Normal Left Ventricular Performance Research Articles

CILP1 and NTproBNP in pulmonary hypertension and right ventricular pressure overload: a translational experimental study

Abstract Introduction Cartilage intermediate layer protein 1 (CILP1) has emerged as a novel marker of right ventricular (RV) dysfunction in pulmonary hypertension (PH), although there is still little evidence on its role in different scenarios of RV pressure overload. The aim of our study was to analyze CILP1 as a biomarker of RV remodeling and PH severity, and compare it with N-terminal pro-brain natriuretic peptide (NTproBNP), in different experimental models of RV pressure overload. Methods Three different experimental models of RV pressure overload compared to a sham procedure were evaluated in 24 Yucatan pigs: chronic postcapillary PH by pulmonary vein banding (M1, n=6); chronic PH by aorto-pulmonary shunting (M2, n=6); RV pressure overload by PA banding (thus without PH) (M3, n=6); and sham procedure (M0, n=6). Animals were evaluated at 8 months after surgery by right heart catheterization, cardiac magnetic resonance (CMR), and blood/histological sampling. Levels of CILP1 and NTproBNP at the RV myocardium and blood were determined with dedicated ELISA and compared among groups by Wilcoxon test with Bonferroni correction. Associations between biomarkers and RV performance indices and pulmonary arterial pressure (PAP) were assessed with Spearman correlation test. Results M1 animals developed chronic postcapillary PH with normal left ventricular (LV) performance and RV maladaptive hypertrophy (RV fibrosis and systolic dysfunction). M2 animals developed chronic precapillary PH associated with LV dilatation and RV maladaptive hypertrophy. On contrast, M3-animals developed severe RV pressure overload (without PH) and hypertrophy but maintained normal RV systolic function. CILP1 and NTproBNP levels were moderately correlated (R=0.56, p=0.002). CILP1 levels in RV myocardium and plasma were significantly higher in M1, whereas NTproBNP plasma levels were significantly higher in M2 (Figure 1). CILP1 in plasma and RV myocardium significantly correlated with PAP, while myocardial CILP1 levels also correlated with RV extracellular volume (RV-ECV) by CMR (Figure 2). NTproBNP myocardial levels correlated with RV ejection fraction and RV-ECV and plasmatic levels correlated with PAP (Figure 2). Conclusions CILP1 levels were increased in the presence of PH and isolated RV dysfunction, whereas NTproBNP levels were increased in the model of PH, RV dysfunction and LV remodeling. Myocardial levels of both peptides correlated with diffuse fibrosis, estimated by CMR, whereas plasmatic levels of both biomarkers correlated with PAP. This suggests that CILP1 may be a more specific marker of RV dysfunction in PH, being less dependent of LV parameters.CILP1 and NTproBNP levels among modelsCorrelation with PAP & RV remodeling

P1321 A case of multiple levels of ventricular obstruction

Abstract Subaortic stenosis (SAS) is a rare entity in adults with unclear etiology and variable presentation. SAS may be presented with symptoms mimicking Hypertrophic Cardiomyopathy (HCM). Often a combination of imaging modalities is needed to distinguish SAS from HCM with obstruction. A 53 years old man, smoker, was referred to our medical center suffering from shortness of breath on exertion. He first presented at another facility with a 2 month history of shortness of breath and chest discomfort during brisk physical activity and the possible diagnosis of HCM was made. On physical examination, a 3/6 systolic murmur was audible along the left sternal border, that became louder with standing and the Valsalva maneuver. The patient had non distended jugular veins, clear lung fields and no ankle edema. The results of laboratory exams did not reveal any pathological sign. The transthoracic echocardiogram revealed significant left ventricular hypertrophy (Interventricular septum 21 mm, Posterior wall 16 mm) with normal left ventricular systolic performance (ejection fraction >70%). The aortic valve was tricuspid and calcified whereas mitral valve was morphologically normal, with systolic anterior motion and mild posterolaterally directed regurgitation. Two systolic gradients, one dynamic, late peaking of 85mmHg and another fixed of 70mmHg were detected in left ventricular outflow track (LVOT). Transesophageal echocardiography was performed for the better evaluation of aortic valve and showed a three level obstruction caused by the systolic motion of the mitral valve towards the hypertrophic septum at LVOT, the presence of a membranous subaortic membrane and the calcified aortic valve respectively. The aortic valve was calcified with a moderate stenosis (0.8cm2 / m2) from 3D planimetry. A Cardiac Magnetic Resonance exam was ordered and confirmed the significance of hypertrophy and the presence of circumferential subaortic membrane. No late enhancement after the administration of Gadolinium was observed. Coronary angiography was performed and demonstrated normal coronary arteries. We hypothesized that the presence of subaortic membrane led to marked myocardial wall thickness and to the destruction of the aortic valve due to turbulent flow in the LVOT. The patient was referred for surgical management Extended septal myectomy combined with complete resection of orbital subaortic membrane were performed. he calcified aortic valve was replaced by bioprosthetic valve No 23mm. The patient tolerated the procedure well with significant symptomatic improvement. TTE performed 1 month postoperatively showed no remarkable LVOT gradient. The results of histopathology and genes investigations are pending. Subaortic membrane is a rare cause of symptoms that can mimic hypertrophic cardiomyopathy. A combination of imaging modalities is needed to distinguish subaortic stenosis from aortic valve stenosis and hypertrophic obstructive cardiomyopathy. Abstract P1321 Figure. Three levels obstruction

