males and three females, aged 59±10. LV volumes as well as retrograde and forward flow rates were determined with echocardiographic and Doppler techniques. RESULTS: The model indicates that the impedance ratio is >1 when the RF ranges from zero to 57%. Clinical data: end-diastolic volume=184±47 mL; EF=0.63±3%; RF=53±4%. Values for retrograde and forward impedance were 0.77±0.17 and 0.63±0.12 (p=0.003); the impedance ratio was 1.22±0.19. Total impedance to LV emptying was low (0.35±0.06). The ratio of systolic wall stress to EF (580±81 g/cm2) was normal. Data are mean±SD. CONCLUSIONS: The model, supported by clinical data, indicates that the impedance to retrograde flow exceeds the impedance to forward flow in chronic severe MR. These findings refute the notion of a low impedance leak into the left atrium. The double outlet of an enlarged ventricle provides a mechanism for low total impedance to ejection in the presence of a normal stress-shortening relation.

Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure.

BACKGROUND: Patients with diastolic heart failure (DHF) have significant abnormalities in left ventricular (LV) diastolic function, including slow and delayed relaxation and increased chamber stiffness. Whether and to what extent these abnormalities in diastolic function occur in association with abnormalities in LV systolic performance, function, and contractility has not been investigated thoroughly. METHODS AND RESULTS: The systolic properties of the LV were examined in 75 patients with heart failure and a normal ejection fraction (ie, DHF) and 75 normal control subjects with no evidence of cardiovascular disease. LV systolic properties were assessed with echocardiographic and cardiac catheterization data. Stroke work (an index of LV systolic performance), preload recruitable stroke work and ejection fraction (indices of LV systolic function), systolic stress-shortening relationship, end-systolic pressure-volume relationship, and peak (+)dP/dt (indices of LV contractility) were examined. The systolic properties of the LV were normal in patients with DHF. Stroke work was 8.4+/-2.3 in DHF versus 8.8+/-2.5 kg . cm in controls (P=0.26). Preload recruitable stroke work was 99+/-22 in DHF versus 109+/-18 g/cm2 in controls (P=0.13). The relationship between stroke work and end-diastolic volume was similar in DHF and controls. Peak (+) dP/dt was 1596+/-362 in DHF versus 1664+/-305 mm Hg/s in controls (P=0.54). The end-systolic pressure-volume relationship was increased in DHF. The systolic stress versus endocardial fractional shortening relationship was similar in DHF and controls. CONCLUSIONS: Patients with DHF had normal LV systolic performance, function, and contractility. The pathophysiology of DHF does not appear to be related to significant abnormalities in these systolic properties of the LV.

Heart failure in pressure overload hypertrophy. The relative roles of ventricular remodeling and myocardial dysfunction.

OBJECTIVES: We sought to explore the relative contributions of ventricular remodeling and myocardial dysfunction to heart failure in pressure overload hypertrophy (POH). BACKGROUND: The mechanism that underlies heart failure in POH is adverse left ventricular (LV) chamber remodeling or decreased myocardial function, or a combination of these. METHODS: Twenty weeks after suprarenal aortic banding in rats, animals with POH were classified as those with heart failure (POH-HF) or those with no heart failure (POH-NHF). The LV chamber and myocardial systolic and diastolic functions were determined from in vivo and ex vivo experiments. RESULTS: The LV mass was similar in both POH groups. Chamber remodeling in the POH-HF group was characterized by marked LV enlargement with a normal relative wall thickness (eccentric remodeling), whereas remodeling in the POH-NHF group was characterized by a normal chamber size and increased relative wall thickness (concentric remodeling). The LV systolic function, as determined in vivo from the end-systolic pressure-diameter relationship and ex vivo from the pressure-volume relationship, was lower in the POH-HF group than in the POH-NHF and sham-operated control groups. In contrast, myocardial function was similar in both POH groups, as determined in vivo from the stress-midwall fractional shortening relationship and myocardial systolic stiffness, and ex vivo from the slope of the LV systolic stress-strain relationship. The diastolic chamber stiffness constant was lower in the POH-HF group than in the POH-NHF group, but the myocardial stiffness constant was similar in the two POH groups. CONCLUSIONS: The two POH groups differed primarily in their remodeling process, which led to a chronically compensated state in one group and to heart failure in the other. Hence, heart failure in POH is more closely related to deleterious LV remodeling than to depressed myocardial function.

Lack of relationship between Doppler indices of diastolic function and left ventricular pressure transients in patients with definite diastolic heart failure.

