Feasibility of Interleukin-6 Receptor Blockade in Cardiac Antibody-mediated Rejection.

BACKGROUND: Antibody-mediated rejection (AMR) remains a significant cause of heart transplant mortality with few effective therapies. METHODS: This study aimed to describe initial experience of using interleukin-6 receptor blockade with tocilizumab in the treatment of acute cardiac AMR at Barnes-Jewish Hospital/Washington University Transplant Center from July 2017 to May 2021 (n = 7). Clinical, echocardiographic, and serum alloantibody data were analyzed before and after treatment. RESULTS: All participants demonstrated marked improvement in functional status. Echocardiographic data following 4-6 mo of tocilizumab revealed significant improvements in biventricular systolic function for all participants. Consistent reductions in donor-specific HLA or angiotensin type I receptor antibodies were not observed, suggesting that tocilizumab may act downstream of antibody production. No patient experienced drug-related complications that necessitated discontinuation of therapy. CONCLUSIONS: These findings provide initial insights into the safety and efficacy of interleukin-6 receptor blockade in the treatment of cardiac AMR and support the design of larger prospective studies.

The Effect of Glycemic Control on Left Ventricular Function in Clinical and Experimental Diabetes.

Background: Glycemic control in diabetes mellitus (DM) has not improved cardiovascular outcomes with normal left ventricular (LV) function. We assessed the effect on LV dysfunction using a canine model of LV dysfunction and DM, and in patients with DM and LV dysfunction. Methods: Chronic LV dysfunction was produced by coronary microsphere embolization in 34 canines (15-25 kg). Following 8 weeks of stabilization, DM was induced in 24 canines and randomized to good or poor glycemic control for 3 months. Ten canines without DM were controls. Hemodynamic and Doppler echocardiographic data were obtained prior to and following pressure loading. We reviewed the Doppler-echocardiography at baseline and follow-up in 207 patients with DM with reduced ejection fraction (EF; median follow-up = 612 days) and 60 age- and sex-matched non-DM patients with normal EF. Laboratory results, medications, and incident adverse events from medical records were obtained. Results: EF = 43.8% ± 11.2% for all canines at 8 weeks. Canines with poor glycemic control (hemoglobin [Hb]A1c = 8.05% ± 3.02%) demonstrated reduced LV mass and rate-corrected velocity of circumferential fiber shortening, compared to those with LV dysfunction (1.36 ± 0.73 vs 0.88 ± 0.13 circumference per second, P < 0.01). Good glycemic control (HbA1c = 3.88% ± 0.89%) demonstrated similar LV parameters, compared to controls (HbA1c = 2.99% ± 0.44%). EF was similar among groups. Patients with vs without DM were followed for up to 3 years. Patients with DM and poor glycemic control had reduced EF, lower rate-corrected velocity of circumferential fiber shortening = 0.93 ± 0.26 vs 1.11 ± 0.26, P < 0.001), and greater incidence of heart failure. Conclusions: Poor glycemic control had an adverse effect on preexisting LV dysfunction experimentally and in patients with type 2 diabetes.