Norepinephrine Induces Endothelial Albumin Uptake via ROS and Src‐Dependent Mechanisms

Hypertensive pulmonary edema often occurs acutely and is typically associated with normal left ventricular performance. Factors other than simple Starling forces may contribute to the molecular mechanisms by which increased blood pressure leads to acute endothelial barrier failure and lung edema.MethodsTo mimic an adrenergically‐mediated hypertensive crisis, we administered norepinephrine (NE) to rats and assessed indices of edema development. Rats were anesthetized with isoflurane and mechanically‐ventilated; subjects received an infusion of NE to target a MAP = 150mmHg. Lung wet/dry ratio, ΔPaO2, plasma hematocrit, lung MPO activity, BAL protein and cell analysis were assessed. Inhibition of nitric oxide synthase (NOS) by L‐NAME was used to test the contribution of endothelial mechanotransduction on changes in permeability. In parallel studies, rat lung microvascular endothelial cells were stimulated with norepinephrine in the presence or absence of propranolol (10−5M, β‐adrenoceptor antagonist), phentolamine (10−5M, α‐adrenoceptor antagonist), PP2 (10−5M, Src inhibitor), apocynin (3×10−5M, ROS scavenger), or L‐NIO (10−4M, NOS inhibitor). Reactive oxygen species (ROS) production was determined by DHE fluorescence. Albumin uptake was assessed by ELISA and albumin transport was measured by fluorimetry.ResultsNE‐treated rats had a decrease in PaO2, an increase in lung albumin content, MPO activity and wet/dry ratio. BAL fluid had increased protein content and number of macrophages indicative of inflammation. L‐NAME significantly attenuated NE‐induced pulmonary edema. In vitro, albumin uptake and transport was increased by NE in a time‐dependent manner. ROS production was augmented by NE. Phentolamine, PP2 and apocynin decreased NE‐induced albumin uptake and ROS generation, effects not altered by L‐NIO.SummaryWe describe a novel pathway whereby norepinephrine stimulates albumin uptake and potentially endothelial permeability which might be important in hypertensive pulmonary edema.Support or Funding InformationDepartment of Anesthesiology, University of Illinois at Chicago

Image Diagnosis: Pericardial Cyst in a Dialysis Patient

Pericardial cysts are rare, usually benign congenital anomalies but may also be acquired. They represent 6% of mediastinal masses and 33% of all mediastinal cysts.1) The vast majority are asymptomatic and are usually found incidentally on chest radiographs, computed tomography scans, magnetic resonance images, or echocardiography.2) Large pericardial cysts may cause compression on adjacent structures and organs, resulting in dyspnea, chest pain, or persistent cough.3) There have been reports of cyst rupture, cardiac compression, atrial fibrillation, and even sudden cardiac death from these cysts, although these complications are uncommon.4) A 55-year-old Italian dialysis patient with a shortness of breath, asthenia and excessive fatigability was referred to our institution. He had history of pericarditis, myocarditis and massive pleural effusion. His electrocardiogram showed sinus rhytm. Transthoracic echocardiography (TTE) revealed normal left and right ventricular systolic performance, with normal wall thicknesses and chamber sizes and a pericardial thickening. Color Doppler imaging showed a mild mitral and tricuspid regurgitation. Apical and subcostal views of TTE showed an oval echolucent structure at the right cardiophrenic angle, minimally compressing the right atrium, and of approximately 10 × 4 cm, consistent with a pericardial cyst (Fig. 1). Cardiac magnetic resonance (CMR) confirmed echocardiography findings, showing the presence of the pericardial cyst with several fibrinous strands inside associated with right-sided massive pleural effusion. Late gadolinium-enhanced CMR images showed intramural myocardial enhancement in anterior and inferior wall and enhancement of pericardium, as an expression of myocardial and pericardial inflammation (Fig. 2). The patient was treated conservatively because of high surgical risk attributed to severe kidney failure. A repeated TTE with the apical 4-chamber view at 20 months later showed minimal increase in the size of the pericardial cyst. The discovery of a pericardial cyst obliges the clinician to perform a broad differential diagnosis with a coronary artery aneurysm, dextrocardia, malignancy, and even pneumonia.5) CMR may help in this diagnosis. Fig. 1 Echocardiographic evaluation revealed a pericardial cyst in the inferior wall of the left ventricle. Fig. 2 Vertical long-axis (A and D) and short-axis (B, C, E, and F) cardiac magnetic resonance (CMR) images of pericardial cyst in patient with pericarditis, myocarditis and massive pleural effusion. Cyst (white asterisks) has low signal intensity on T1-weighted ...

