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.

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.

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.

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.

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.

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.

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.

Left ventricular structural remodeling in health and disease: with special emphasis on volume, mass, and geometry.

The changes in left ventricular (LV) structure and geometry that evolve after myocardial injury or overload usually involve chamber dilation and/or hypertrophy. Such architectural remodeling can be classified as eccentric or concentric. Consideration of LV volume, mass, and relative wall thickness (or mass/volume) allows classification of LV remodeling that includes virtually all LV remodeling changes that are seen in health and disease. These various architectural changes generally include the development of LV hypertrophy in a pattern that is closely related to the type of injury or overload, and they are accompanied by differences in cardiac function and hemodynamics. Some patterns of remodeling are associated with adverse outcomes whereas others appear to be adaptive and physiologic without adverse consequences. Considering all patients with LV hypertrophy as a homogenous group is inconsistent with our understanding of the various remodeling patterns that are discussed in this review.

Prevalence and clinical characteristics of nondilated cardiomyopathy and the effect of atrial fibrillation.

The treatment of patients with chronic heart failure and those with asymptomatic left ventricular (LV) dysfunction has focused primarily on patients with LV enlargement and a low ejection fraction (EF). Little attention has been paid to those with a normal chamber size and a low EF. We sought to examine the LV geometry and clinical characteristics in such patients with nondilated cardiomyopathy. Of 3,350 transthoracic echocardiograms performed during a 6-month period, 696 showed an EF of < or =0.45. The patients with an end-diastolic diameter of >56 mm, regional wall motion abnormalities, or valvular disease were excluded. Of the 696 patients, 98 met these criteria, and their medical records were reviewed. The average age was 71 +/- 14 years, and 56% were men. Common co-morbidities included hypertension in 52% and atrial fibrillation (AF) in 43%. Only 22% had disabling cardiac symptoms (functional class III or greater). The average end-diastolic dimension was 49 +/- 5 mm, and the EF was 34 +/- 8%. LV hypertrophic remodeling was present in 53%. A second echocardiogram (422 +/- 177 days after the baseline study) was available for 54 patients. The chamber size was unchanged, but the EF had increased from 33 +/- 8% to 40 +/- 14% (p <0.01). The improvement in EF was seen in the group with AF (33 +/- 6% to 44 +/- 15%, p <0.01) but not in those with normal sinus rhythm (33 +/- 9% to 37 +/- 12%, p = NS). In conclusion, 14% of patients with an EF of < or =0.45 had nondilated cardiomyopathy, often with LV hypertrophic remodeling and/or AF. An improvement in LV function can be expected in many patients with nondilated cardiomyopathy, particularly those with AF.

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.

Distribution of left ventricular ejection fraction in patients with ischemic and hypertensive heart disease and chronic heart failure.

The clinical manifestations and eventual outcomes of chronic heart failure (HF) are not closely related to the left ventricular ejection fraction (EF). This has contributed to the single syndrome hypothesis of HF that assumes a continuum, with the EF evolving and decreasing as the ventricle remodels and dilates. Such a continuum might be expected to be manifest as a unimodal distribution of EF in populations with chronic HF. We examined the distribution of EF in 2 populations of patients with HF (EF range 0.10 to 0.85), and we tested the hypothesis that the EF distribution is unimodal. In both populations, the distribution histogram was bimodal. This result is consonant with the 2 different patterns of cardiac structural and functional remodeling seen in patients with HF and normal and depressed EF. It is also consonant with published differences in response to the inhibition of the renin-angiotensin system in these 2 groups. In conclusion, the observed bimodal distribution of EF in patients with chronic HF is a reflection of 2 HF phenotypes with different underlying pathophysiologic features.