Contexte: Chez les personnes atteintes de diabète sucré (DS), la maîtrise glycémique n'a pas amélioré les résultats cardiovasculaires en présence d'une fonction ventriculaire gauche (VG) normale. Nous avons évalué l'effet d'une dysfonction VG au moyen d'un modèle canin de dysfonction VG et de DS, ainsi que chez des patients atteints de ces deux troubles. Méthodologie: Une dysfonction VG chronique a été produite chez 34 chiens (pesant de 15 à 25 kg) au moyen d'une embolisation coronarienne par microsphères. Après huit semaines de stabilisation, un DS a été provoqué chez 24 chiens, qui ont été répartis aléatoirement pour faire l'objet d'une bonne ou d'une mauvaise maîtrise glycémique pendant trois mois. Les 10 chiens sans DS ont servi de témoins. Des données hémodynamiques et échocardiographiques (Doppler) ont été obtenues avant et après la mise en charge. Nous avons aussi étudié l'échocardiogramme Doppler, au départ et lors du suivi, de 207 patients atteints de DS et présentant une fraction d'éjection (FE) réduite (suivi médian de 612 jours) et de 60 patients non atteints de DS qui ont été appariés en fonction de l'âge et du sexe et dont la FE était normale. Enfin, nous avons obtenu leurs dossiers médicaux : résultats des épreuves de laboratoire, listes de médicaments et manifestations indésirables découvertes fortuitement. Résultats: La FE était de 43,8 % ± 11,2 % pour l'ensemble des chiens après huit semaines. Chez les chiens dont la maîtrise glycémique était mauvaise (hémoglobine [Hb]A1c = 8,05 % ± 3,02 %), la masse VG et la vitesse de raccourcissement circonférentiel des fibres myocardiques corrigée en fonction de la fréquence cardiaque (VCFc) étaient toutes deux réduites comparativement à celles observées chez les chiens présentant une dysfonction VG (1,36 ± 0,73 vs 0,88 ± 0,13 circonférence par seconde [circ/s], p < 0,01). Chez les chiens avec une bonne maîtrise glycémique (HbA1c = 3,88 % ± 0,89 %), les paramètres VG étaient semblables à ceux observés chez les témoins (HbA1c = 2,99 % ± 0,44 %). La FE était également similaire dans tous les groupes. Les patients atteints de DS ont été suivis et comparés à des patients non atteints de DS pendant une durée allant jusqu'à trois ans. Les patients qui étaient atteints de DS et dont la glycémie était mal maîtrisée présentaient une FE réduite, une diminution de la VCFc (0,93 ± 0,26 vs 1,11 ± 0,26; p < 0,001) et une incidence accrue de cas d'insuffisance cardiaque. Conclusions: Une mauvaise maîtrise glycémique a eu un effet indésirable sur une dysfonction VG préexistante, tant dans le modèle animal que chez les patients atteints de diabète de type 2.

Predictors of heart failure and all-cause mortality in asymptomatic patients with moderate and severe aortic regurgitation.

BACKGROUND: Class I indications for aortic valve replacement (AVR) for severe chronic aortic regurgitation (AR) include AR attributable symptoms or left ventricular (LV) ejection fraction <50%. As noninvasive estimates of elevated LV filling pressures (LVFP's) have been noted to predict heart failure (HF) readmission and all-cause mortality (ACM) in HF patients, we hypothesize that elevated LVFP's may also be independent predictors of HF and ACM in chronic AR. METHODS: We developed a single center patient database of moderate or greater AR diagnoses between 2003 and 2008 and followed each patient through January 2013. We included patients with >30 days follow-up with interpretable Doppler-echocardiograms. We recorded demographic variables, EuroScore II, incident HF and ACM, and Doppler-echo variables of LV size, systolic and diastolic function. RESULTS: Patients with severe AR (105 patients) and moderate AR (201 patients) had similar EuroScore II values and similar incident HF and ACM. For the 180 patients who developed HF, effective arterial elastance (aHR = 1.70 (1.01-2.83), p = .041), LV end-diastolic dimension (aHR = 1.83, (1.11-3.03), p = .0176), E/e' (aHR = 3.04, (1.83-5.05), p < .0001), eccentric hypertrophy (EH) (aHR = 2.39, (1.62-5.12), p = .0004), and tricuspid regurgitation (TR) velocity (aHR = 5.75, (3.70-10.36), p < .0001) were independent predictors. For the 118 patients with ACM, EH (aHR = 1.73, (1.02-3.28), p = .0414), systolic blood pressure (aHR = .58, (.33-.95), p = .0301), left atrial volume index (aHR = 1.82, (1.06-3.06), p = .0293), E/e' (aHR = 1.83, (1.07-3.08), p = .0280), and TR velocity (aHR = 4.14, (2.22-6.49), p < .0001) were independent predictors. CONCLUSIONS: Elevated TR velocity and EH were strong markers of HF and ACM in patients with asymptomatic severe AR and in moderate AR.

Diastolic function grading by American Society of Echocardiography guidelines and prediction of heart failure readmission and all-cause mortality in a community-based cohort.