ATP Production Rate via Creatine Kinase or ATP Synthase In Vivo

Rationale: 31 P magnetization saturation transfer (MST) experiment is the most widely used method to study ATP metabolism kinetics. However, its lengthy data acquisition time greatly limits the wide biomedical applications in vivo, especially for studies requiring high spatial and temporal resolutions. Objective: We aimed to develop a novel superfast MST method that can accurately quantify ATP production rate constants ( k f ) through creatine kinase (CK) or ATP synthase (ATPase) with 2 spectra. Methods and Results: The T 1 nom (T 1 nominal) method uses a correction factor to compensate the partially relaxed MST experiments, thus allowing measurement of enzyme kinetics with an arbitrary repetition time and flip angle, which consequently reduces the data acquisition time of a transmurally differentiated CK k f measurement by 91% as compared with the conventional method with spatial localization. The novel T 1 nom method is validated theoretically with numeric simulation, and further verified with in vivo swine hearts, as well as CK and ATPase activities in rat brain at 9.4 Tesla. Importantly, the in vivo data from swine hearts demonstrate, for the first time, that within an observation window of 30 minutes, the inhibition of CK activity by iodoacetamide does not limit left ventricular chamber contractile function. Conclusions: A novel MST method for superfast examination of enzyme kinetics in vivo has been developed and verified theoretically and experimentally. In the in vivo normal heart, redundant multiple supporting systems of myocardial ATP production, transportation, and utilization exist, such that inhibition of one mechanism does not impair the normal left ventricular contractile performance.

Prognostic implication of valvular lesion and left ventricular size in asymptomatic patients with chronic organic mitral regurgitation and normal left ventricular performance

To date, few studies have evaluated asymptomatic patients with organic mitral regurgitation (MR). The goal of the present study was to assess the presence of independent predictive factors for progression of symptoms and/or left ventricular dysfunction (SLVSD) in this population. We prospectively evaluated 128 consecutive patients (mean age 60 +/- 8 years, 68% men; ejection fraction 66 +/- 3%) who were asymptomatic, with severe organic MR. Mean follow-up was 29 +/- 12 months. The combined end point was SLVSD. Clinical and echocardiographic variables were evaluated. Follow-up data were also estimated considering the annualized rate (?) of the echocardiographic indices. Thirty-seven patients (29%) had SLVSD during follow-up. Cox regression model identified the effective regurgitant orifice area (EROA) >55 mm2 (risk ratio 6.3, 95% CI 2.3-8.1, P < .001) and end-systolic diameter >22 mm/m2 (risk ratio 4.5, 95% CI, 1.8-9.4, P < .02) as the only independent predictors of SLVSD. When the follow-up data were added, the ?EROA (>15 mm2/y) was independently associated with the end point. In asymptomatic patients with organic MR, the EROA and the end-systolic diameter are independent predictors of SLVSD and allow a better risk stratification in this group of patients. ANALYTICAL SUMMARY: The goal of this study was to determine the presence of independent predictors of symptomatic progression, and/or left ventricular dysfunction in asymptomatic patients with severe mitral regurgitation. We prospectively evaluated 128 consecutive patients (mean age 60 +/- 8 years, 68% male; ejection fraction 66 +/- 3%). During follow-up (mean 29 +/- 12 months). The end point occurred in 37 patients (29%). Multivariate analysis using Cox model identified the effective regurgitant orifice area (EROA) >55 mm2 (RR: 6.3; 95% CI: 2.3-8.1; P < .001) and an end-systolic diameter (ESD) >22 mm/m2 (RR: 4.5; 95%CI: 1.8-9.4; P < .02) as the only independent predictors of the end point. When the follow-up data were added, the annualized change rate of the EROA (>15 mm2/year) was independently associated with the end point. In asymptomatic patients with organic mitral regurgitation, the EROA and ESD at study entry were independent predictors of the combined end point and allowed a better risk stratification in this group of patients.