OBJECTIVES: The purpose of this study was to compare invasive with noninvasive indices of diastolic function in a well-defined group of patients with diastolic dysfunction and a history of diastolic heart failure. BACKGROUND: Patients with heart failure and a normal left ventricular (LV) ejection fraction comprise a very large portion of the heart failure population and most are thought to have diastolic heart failure. While clinical and Doppler criteria for diastolic dysfunction and diastolic heart failure have been developed, there remains some controversy about the need for invasive cardiac catheterization and/or echo-Doppler evaluation of LV diastolic function. To date, there is no consensus as to the utility of these 2 methods in the diagnosis of diastolic heart failure. METHODS: Forty-seven patients (mean age 58 +/- 11 years) with a history of congestive heart failure and preserved ejection fraction (> or =50%) by echocardiography underwent a combined hemodynamic/echo-Doppler study. Patients with coronary disease were excluded. Invasive parameters of LV diastolic function (tau, LV diastolic pressures) and Doppler parameters (peak E, peak A, E/A ratio, isovolumic relaxation time, and E deceleration time) were measured using standard techniques. RESULTS: There was a close correlation between invasively-determined parameters (tau vs end diastolic pressure: r = 0.62, P <.001). The relationships between standard Doppler parameters and LV diastolic pressures were uniformly poor. However, the relationship between Doppler isovolumic relaxation time and tau improved considerably when patients were subgrouped by hemodynamic load. CONCLUSIONS: Standard echo-Doppler indices of diastolic function correlate poorly with LV diastolic pressure transients. The diagnosis of diastolic heart failure cannot be made on the basis of a single echo-Doppler parameter but, rather, all parameters must be examined in concert and used in combination with clinical observations.

Hypertension in patients with severe aortic stenosis: emphasis on antihypertensive treatment and the risk of syncope.

Published guidelines for the management of hypertension (HTN) do not discuss HTN in patients with aortic stenosis (AS). Some clinicians have considered severe AS to be a relative contraindication to the use of antihypertensive agents. We sought to determine the incidence of syncope in AS patients who were treated with antihypertensive agents. We identified 89 patients with asymptomatic severe AS and normal ejection fraction. The prevalence of HTN, its treatment, and the occurrence of syncope was abstracted from medical records. HTN was documented in 63 of the 89 patients with severe AS; 62 were being treated (mean 2.2 drugs). The incidence of syncope (mean follow-up: 44 months) was similar in patients with treated HTN compared to those without HTN (8 vs 11%, p=NS). Of the 62 with treated HTN, those with syncope were older than those without syncope (88+/- 6 vs 78 +/- 9 years, p=0.02). When those with treated HTN and syncope were compared to an age and sex matched cohort without syncope there were no significant differences in severity of AS, ejection fraction, or arterial pressure. Patients with treated HTN and syncope had a lower stroke volume index than those without syncope (32 +/- 4 vs 40 +/- 6 mL/m2, p=0.01). In conclusion, the risk of syncope in patients with severe AS and treated HTN is low and similar to that seen in AS patients without HTN. Syncope is related to age, female sex, and a low stroke volume index.

Adverse left ventricular remodeling in community-dwelling older adults predicts incident heart failure and mortality.

OBJECTIVES: This study sought to determine whether specific patterns of adverse left ventricular (LV) structural remodeling are associated with differential rates of cardiovascular (CV) outcomes. BACKGROUND: It is not known whether a stepwise combinatorial assessment of LV volume, mass, and geometry done to define specific remodeling patterns provides incremental prognostic information. METHODS: A total of 3,181 Cardiovascular Health Study participants (mean age, 73 years of age; 60% women, 5% African American) were categorized by LV remodeling patterns and related to a multivariate-adjusted (age, sex, race, ejection fraction, hypertension, myocardial infarction, diabetes mellitus, chronic kidney disease) analysis of CV outcomes (incident heart failure [HF], all-cause mortality, and a combined endpoint of HF and mortality) over a 13-year follow-up period. RESULTS: Examined independently, either left ventricular enlargement (LVE) or left ventricular hypertrophy (LVH) was associated with a higher risk of HF (32%, 34%, respectively) than with normal geometry (17%; p < 0.001). When LV volume and mass were used in combination, important incremental prognostic information was achieved. In the absence of LVE, HF was more common in those with LVH than in those with normal mass (32% vs. 16%, respectively; p < 0.001). In the presence of LVE, HF was more common in those with LVH than in those with normal mass (37% vs. 29%, respectively; p = 0.021). The subgroup with normal volume and mass but relative wall thickness (RWT) >0.42 carried a higher risk of HF (21%) than those with normal geometry (15%; p = 0.011). Once LVH or LVE was present, the addition of RWT to this analysis did not affect HF rate. Similar results were obtained for the other CV outcomes. CONCLUSIONS: Stepwise combinatorial assessment of LV volume, mass, and geometry provides incremental prognostic information regarding CV outcomes.