BACKGROUND: Diastolic function (DF) guidelines have been simplified but lack extensive outcome data. Using a rural university heart failure (HF) database, we assessed whether DF grading could predict HF, HF readmission, and all-cause mortality (ACM). METHODS: In this single-center retrospective study that included 613 patients in sinus rhythm hospitalized for HF (HF with preserved-254 patients, with mid-range-216 patients, and reduced ejection fraction-143 patients), we recorded demographics, Doppler-echo, Framingham HF score, laboratories, HF readmission, and ACM with follow-up to 2167 days. RESULTS: Diastolic dysfunction (Ddys) parameters (left atrial volume index [LAVI] > 34 ml/m2 , tricuspid regurgitation [TR] velocity > 2.8 m/sec, and E/e' > 14) had moderate sensitivity (46.2%-65.0%) for predicting HF among all phenotypes combined with DF grading having moderate predictability and additive to a clinical composite for HF prediction (AUC = .677, P < 0.0001; difference = .043, P < 0.001) for combined phenotypes. Ddys parameters and Ddys severity (2016 ASE criteria: grade II and III) were significantly associated with HF readmission for decompensated HF within 60-2167 days of follow-up (LAVI > 34 ml/m2 : HR 1.56 [1.26-2.19]; E/e' > 14: HR 1.44 [1.21-1.99]; TR > 2.8 m/sec: H1.43 [1.19-1.88]; LV Dys grade II: HR 2.12 [1.42-2.96]; LV Ddys grade III: HR 2.39 [1.57-4.82]). CONCLUSION: The findings of this study highlight the clinical and prognostic relevance of determining the severity of LV Ddys in patients with HF with regard to HF verification and HF readmission.

Adverse Outcomes with Eccentric Hypertrophy in a Community Based University Cohort with Aortic Stenosis.

OBJECTIVE: Aortic stenosis (AS) patients with eccentric hypertrophy (Ecc-LVH) have increased left ventricular (LV) size and possibly reduced ejection fraction (EF). However, previous studies suggest worse outcomes with concentric remodeling and hypertrophy. We hypothesized that Ecc-LVH pattern in AS patients will also be associated with greater heart failure (HF) and all-cause mortality (ACM). METHODS: We queried the electronic medical record from a community-based university practice for all AS patients. We included patients with >60 days follow-up and interpretable Doppler echocardiograms. We recorded demographics, Doppler-echo parameters, laboratories, HF readmission and ACM with follow-up to 2083 days. There were 329 patients divided into 4 groups based on the presence of LV hypertrophy (LVH) and relative wall thickness (RWT) by echocardiography. Ecc-LVH had RWT<0.43 and LVH. RESULTS: Patients with severe AS were older, had greater coronary disease prevalence, lower hemoglobin, greater LV mass index, more abnormal diastolic function, greater HF and ACM. Multivariate Cox proportional analysis revealed that valvulo-arterial impedance (p=0.017) and Ecc-LVH (p=0.033) were HF predictors. Brain natriuretic peptide>100 pg/ml (p<0.001) and Ecc-LVH (p=0.019) were ACM predictors. ACM was increased in Ecc-LVH patients with both moderate (HR=3.67-8.18 vs other geometries, p=0.007-0.0007) and severe AS (HR=3.94-9.48 vs normal and concentric remodeling, p=0.0002). In patients with HF, Ecc-LVH was associated with greater HF in moderate AS vs normal geometry (HR=3.28, p=0.0135) and concentric remodeling (HR=2.66, p=0.0472). CONCLUSIONS: Patients with AS and Ecc-LVH have greater ACM than other LV geometries with both moderate and severe AS and greater HF in moderate AS.

Clinical Characteristics, Comorbidities and Prognosis in Patients With Heart Failure With Mid-Range Ejection Fraction.

BACKGROUND: Patients with left ventricular ejection fractions between 40% and 49% either discovered de novo, having declined from ≥50%, or improved from <40% have been described as heart failure (HF) with mid-range ejection fraction (HFmrEF). Though clinical signs and symptoms are similar to other phenotypes, possible prognostic differences and therapeutic responses reinforce the need for further understanding of patients' characteristics especially in a rural community based population. The purpose of this study is to evaluate the clinical characteristics, comorbidities and prognosis of a rural patient population with HFmrEF. MATERIALS AND METHODS: We queried the electronic medical record from a community based university practice for all patients with a HF diagnosis. We included only those patients with >3 months follow-up and interpretable Doppler echocardiograms. We recorded demographic, Doppler-echo, and outcome variables (up to 2,083 days). RESULTS: There were 633 HF patients: 42.4% with preserved ejection fraction (HFpEF, EF ≥50%), 36.4% with HFmrEF, and 21.0% with reduced ejection fraction (HFrEF, EF <40%). HFmrEF patients were older, had greater coronary disease prevalence, lower systolic blood pressure, elevated brain natriuretic peptide, lower hemoglobin, and higher creatinine than HFpEF. All-cause mortality was intermediate between HFrEF and HFpEF but was not significantly different. Landmark analysis revealed a trend toward greater second readmission in HFmrEF as compared to HFpEF (hazard ratio: 1.43 [0.96-2.14],P = 0.0767). CONCLUSIONS: Rural patients with HFmrEF without an ambulatory HF clinic represent a higher percentage of HF patients than previously reported with greater coronary disease prevalence with comparable readmission rates and nonsignificantly different all-cause mortality.