Response to Letter Regarding Article “Contractile Behavior of the Left Ventricle in Diastolic Heart Failure: With Emphasis on Regional Systolic Function”

We appreciate Dr Sanderson’s interest and support of our efforts to better understand cardiac function in patients with diastolic heart failure (DHF) and welcome the opportunity to respond. We have previously reported normal left ventricular systolic performance, function, and contractility in patients with DHF and have concluded that the pumping ability of the whole ventricle is normal in the basal state.1 To our knowledge, there are no published data that refute this …

Stroke Volume and Mitral Annular Velocities: Insights from Uremic Patients with Significant Valvular Regurgitation

This study investigates the change in new diastolic indices in uremic patients who undergo regular hemodialysis (H/D). We studied uremic patients receiving regular H/D. All patients were sinus rhythm before H/D. They had normal left ventricular systolic performance without regional wall motion abnormality. Patients were separated into two groups according to whether they had significant aortic or mitral regurgitation (AR or MR) or not. They received complete transthoracic echocardiographic examinations. Stroke volume (SV) was calculated as the product of the time-velocity integral (TVI) and cross-sectional area of aortic annulus. Flow propagation velocity (FPV) was measured by color M-mode echocardiography in apical four-chamber view. Mitral annulus tissue Doppler velocities--peak systolic (Sa), early diastolic, and late diastolic--were measured from septal and lateral wall. All these parameters were obtained immediately before and after H/D. Paired data were compared. H/D amount was strongly correlated with the change of SV. After H/D, the reduction of SV in patients without AR or MR (control group) was obvious but it was not significant in patients with significant AR or MR (study group). There were significant differences in mitral inflow velocities, FPV, and mitral annular velocities (except septal Sa) in the control group. In the study group, predialytic and postdialytic parameters of new diastolic indexes had no statistical difference. New echocardiographic indexes of uremic patients with significant AR or MR were relatively preload-independent. The phenomenon was possibly related to insignificant change of SV after H/D.

Doppler Tissue Imaging and Color M-Mode Flow Propagation Velocity: Are They Really Preload Independent?

This study investigated the change in new diastolic indexes in patients with uremia who undergo regular hemodialysis (H/D). We studied 81 patients with uremia (41 men and 40 women) receiving regular H/D. All patients were in sinus rhythm before H/D. They had normal left ventricular systolic performance without regional wall-motion abnormality. Three patients were excluded because of atrial fibrillation after H/D. Patients were separated by the amount of body fluid removed during H/D procedure: 30 patients with H/D amount less than 2 kg (group 1), 33 patients with H/D amount between 2 and 3 kg (group 2), and 18 patients with H/D amount larger than 3 kg (group 3). They received complete transthoracic echocardiographic examinations. Flow propagation velocity (FPV) was measured by color M-mode echocardiography in apical 4-chamber view. Mitral annulus Doppler tissue velocities (peak systolic [Sa], early diastolic [Ea], and late diastolic [Aa]) were measured from septal, lateral, inferior, and posterior walls. All these parameters were obtained immediately before and after H/D. Paired data were compared. In patients with removed fluid amount less than 2 kg (group 1), the change of all diastolic parameters showed insignificant change except FPV (peak mitral E, P = .14; peak mitral A, P = .916; FPV, P = .009; septal Sa, P = .173; septal Ea, P = .295; septal Aa, P = .649). In patients with H/D amount between 2 and 3 kg, the change of all diastolic parameters showed statistically significant difference except Sa (peak mitral E, P = .001; peak mitral A, P = .001; FPV, P = .001; Sa, P = .589; Ea, P = .001; Aa, P = .015). In patients with H/D amount larger than 3 kg, Sa still showed insignificant change. Ea, Aa, and FPV showed significant difference after H/D (peak mitral E, P = .001; peak mitral A, P = .035; FPV, P = .008; septal Sa, P = .777; septal Ea, P = .014; septal Aa, P = .048). In patients with normal left ventricular systolic function, FPV was preload dependent. Diastolic phase mitral annulus Doppler tissue velocities (Ea and Aa) behaved differently according to the amount removed during H/D. They were preload independent when the amount removed during H/D was less than 2 kg. When the amount removed during H/D was larger than 2 kg, diastolic phase mitral annulus Doppler tissue velocities changed significantly. That is to say, diastolic phase mitral annulus Doppler tissue velocities were not totally preload independent. For systolic phase mitral annulus Doppler tissue velocity index (Sa), it was preload independent.

