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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 (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., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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/cm 2 ) 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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright 2010 Elsevier Inc. All rights reserved.)

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.

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.

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.

Current noninvasive techniques used to evaluate left ventricular systolic function are limited by dependence on the angle of insonation (tissue Doppler imaging/TDI) or limited by availability (MRI tagging). We utilized 2-dimensional speckle strain (epsilon) imaging (1) to establish normal values for all three epsilon vectors; (2) to compare circumferential epsilon values with circumferential shortening (midwall fractional shortening (FS(mw)); (3) to examine the relationship between left ventricular epsilon and wall stress; and (4) to compare 2D echocardiographic characteristics by gender. Echocardiography was performed in 60 normal subjects (mean 39 +/- 15 years). Small, but significant regional heterogeneity was seen in circumferential epsilon, but not in radial or longitudinal epsilon. We found an inverse correlation between circumferential epsilon and stress (r =-0.29, p<0.05) as well as longitudinal epsilon and stress (r =-0.11, P < 0.05), though the relationships were not close. We also observed a linear relationship between mean circumferential epsilon and FS(mw) (r = 0.29, P < 0.05). In conclusion, (1) 2-dimensional epsilon imaging permits measurement of regional systolic epsilon values in the majority of normal individuals; (2) epsilon values furnished by this method obey expected stress-shortening relationships; (3) systolic epsilon displays minor regional heterogeneity in the circumferential direction; (4) for the first time, a close relationship between FS(mw) and mean circumferential epsilon was demonstrated; and (5) there are minor gender-related differences in LV geometry and function.

Physician-supervised exercise testing in asymptomatic patients with aortic stenosis allows an objective assessment of the hemodynamic response to exercise and it provides a measure of exercise capacity. Exercise testing cannot be used to determine the presence or absence of coronary artery disease, but limited data indicate that exercise testing can provide prognostic information. The results of such testing can be used to provide an exercise prescription and to reassure the patient who might otherwise excessively limit his or her activity.

A diagnosis of diastolic heart failure can be made if the patient exhibits clinical evidence of heart failure and has a normal left ventricular ejection fraction. The diagnosis is confirmed if there is evidence of ventricular hyperthrophy and/or concentric remodeling, left atrial enlargement, or laboratory evidence of diastolic dysfunction.

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.

Thirty to fifty percent of patients presenting with signs and symptoms of heart failure have a normal left ventricular (LV) systolic ejection fraction. The clinical examination cannot distinguish these patients (diastolic heart failure) from those with a depressed ejection fraction (systolic heart failure), but echocardiography can. The management of diastolic heart failure has two major objectives. The first is to reverse the consequences of diastolic dysfunction (e.g., venous congestion), and the second is to eliminate or reduce the factors responsible for diastolic dysfunction (e.g., myocardial hypertrophy, fibrosis, and ischemia).

Background: Paired electrical stimulation and postextrasystolic potentiation (PESP) of contractility has been extensively studied in ventricular myocardium, but less is known about PESP of atrial contractility. Our aim was to determine whether PESP of atrial contractility could augment left ventricular (LV) preload and improve LV systolic performance., Methods and Results: A paired electrical stimulus closely following the pacing stimulus was applied to isolated atrial and ventricular myocardium from 4 dog hearts, and the interval dependent force potentiation was examined. In isolated atrial myocardium, paired pacing increased the active tension from a baseline of 1.36 +/- 0.23 to 2.60 +/- 0.57 g/mm(2); in ventricular myocardium active tension increased from 2.58 +/- 0.42 to 3.81 +/- 0.27 g/mm(2) (both P <.01). Then, LV pressure (micromanometer) and segment length (ultrasonic crystals) were measured in the intact hearts of 7 anesthetized dogs in which premature stimuli were applied to the atrium. In intact hearts, paired pacing of the atrium (coupling interval 200 ms) increased LV end-diastolic pressure from 3.8 +/- 1.0 to 6.4 +/- 1.0 mm Hg; systolic pressure increased from 105 +/- 6 to 112 +/- 7 mm Hg (both P <.05). LV pressure-length loop area (regional stroke work) increased 10.5 +/- 0.2%., Conclusions: Isolated atrial myocardium exhibits substantial PESP of contractility, which is similar to ventricular myocardium. In the intact heart, atrial PESP augments LV systolic performance by effecting an increase in LV preload. This technique may provide a means of improving cardiac performance in patients with heart failure.