The relation of left ventricular geometry to left ventricular outflow tract shape and stroke volume index calculations.

BACKGROUND: Stroke volume (SV) and aortic valve area calculations require the left ventricular (LV) outflow tract (LVOT) or aortic annular area calculations that involve squaring the respective diameters. Area calculation errors became evident with transcatheter aortic valve replacement where areas were underestimated due to an elliptical annulus. We hypothesized that LVOT and annular shape are more elliptical in patients with greater relative LV wall thickness (RWT) leading to underestimation of SV index using 2D Doppler echocardiography. METHODS: We studied 203 consecutive patients referred to an outpatient noninvasive laboratory for Doppler echocardiograms which included acceptable 3-dimensional images. 3-dimensional assessment of the LVOT at 3-5 mm from the valve insertion, at the site of valve insertion, and at the sinus of Valsalva (SOV) was performed with assessment of the minor axis (MN), major axis (MJ), and areas at mid-systole. SV index was calculated from LVOT and annular diameters obtained from 2-dimensional echo and from 3-dimensional LVOT areas. RESULTS: An inverse relation of RWT with MN/MJ at mid-systole for the LVOT (r = 0.5812, P < 0.0001) and annulus (r = 0.6865, P < 0.0001) was noted. LVOT and annulus areas were similar among groups at mid-systole. SV index calculated from 2D LVOT dimensions was significantly smaller than using 3D LVOT areas (35.6 ± 8.9 vs 53.6 ± 16.1 mL, P < 0.0001). CONCLUSION: There is an inverse relation between MN/MJ and RWT at the LVOT and aortic annulus despite the LVOT and annular areas being similar across most geometries resulting in SV index underestimation calculated using LVOT diameters vs 3D LVOT areas.

Indexing peak rapid filling velocity to both relaxation and filling volume to estimate left ventricular filling pressures.

AIMS: The peak transmitral velocity/peak mitral annular velocity (E/e') ratio has been used as a left ventricular (LV) filling pressure (LVFP) correlate. However, the E/e' and its changes with haemodynamic alterations have not always correlated with changes in LVFP's. We hypothesized that indexing E/e' to a measure of LV filling volume may enhance the correlation with LVFP and LVFP changes. METHODS AND RESULTS: We summarized previously obtained haemodynamic and Doppler echo data in 137 dogs with coronary microsphere embolization induced-chronic LV dysfunction prior to and following haemodynamic induced alterations in LVFP's. E/e' values were obtained as E*tau where tau is the inverse logarithmic LV pressure decay. E*tau was indexed to LV filling volume by dividing by the diastolic time velocity integral (DVI) and correlated with LV mean diastolic pressure (LVmDP). Similarly, the relationship of E/e' and E/e'/DVI to LV pre A wave pressure was evaluated in 84 patients by invasive haemodynamics and Doppler echo. Combining data from all interventions, LVmDP correlated with E*tau (r = 0.408) but more strongly with E*tau/DVI (r = 0.667, z = 3.03, P = 0.0008). The change in LVmDP correlated with the change in E*tau/DVI (r = 0.742) more strongly than E*Tau (r = 0.187, Z = 4.01, P < 0.0001). In the patient cohort, E/e' was modestly correlated with LV pre A wave pressure (r = 0.301) but more strongly correlated with E/e'/DVI (r = 0.636, z = 2.36, P = 0.0161). CONCLUSION: Indexing E to both LV relaxation and filling volume results in a more robust relation with LVFP's and with LVFP changes.

Aortic Dissection in a Healthy Male Athlete: A Unique Case with Comprehensive Literature Review.