Prognostic Impact of Systolic Hypertension on Asymptomatic Patients With Chronic Severe Aortic Regurgitation and Initially Normal Left Ventricular Performance at Rest

The influence of systolic hypertension (SH) on the natural history of chronic aortic regurgitation (AR) and the clinical effect of antihypertensive medication on patients who have hypertension and AR are incompletely defined. Therefore, we reviewed the clinical course of 80 unoperated patients who were entered prospectively into an assessment of natural history of AR and its predictors and were asymptomatic with normal left ventricular ejection fraction (LVEF) at rest at study entry; 30 of 80 patients had SH (systolic blood pressure >140 mm Hg); 20 of 80 patients (16 had SH) used antihypertensive drugs for the long term (not mandated by protocol). During an average 7.2-year event-free follow-up, 24 patients developed symptoms alone (n = 14), subnormal LVEF with or without symptoms (n = 8), or died suddenly (n = 2). SH tripled the average annual risk of cardiac events (8.47% vs 2.85%, p = 0.004). The effect of systolic blood pressure was independent of age, gender, diastolic blood pressure, LV diastolic dimension, fractional shortening, and LVEF at rest (p = 0.004 to <0.008). However, positive prognostic interactions existed between systolic blood pressure and pulse pressure (p <0.001), LVEF during exercise (p <0.001), change in LVEF from rest to exercise (p <0.001), and the contractility index (p <0.02). Among patients who had SH, antihypertensive therapy predicted increased event risk (average annual risk 15.46% vs 3.98%, p <0.02) and remained predictive when analysis was adjusted for potentially confounding subgroup variations at study entry (p <0.03, all models). In conclusion, SH portends poor clinical outcome in chronic severe AR. As a group, antihypertensive drugs do not mitigate outcome, although the effect of individual drugs is uncertain and at least some may be deleterious. The theoretically based practice of giving antihypertensive drugs to patients who have AR requires reexamination.

Role of p90 Ribosomal S6 Kinase (p90RSK) in Reactive Oxygen Species and Protein Kinase C β (PKC-β)-mediated Cardiac Troponin I Phosphorylation

Protein kinase C (PKC)-induced phosphorylation of cardiac troponin I (cTnI) depresses the acto-myosin interaction and may be important during the progression of heart failure. Although both PKCbetaII and PKCepsilon can phosphorylate cTnI, only PKCbeta expression and activity are elevated in failing human myocardium during end-stage heart failure. Furthermore, although increased cTnI phosphorylation was observed in mice with cardiac-specific PKCbeta II overexpression, no differences were observed in cTnI phosphorylation status between wild type and cardiac-specific PKCepsilon overexpression mice. A potentially important downstream effector of PKCs is p90 ribosomal S6 kinase (p90RSK), which plays an important role in cell growth by activating several transcription factors as well as Na+/H+ exchanger. Since both Ser23 and Ser24 of cTnI are contained in putative consensus sequences of p90RSK phosphorylation sites, we hypothesized that p90RSK is downstream from PKCbeta II and can be a cTnI (Ser(23/24)) kinase. p90RSK, but not ERK1/2 activation, was increased in PKCbetaII overexpression mice but not in PKCepsilon overexpression mice. p90RSK could phosphorylate cTnI in vitro with high substrate affinity but not cardiac troponin T (cTnT). To confirm the role of p90RSK in cTnI phosphorylation in vivo, we generated adenovirus containing a dominant negative form of p90RSK (Ad-DN-p90RSK). We found that the inhibition of p90RSK prevented H2O2-mediated cTnI (Ser(23/24)) phosphorylation but not ERK1/2 and PKCalpha/betaII activation. Next, we generated cardiac-specific p90RSK transgenic mice and observed that cTnI (Ser(23/24)) phosphorylation was significantly increased. LY333,531, a specific PKCbeta inhibitor, inhibited both p90RSK and cTnI (Ser(23/24)) phosphorylation by H2O2. Taken together, our data support a new redox-sensitive mechanism regulating cTnI phosphorylation in cardiomyocytes.

Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca2+-ATPase in mice lacking the CREM gene.