Paired pacing has been shown to potentiate contractile function of cardiac muscle, and it has been suggested that this may enhance contractile function of diaphragmatic muscle. The primary goal of this study was to study the effect of paired pacing on potentiation of contractile function of diaphragmatic muscle compared to atrial and ventricular myocardium. Diaphragmatic muscle was isolated from mouse and rat, and atrial and ventricular myocardium from dogs. Potentiation was induced by isolated extrastimuli (equal in duration and intensity to the pacing stimulus) and by repetitive extrastimuli (i.e. paired pacing) at a paced rate of 12, 30 and 60 beats/min. Baseline studies were performed while preparations were isometrically contracting at L(max) in oxygenated Krebs-Henseleit solution at 28 degrees C. Maximal force generation in response to a premature stimulus was determined at each rate by scanning the coupling interval between paced beats. Under baseline conditions, diaphragmatic muscle contracted faster than atrial and ventricular muscle. In all tissues, maximum potentiation (increase in force above baseline) was approximately 100% of baseline force, and peak potentiation occurred at shorter coupling intervals with increasing rates of stimulation. Single and paired pacing of diaphragm potentiated the contraction during which the extrastimuli were introduced, while in cardiac muscle, extrastimuli potentiated the contraction following the extrastimulus. The maximum potentiated response occurred when the extrastimulus was introduced prior to the development of peak force in diaphragmatic muscle. In contrast, in atrial and ventricular muscle, a single or paired premature stimulus potentiated the subsequent beat when delivered late during relaxation. In cardiac muscle, maximal potentiation gradually occurred following several repetitive stimuli. Following cessation of single and paired pacing, the beat following the potentiated response immediately returned to baseline in diaphragmatic muscle, while a gradual decline was evident over several subsequent beats in cardiac muscle. Increasing the bath temperature from 28 to 37 degrees C resulted in a leftward shift in the peak potentiated force vs. coupling interval curve without a decline in the magnitude of potentiated force in diaphragmatic muscle. In diaphragm muscle, exposure to ryanodine markedly decreased baseline force and maximal potentiation. We conclude that closely timed extrastimuli applied to diaphragmatic muscle can potentiate developed force in a given contraction, while in cardiac tissue a delayed stimulus potentiates the subsequent beat. These differences in contractile responsiveness are not due to differences in loading conditions, but appear to reflect intrinsic differences in calcium handling.

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.

Background: The diagnosis of diastolic heart failure is generally made in patients who have the signs and symptoms of heart failure and a normal left ventricular (LV) ejection fraction. Whether the diagnosis also requires an objective measurement of parameters that reflect the diastolic properties of the ventricle has not been established., Methods and Results: We hypothesized that the vast majority of patients with heart failure and a normal ejection fraction exhibit abnormal LV diastolic function. We tested this hypothesis by prospectively identifying 63 patients with a history of heart failure and an echocardiogram suggesting LV hypertrophy and a normal ejection fraction; we then assessed LV diastolic function during cardiac catheterization. All 63 patients had standard hemodynamic measurements; 47 underwent detailed micromanometer and echocardiographic-Doppler studies. The LV end-diastolic pressure was >16 mm Hg in 58 of the 63 patients; thus, 92% had elevated end-diastolic pressure (average, 24+/-8 mm Hg). The time constant of LV relaxation (average, 51+/-15 ms) was abnormal in 79% of the patients. The E/A ratio was abnormal in 48% of the patients. The E-wave deceleration time (average, 349+/-140 ms) was abnormal in 64% of the patients. One or more of the indexes of diastolic function were abnormal in every patient., Conclusions: Objective measurement of LV diastolic function serves to confirm rather than establish the diagnosis of diastolic heart failure. The diagnosis of diastolic heart failure can be made without the measurement of parameters that reflect LV diastolic function.