A young otherwise healthy 27-year-old male who has been using anabolic steroids for a long time developed Type I aortic dissection associated with heavy weightlifting. The patient did not have a recent history of trauma to the chest, no history of hypertension, and no illicit drug use. He presented with severe chest pain radiating to back and syncopal event with exertion. Initial vitals were significant for blood pressure of 80/50 mmHg, pulse of 80 beats per minute, respirations of 24 per minute, and oxygen saturation of 92% on room air. Physical exam was significant for elevated jugular venous pressure, muffled heart sounds, and cold extremities with diminished pulses in upper and absent pulses in lower extremities. Bedside echocardiogram showed aortic root dilatation and cardiac tamponade. STAT computed tomography (CT) scan of chest revealed dissection of ascending aorta. Cardiothoracic surgery was consulted and patient underwent successful repair of ascending aorta. Hemodynamic stress of weightlifting can predispose to aortic dissection. Aortic dissection is a rare but often catastrophic condition if not diagnosed and managed acutely. Although rare, aortic dissection needs to be in the differential when a young weightlifter presents with chest pain as a delay in diagnosis may be fatal.

Fractional flow reserve using computed tomography for assessing coronary artery disease: a meta-analysis.

AIMS: Noninvasive fractional flow reserve (FFR) measurement with computed tomography (FFRCT) is a newly described method for assessing functional significance of coronary disease. The objective of this meta-analysis is to determine the diagnostic performance of FFRCT in the assessment of hemodynamically significant coronary artery stenosis. METHODS: PubMed and the Cochrane Center Register of Controlled Trials were searched from January 2000 through February 2015. Six original studies were found comparing FFRCT to invasive FFR in evaluating hemodynamic significance of coronary lesions (1354 vessels; 812 patients). Lesions were considered hemodynamically significant if invasive FFR was 0.80 or less. FFRCT used the same cutoff as invasive FFR to be considered as a positive test. Sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio were calculated. RESULTS: One-third of the lesions (n = 443) were hemodynamically significant. The pooled per-vessel analysis showed that the sensitivity, specificity, negative and positive likelihood ratios, and diagnostic odds ratio of FFRCT to diagnose hemodynamically significant coronary disease were 0.84 [95% confidence interval (CI): 0.80-0.87], 0.76 (95% CI: 0.73-0.79), 0.22 (95% CI: 0.17-0.29), 3.48 (95% CI: 2.21-5.47), and 16.82 (95% CI: 8.20-34.49), respectively. CONCLUSION: The results of this meta-analysis demonstrate that FFRCT results correlate closely with invasive coronary angiography and FFR measurement. It is a feasible noninvasive method to assess hemodynamic significance of coronary lesions in patients with stable coronary artery disease.

Adverse Cardiac Events and the Impaired Relaxation Left Ventricular Filling Pattern.

BACKGROUND: Increasing diastolic dysfunction (DD) grade is associated with increased heart failure (HF). Patients with preserved ejection fractions and grade 1 DD may have left atrial dilatation, e' < 8 cm/sec, increased left ventricular (LV) mass, or variable E/e' ratios. The aim of this study was to test the hypothesis that LV hypertrophy or E/e' ratio > 8 may be associated with a greater incidence of HF. METHODS: Two hundred twelve patients with grade 1 DD and ejection fractions > 50% were retrospectively studied. Group 1 comprised 108 patients with E/A ratios < 0.8, without LV hypertrophy, e' < 8 cm/sec, and E/e' ratios < 8. Group 2 comprised 104 patients with LV hypertrophy or E/e' ratios > 8. Patients with incident HF and valvular or coronary disease were excluded. Using two-dimensional Doppler echocardiography, LV and left atrial volumes and transmitral spectral and tissue Doppler were analyzed. Medical records were examined for laboratory data, HF admissions, and all-cause mortality from 2004 to 2012. RESULTS: Despite similar ejection fractions, patients in group 2 had greater LV and left atrial volumes, LV mass index values, and E/e' ratios (P < .01 for all). HF incidence was greater in group 2 (30 vs 4, P < .001). Combined HF or all-cause mortality was greater in group 2 (46 vs 14, P < .001). Multivariate analysis revealed that HF was associated with E/e' ratio (P < .0001), systolic blood pressure (P = .0123), and LV mass index (P = .042). Combined HF or all-cause mortality was associated with E/e' ratio (P < .0001), LV mass index (P = .009), and lower calcium channel blocker use (P = .0011). CONCLUSIONS: HF alone or HF and all-cause mortality were increased in patients with grade 1 DD in the presence of LV hypertrophy or elevated LV filling pressures.

Reduced Longitudinal Function in Chronic Aortic Regurgitation.