Congestive heart failure is the common endpoint of various cardiac diseases representing a leading cause of cardiovascular mortality in Western countries. Characteristic functional alterations of the failing heart are explained by expressional changes of myocardial regulatory proteins; however, little is known about underlying mechanisms regulating cardiac gene expression in the failing heart. Here, we address the specific role of transcription factor CREM for cardiac function in CREM mutant mice with complete inactivation of the CREM gene. We show that CREM mutant mice display distinct alterations of cardiac function resembling characteristic functional defects of the failing heart. Left ventricular hemodynamic assessment of CREM mutant mice revealed impairment of both cardiac contraction and relaxation in basal state, as well as a decreased responsiveness to beta-adrenergic stimulation. The diminished cardiac contractile performance was associated with a selective down-regulation of beta1-adrenergic receptors and a decreased ventricular expression of SERCA, the Ca2+-ATPase of the sarcoplasmic reticulum. The cardiac phenotype of CREM mutant mice provides the first evidence that CREM represents an important key regulator of cardiac gene expression, which is essential for normal left ventricular contractile performance and response to beta-adrenoreceptor stimulation.

Increasing the Colloid Osmotic Pressure of Cardiopulmonary Bypass Prime and Normothermic Blood Cardioplegia Minimizes Myocardial Oedema and Prevents Cardiac Dysfunction

Our recent work demonstrated that normothermic continuous antegrade blood cardioplegia results in cardiac dysfunction related to myocardial oedema. This oedema was partially due to increased myocardial microvascular fluid filtration induced by crystalloid hemodilution. We hypothesized that increasing the colloid osmotic pressure of blood cardioplegia would stop fluid filtration into the cardiac interstitium, thus preventing myocardial oedema and cardiac dysfunction. Methods: We determined myocardial water content in six dogs by microgravimetry and myocardial lymph flow from the major prenodal cardiac lymphatic. Preload recruitable stroke work was derived from sonomicrometry and micromanometry. The dogs were subjected to normothermic cardiopulmonary bypass primed with 6% hetastarch and 1 h of normothermic continuous antegrade blood cardioplegia (4:1 blood:6% hetastarch colloid osmotic pressure 21 ± 2 mmHg) delivered at 50 mmHg perfusion pressure. Results: We found that despite increased colloid osmotic pressure, a small but significant increase in myocardial water content still occurred during blood cardioplegia. As myocardial Jymph flow virtually ceased during cardioplegia, myocardial microvascular filtration must have been present. However, increased myocardial lymph flow following cardioplegia resulted in complete oedema resolution associated with normal left ventricular performance post-cardiopulmonary bypass. Conclusions: Our data show that the plegic myocardium is prone to oedema formation because of both relatively enhanced fluid filtration and lymph flow cessation. We conclude that increasing the colloid osmotic pressure of normothermic blood cardioplegia minimizes myocardial oedema, thus preventing post-cardiopulmonary bypass cardiac dysfunction.

Increasing the colloid osmotic pressure of cardiopulmonary bypass prime and normothermic blood cardioplegia minimizes myocardial oedema and prevents cardiac dysfunction

Our recent work demonstrated that normothermic continuous antegrade blood cardioplegia results in cardiac dysfunction related to myocardial oedema. This oedema was partially due to increased myocardial microvascular fluid filtration induced by crystalloid hemodilution. We hypothesized that increasing the colloid osmotic pressure of blood cardioplegia would stop fluid filtration into the cardiac interstitium, thus preventing myocardial oedema and cardiac dysfunction. Methods: We determined myocardial water content in six dogs by microgravimetry and myocardial lymph flow from the major prenodal cardiac lymphatic. Preload recruitable stroke work was derived from sonomicrometry and micromanometry. The dogs were subjected to normothermic cardiopulmonary bypass primed with 6% hetastarch and 1 h of normothermic continuous antegrade blood cardioplegia (4:1 blood:6% hetastarch colloid osmotic pressure 21±2 mmHg) delivered at 50 mmHg perfusion pressure. Results: We found that despite increased colloid osmotic pressure, a small but significant increase in myocardial water content still occurred during blood cardioplegia. As myocardial lymph flow virtually ceased during cardioplegia, myocardial microvascular filtration must have been present. However, increased myocardial lymph flow following cardioplegia resulted in complete oedema resolution associated with normal left ventricular performance post-cardiopulmonary bypass. Conclusions: Our data show that the plegic myocardium is prone to oedema formation because of both relatively enhanced fluid filtration and lymph flow cessation. We conclude that increasing the colloid osmotic pressure of normothermic blood cardioplegia minimizes myocardial oedema, thus preventing post-cardiopulmonary bypass cardiac dysfunction.

Prediction of indications for valve replacement among asymptomatic or minimally symptomatic patients with chronic aortic regurgitation and normal left ventricular performance.