This study assesses and evaluates left ventricular (LV) contractile function after treatment of hypertension, with an emphasis on LV midwall mechanics. Although prior studies have assessed cardiac function after hypertension treatment, none has performed an analysis of LV midwall mechanics. The Veterans Affairs Study of monotherapy in hypertension was a study large enough to permit analysis of midwall mechanics across a wide spectrum of mass changes accompanying hypertension treatment. LV chamber function was assessed by computing fractional shortening at the endocardial surface; LV midwall shortening was used to define myocardial function. Both shortening indexes were related to end-systolic circumferential stress in the entire population by partitioning values of mass and relative wall thickness changes. Two hundred sixty-eight patients were studied at baseline and again after a 1- or 2-year period. In the entire group, there was no significant change in circumferential shortening either at the endocardium (38 +/- 8% at baseline vs 37 +/- 7% at follow up, p = 0.29) or in shortening at the midwall (20 +/- 3% vs 20 +/- 3%, p = 0.53). However, 83 patients had a reduction in relative wall thickness and an increase in midwall shortening. The change in midwall shortening was significantly related to changes in relative wall thickness (r = -0.53, p = 0.0001). Thus, reductions in LV mass associated with antihypertensive therapy are generally not accompanied by a decrement in LV chamber or myocardial function. Improvement in midwall shortening is more closely related to normalization of LV geometry than to reduction in LV mass.

Echocardiographic techniques were used to measure left ventricular isovolumic and ejection phase indexes of contractility in 54 patients with atrial fibrillation, and the relations between cycle lengths and contractility were compared in patients with normal and depressed ejection fractions. Data indicate that variations in contractility occur in a pattern that is consistent with postextrasystolic potentiation and that such interval-dependent potentiation is preserved in patients with atrial fibrillation and depressed ejection fraction.

Objectives: We sought to study the rate related effects of sotalol on myocardial contractility and to test the hypothesis that the class III antiarrhythmic effect of sotalol has a reverse use-dependent positive inotropic effect in the intact heart., Background: Antiarrhythmic drugs exert significant negative inotropic effects. Sotalol, a beta-adrenergic blocking agent with class III antiarrhythmic properties, may augment contractility by virtue of its ability to prolong the action potential duration (APD)., Methods: In 10 anesthetized dogs, measurements of left ventricle (LV) peak (+)dP/dt and simultaneous endocardial action potentials were made during baseline conditions and after sequential administration of esmolol and sotalol. In addition, electrical and mechanical restitution curves were constructed at a basic pacing cycle length of 600 ms by introducing a test pulse of altered cycle length ranging from 200 ms to 2,000 ms., Results: In the steady state pacing experiments, sotalol prolonged the APD in a reverse use-dependent manner; such an effect was not seen with esmolol. At cycle lengths exceeding 400 ms, LV (+)dP/dt was significantly higher with sotalol than it was with esmolol. There was a direct relation between APD and LV (+)dP/dt with sotalol (r = 0.46, p < 0.001), but there was no significant relation between APD and LV (+)dP/dt with esmolol (r = 0.27, p = NS). Results in the single beat (restitution) studies were qualitatively similar to the steady state results; APD (at cycle length >400 ms) and LV (+)dP/dt (at cycle length >600 ms) were significantly higher with sotalol than they were with esmolol., Conclusions: The reverse use-dependent prolongation of APD by sotalol is associated with a positive inotropic effect.

In 10 patients with atrial fibrillation, echocardiographic measures of left ventricular function-interval relations were used to assess contractility and to test the hypothesis that rhythm regularization produces a higher contractile state than is seen when the rhythm is irregular. Regularization, following direct-current cardioversion, did not augment ventricular contractility above that seen during atrial fibrillation.