BACKGROUND: Chronic aortic regurgitation (AR) patients demonstrate left ventricular (LV) remodeling with increased LV mass and volume but may have a preserved LV ejection fraction (EF). We hypothesize that in chronic AR, global longitudinal systolic and diastolic function will be reduced despite a preserved LV EF. METHODS: We studied with Doppler echocardiography 27 normal subjects, 87 patients with chronic AR with a LV EF > 50% (AR + PEF), 66 patients with an EF < 50% [AR + reduced LV ejection fraction (REF)] and 82 patients with hypertensive heart disease. LV volume, transmitral spectral and tissue Doppler were obtained. Myocardial velocities and their timing and longitudinal strain of the proximal and mid wall of each of the 3 apical views were obtained. RESULTS: As compared to normals, global longitudinal strain was reduced in AR + PEF (13.8 ± 4.0%) and AR + REF (11.4 ± 4.7%) vs. normals (18.4 ± 3.6%, both p < 0.001). As an additional comparison group for AR + PEF, global longitudinal strain was reduced as compared to patients with hypertensive heart disease (p = 0.032). The average peak diastolic annular velocity (e') was decreased in AR + PEF (6.9 ± 3.3 cm/s vs. 13.4 ± 2.6 cm/s, p < 0.001) and AR + REF (4.8 ± 2.1 cm/s, p < 0.001). Peak rapid filling velocity/e' (E/e') was increased in both AR + PEF (14.4 ± 6.2 vs. 6.2 ± 1.3, p < 0.001) and AR + REF (18.8 ± 6.4, p < 0.001 vs. normals). Independent correlates of global longitudinal strain (r = 0.6416, p < 0.001) included EF (p < 0.0001), E/e' (p < 0.0001), and tricuspid regurgitation velocity (p = 0.0176). CONCLUSION: With chronic AR, there is impaired longitudinal function despite preserved EF. Moreover, global longitudinal strain was well correlated with noninvasive estimated LV filling pressures and pulmonary systolic arterial pressures.

Candidates for transcatheter aortic valve replacement: fitting the PARTNERS criteria.

OBJECTIVES: To determine an estimate patient volume with severe AS meeting PARTNER-B criteria, with the objective of providing insights into the annual volume needed to sustain a TAVR program. BACKGROUND: While the prevalence of AS is well documented, potential TAVR candidates remains less established. A better understanding of this population is critical for the development of TAVR programs. Though no clear volume has been determined, societies suggest a minimum of 20-24 annual cases to establish a TAVR program. METHODS: A total of 21,652 patients were screened from a single center echocardiography registry over a 3-year period. From them, 833 patients with AS were identified representing our study population. Severity was stratified by echocardiographic criteria. Those identified to have moderate-to-severe and severe AS were further investigated to determine clinical status and surgical candidacy. Nonsurgical candidates were cross referenced with the PARTNER-B exclusion criteria to determine eligibility for TAVR. RESULTS: Symptomatic AS was present in 133 patients (16%). Fifty (38%) were considered nonsurgical candidates. Nonsurgical patients had higher STS score (11.1 ± 10.8 vs. 4.0 ± 3.3, P < 0.001). After applying PARTNERS-B exclusion criteria, only 18 patients (14%) were considered TAVR candidates. These findings indicate that to meet the recommended annual volume of 20-24 TAVR cases, a minimum of 150-170 symptomatic severe AS patients are required. CONCLUSION: In real world clinical practice, the prevalence of AS meeting PARTNERS-B criteria for TAVR can be low. These findings suggest that either high volume valvular centers or regional referral centers will need to be considered as part of the strategy to incorporate this new technology into clinical practice.

Exercise Tolerance and the Post Exercise Diastolic Filling Pattern in Patients With the Resting Impaired Relaxation.