Optimal criteria for valve replacement are unclear in asymptomatic/minimally symptomatic patients with aortic regurgitation (AR) and normal left ventricular (LV) performance at rest. Moreover, previous studies have not assessed the prognostic capacity of load-adjusted LV performance ("contractility") variables, which may be fundamentally related to clinical state. Therefore, 18 years ago, we set out to test prospectively the hypothesis that objective noninvasive measures of LV size and performance and, specifically, of load-adjusted variables, assessed at rest and during exercise (ex), could predict the development of currently accepted indications for operation for AR. Clinical variables and measures of LV size, performance, and end-systolic wall stress (ESS) were assessed annually in 104 patients by radionuclide cineangiography at rest and maximal ex and by echocardiography at rest; ESS was derived during ex. During an average 7.3-year follow-up among patients who had not been operated on, 39 of 104 patients either died suddenly (n = 4) or developed operable symptoms only (n = 22) or subnormal LV performance with or without symptoms (n = 13) (progression rate=6.2%/y). By multivariate Cox model analysis, change (delta) in LV ejection fraction (EF) from rest to ex, normalized for deltaESS from rest to ex (deltaLVEF-deltaESS index), was the strongest predictor of progression to any end point or to sudden cardiac death alone. Unadjusted deltaLVEF was almost as efficient. Symptom status modified prediction on the basis of the deltaLVEF-deltaESS index. The population tercile at highest risk by deltaLVEF-deltaESS progressed to end points at a rate of 13.3%/y, and the lowest-risk tercile progressed at 1.8%/y. Currently accepted symptom and LV performance indications for valve replacement, as well as sudden cardiac death, can be predicted in asymptomatic/minimally symptomatic patients with AR by load-adjusted deltaLVEF-deltaESS index, which includes data obtained during exercise.

Cardiac surgical conditions induced by β-blockade: Effect on myocardial fluid balance

Both crystalloid and blood cardioplegia result in cardiac dysfunction associated with myocardial edema. This edema is partially due to the lack of myocardial contraction during cardioplegia, which stops myocardial lymph flow. As an alternative, acceptable surgical conditions have been created in patients undergoing coronary artery bypass operations with esmolol-induced minimal myocardial contraction. We hypothesized that minimal myocardial contraction during circulatory support using either standard cardiopulmonary bypass (CPB) or a biventricular assist device would prevent myocardial edema by maintaining cardiac lymphatic function and thus prevent cardiac dysfunction. We placed 6 dogs on CPB and 6 dogs on a biventricular assist device and serially measured myocardial lymph flow rate and myocardial water content in both groups and preload recruitable stroke work only in the CPB dogs. In all dogs we minimized heart rate with esmolol for 1 hour during total circulatory support. Although myocardial lymph flow remained at baseline level during CPB and increased during biventricular assistance, myocardial water accumulation still occurred during circulatory support. However, as edema resolved rapidly after separation from circulatory support, myocardial water content was only slightly increased after CPB and biventricular assistance, and preload recruitable stroke work was normal. Our data suggest that minimal myocardial contraction during both CPB and biventricular assistance supports myocardial lymphatic function, resulting in minimal myocardial edema formation associated with normal left ventricular performance after circulatory support. The concept of minimal myocardial contraction may be a useful alternative for myocardial protection, especially in high-risk patients with compromised left ventricular function.

Congestive Heart Failure in Patients with Valvular Aortic Stenosis

The aim of this study was to evaluate echographically anatomic and functional features of the left ventricle in adult patients with valvular aortic stenosis according to the presence or absence of congestive heart failure and the level of ventricular performance. Fifty-six adult patients with moderate-to-severe aortic stenosis underwent echocardiographic Doppler examination in order to evaluate left ventricular mass and dimensions, systolic function and filling dynamics. Twenty-seven patients had no heart failure and were symptomatic for angina (5), syncope (4) or were symptom-free (group I); the other 29 had heart failure (group II): 16 with normal left ventricular systolic performance (fractional shortening > 25%, group IIa) and 13 with systolic dysfunction (fractional shortening < or = 25%, group IIb). Despite a similar left ventricular mass, compared to group IIa, group IIb showed a significant left ventricular dilatation (end-diastolic diameter: 61 +/- 6.5 vs. 45.5 +/- 6.1 mm, p < 0.001) and mild or no increase in wall thickness (11.5 +/- 1.6 vs. 14.9 +/- 2 mm, p < 0.001). Indices of left ventricular filling on Doppler transmitral flow were also significantly different between the two groups, with a higher early-to-late filling ratio and a shorter deceleration time of early filling in group IIb (2.8 +/- 1.9 vs. 1.2 +/- 0.85, p < 0.01, and 122 +/- 66 vs. 190 +/- 87 ms, p < 0.05, respectively), both indirectly indicating higher left atrial pressure. Finally, heart failure was generally more severe in group IIb patients. In some patients with aortic stenosis, symptoms of heart failure may be present despite a normal left ventricular systolic function and seem to depend on abnormalities of diastolic function. The presence of systolic or isolated diastolic dysfunction appears to be related to a different geometric adaptation of the left ventricle to chronic pressure overload.