BACKGROUND: In patients with normal LV systolic function, cardiac output increases with exercise mediated by increased stroke volume early in exercise and an increase in heart rate later in exercise. Despite normal LV systolic function, patients who display an impaired relaxation pattern may have a reduced exercise tolerance. We hypothesized that the resting impaired relaxation pattern that persists during exercise results in reduced LV filling volume and reduced exercise tolerance. METHODS: We evaluated consecutive exercise echocardiograms performed at Harper Hospital from 1998-2000 for patients with sinus rhythm, normal resting wall motion and ejection fraction (> 55%), evidence of resting impaired relaxation, and a negative exercise echocardiogram. There were 49 patients fitting the above criteria who were compared with a group of age and sex matched patients (43 patients) with a normal rest and exercise echocardiogram with normal resting transmitral Doppler. Rest and post exercise echocardiography and Doppler parameters were obtained. RESULTS: Patients in the impaired relaxation group demonstrated shorter exercise times as compared to the normal control group (8.8 ± 1.6 versus 9.7 ± 2.0 minutes, P < 0.001). In patients with normal resting transmitral diastolic filling, there was an increased the extent of atrial contribution to LV filling volume post exercise associated with shortening of isovolumic relaxation. Two patterns were seen in the impaired relaxation group post exercise. In 1 subgroup in which E/A ratio decreased post exercise, exercise duration was reduced (7.4 ± 1.3 minutes, P < 0.001) as compared to the subgroup with E/A increase (9.6 ± 1.2 minutes) post exercise which was similar to normal controls. Forward stepwise regression indicated that exercise time was primarily related to E/A change post exercise for all patient groups (r = 0.625, P = 0.0008). Specifically, this was true for patients with E/A reversal at rest (r = 0.584, P = 0.0028). However, for patients with normal diastolic filling at rest, the diastolic velocity integral was the major predictor (r = 0.695, P < 0.0084). CONCLUSION: We conclude that the transmitral Doppler pattern post exercise provides insight into the mechanism of reduced exercise tolerance in some patients with the resting impaired relaxation pattern. Preservation of this pattern post exercise is associated with reduced exercise tolerance.

Comparison of the effect of pressure loading on left ventricular size, systolic and diastolic function in canines with left ventricular dysfunction with preserved and reduced ejection fraction.

BACKGROUND: Decompensated heart failure may present with severe hypertension in patients with preserved (PreEF) or reduced left ventricular (LV) ejection fraction (RedEF) and is clinically indistinguishable. Previously, we demonstrated that arterial pressure elevation increases LV filling pressures in a canine model of chronic LV dysfunction with PreEF or RedEF. It is not clear whether any differences in hemodynamics, LV volume or performance, or diastolic function can be demonstrated between canines with PreEF or RedEF in response to arterial pressure elevation. We hypothesized that the LV systolic, diastolic, and hemodynamic response to pressure loading would be similar in RedEF or PreEF. METHODS: We studied 25 dogs with chronic LV dysfunction due to coronary microsphere embolization with RedEF (35 +/- 4%) and 20 dogs with PreEF (50 +/- 3%). Arterial pressure was increased with methoxamine infusion and hemodynamics and echo-Doppler parameters of LV size, function, transaortic and transmitral pulsed Doppler prior to and with methoxamine infusion was obtained. RESULTS: Though LV filling pressures were similar at baseline, LV size was larger (p < 0.01) and ejection fraction lower in dogs with RedEF (p < 0.001). With methoxamine, there were similar increases in LV size, LV pressures, and index of myocardial performance with the ejection fraction reduced similarly. Diastolic parameters demonstrated similar tau increases, E/A reduction, and diastolic filling shortening in RedEF and PreEF dogs. A similar extent of isovolumic contraction and relaxation times and index of myocardial performance prolongation occurred with pressure loading. CONCLUSION: Pressure loading in a canine model of LV dysfunction with PreEF and RedEF resulted in similar degrees of LV dilatation, increased filling pressures, and increased index of myocardial performance.

Effect of external constraint on the index of myocardial performance in a canine model of left ventricular dysfunction.

BACKGROUND: With left ventricular (LV) dysfunction, it is not clear how alterations in external constraint influence the index of myocardial performance (IMP). We have previously demonstrated that pericardial constraint is a factor in the production of the restrictive filling pattern. We hypothesized that altering pericardial constraint by changing intracardiac volume or removing the pericardium would produce similar directional changes in LV ejection time (LVET) and isovolumic relaxation time (IRT) resulting in minimal IMP changes. METHODS: We studied 13 canines with chronic moderate LV dysfunction. LV pressures, transmitral and transaortic Doppler were obtained prior to and following pericardiectomy (PECT) with alterations of intracardiac volume, using inferior vena caval occlusion (IVCO) and volume loading. RESULTS: With an intact pericardium, IVCO reduced LV size, LV end diastolic pressure (LVEDP), and increased deceleration time (all P < 0.05) but did not affect IMP. Volume loading increased LV size, LVEDP, and shortened deceleration time (all P < 0.05). LVET and IRT lengthened (P < 0.05), and IMP declined (0.58 +/- 0.24 to 0.52 +/- 0.13, P < 0.05). Following PECT, IVCO reduced LV volumes and LVEDP (P < 0.05), but did not change IMP. Volume loading increased LV size, stroke volume, and LVEDP (all P < 0.05). IMP declined (0.57 +/- 0.13 vs 0.51 +/- 0.14, P < 0.05) due to an increase in both LVET and IRT (P < 0.05). Comparison of stages prior to and following PECT revealed an increased LVET and stroke volume (P < 0.05) but a similar IMP. CONCLUSION: Increases in intracardiac volume associated with elevated LVEDP resulted in reduced IMPs. Pericardiectomy increases LV volumes, stroke volume, and LVET but did not influence IMP.

The effect of acute hypertension on left ventricular diastolic pressures in a canine model of left ventricular dysfunction with a preserved ejection fraction and elevated left ventricular filling pressures.

BACKGROUND: Decompensated heart failure with preserved left ventricular (LV) ejection fraction (EF) is often accompanied by hypertensive episodes. We hypothesized that acute increase in arterial pressure results in elevated early and late diastolic LV pressures as a result of further impaired LV relaxation. METHODS: To test this hypothesis, we used a chronic canine model of LV systolic dysfunction with preserved LV function (LVDPEF) (EF > 50%) and elevated LV end-diastolic pressure using coronary microsphere embolization. At baseline and with LVDPEF, each dog was paced 10 beats above their baseline heart rate and high-fidelity LV pressures, echocardiographic LV volumes, and transmitral Doppler were obtained before and after methoxamine pressure loading. RESULTS: With normal LV function, LV pressures at peak negative dP/dt (+18 mm Hg, P < .05) and at LV pressure minimum (+3.6 mm Hg, P < .01) increased. Both tau (P < .05) and LV end-diastolic pressure increased (5 +/- 3 vs 13 +/- 4 mm Hg, P < .01). EF was unchanged, although LV end-diastolic volume increased (P < .01). Pressure loading with LVDPEF resulted in a timing delay (P < .05) and a greater increase in LV pressures at peak negative dP/dt (+45 mm Hg) and LV minimal pressure (+7.5 mm Hg) as compared with normal LV function (P < .01). LV end-diastolic pressure increased (9 +/- 2-23 +/- 5 mm Hg, P < .001), diastolic filling period shortened (288 +/- 51-204 +/- 54 milliseconds, P < .01), and tau increased (P < .001). EF declined from 54 +/- 9% to 43 +/- 9% (P < .05) and LV size increased (P < .01). CONCLUSIONS: Pressure loading with normal LV function and with LVDPEF results in increased LV diastolic pressures, which are further exaggerated with LVDPEF as a result of prolonged relaxation and shortened diastolic filling.

Effect of changes in contractility on the index of myocardial performance in the dysfunctional left ventricle.

BACKGROUND: The index of myocardial performance has prognostic power in patients with cardiomyopathy and following myocardial infarction. As the index of myocardial performance has been shown to be preload and afterload dependent, the effect of altering contractility on IMP and its components with left ventricular dysfunction has been incompletely delineated. METHODS: Chronic left ventricular dysfunction was induced in 10 canines using coronary microsphere embolization. Each dog was instrumented and imaged with 2D echo and Doppler. At the same atrially paced rate, contractility was increased with a dobutamine infusion and then following 4 weeks of oral digoxin. RESULTS: With chronic left ventricular dysfunction, a reduced left ventricular ejection fraction (42 +/- 3%, p < 0.001) and increased index of myocardial performance (0.58 +/- 0.17, p < 0.01) due to isovolumic contraction time lengthening and shortened left ventricular ejection time were noted. Dobutamine increased ejection fraction (p < 0.001), reduced left ventricular end diastolic pressure (p < 0.01), and reduced the index of myocardial performance (0.33 +/- 0.17, p < 0.001) due to isovolumic contraction time, isovolumic relaxation time, and left ventricular ejection time shortening. Digoxin increased ejection fraction (p < 0.05), reduced left ventricular end diastolic pressure (p < 0.05), and reduced the index of myocardial performance (0.42 +/- 0.13, p < 0.01) due to isovolumic contraction time shortening (p < 0.001). Both dobutamine and digoxin lengthened the diastolic filling period (p < 0.01). CONCLUSION: Increased inotropy with digoxin and dobutamine reduced the index of myocardial performance in dogs with left ventricular dysfunction. Shortened isovolumic contraction time, increased diastolic filling period, and reduced left ventricular end diastolic pressure with digoxin may provide insight into its efficacy in heart failure.