Natural history of the asymptomatic/minimally symptomatic patient with severe mitral regurgitation secondary to mitral valve prolapse and normal right and left ventricular performance

The natural history of patients with severe nonischemic mitral regurgitation (MR) from mitral valve prolapse, who are asymptomatic or minimally symptomatic and have normal right ventricular (RV) and left ventricular (LV) performance, has not been evaluated previously. To define natural history in this population and to determine if any objective variables could predict disease progression, 31 patients were followed annually with severe MR due to prolapse, who at entry were asymptomatic or minimally symptomatic and had normal RV and LV performance at rest by radionuclide cineangiography. Average follow-up in patients not reaching surgical end point was 4.7 years. The Kaplan-Meier product limit estimates were used to determine the rate of progression to either “operable” symptoms or to previously defined “high risk” ventricular performance descriptors, if the latter occurred first. Univariate comparisons of Kaplan-Meier curves and multivariate Cox proportional hazards analyses were used to define prognostically important variables measured at entry. Fourteen patients developed symptoms warranting referral for operation; none developed high-risk ventricular performance descriptors. The annual end point risk was 10.3%. Of all covariates, only change in RV ejection fraction from rest to exercise was significantly associated with disease progression. Annual risk of progression to surgical end point was 4.9% in the subgroup in which this parameter increased with exercise and 14.7% in the subgroup without an increase (p = 0.04). Patients with severe MR due to mitral valve prolapse, who are asymptomatic or minimally symptomatic with normal ventricular performance, can be expected to progress to surgical indications at an annual rate of 10.3%. The change in RV ejection fraction during exercise is useful in predicting the likelihood of such progression.

Non-Invasive Detection of Reduced Regional Myocardial Perfusion at Rest in Patients with Unstable Angina Pectoris: Increased Regional 81mKr Deposition following Intravenous Injection of 81 Rb

The present study was to investigate whether combined imaging of 81Rb and 81mKr distributions after i.v. injection of 81Rb at rest might improve the differentiation between ischemic and irreversibly damaged myocardium as compared to 201Tl scintigraphy at rest. In 21 patients who had undergone diagnostic cardiac catheterization for evaluation of chest pain, 148 MBq ultrapure 81Rb were injected i.v. at rest immediately following 201Tl scintigraphy at rest. Of 14 patients with earlier myocardial infarction, 10 patients revealed decreased regional tracer uptake of 81Rb and/or 81mKr, compared to 12 patients with regional 201Tl uptake abnormalities. In 3 patients with unstable angina pectoris, however, an evident mismatch between either the regional 201Tl or 81Rb distributions and the distribution of 81mKr was observed: in contrast to the reduced uptake of 201Tl and/or 81Rb, 81mKr activity was increased in 3 myocardial segments with normal left ventricular performance but supplied by coronary arteries with high-grade stenoses. In patients with contraindications to exercise tests (e.g. unstable angina) 81Rb/81mKr rest scintigraphy may therefore assist the differentiation between malperfused but potentially viable and irreversibly damaged myocardium.

Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance

Normal left ventricular systolic performance with impaired left ventricular diastolic filling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset, 20 men (mean age 68 ± 5 years) with CHF, intact left ventricular function (ejection fraction >45%) and abnormal diastolic filling (peak filling rate <2.5 end-diastolic volumes per second [edv/s]) were studied in a placebo-controlled, double-blind 5-week crossover trial. All patients underwent echocardiography to rule out significant valvular disease, and thallium-201 stress scintigraphy to exclude major active ischemia. Compared to baseline values, verapamil significantly improved exercise capacity by 33% (13.9 ± 4.3 vs 10.7 ± 3.4 minutes at baseline) and peak filling rate by 30% (2.29 ± 0.54 vs 1.85 ± 0.45 edv/s at baseline) (all p < 0.05). Placebo values were 12.3 ± 4.0 minutes and 2.16 ± 0.48 edv/s, respectively (difference not significant for both). Improvement from baseline in an objective clinicoradiographic heart failure score (scale 0 to 13) was significantly greater with verapamil compared to placebo (median improvement in score: 3 vs 1, p < 0.01). Mean ejection fraction and systolic blood pressure were unchanged from baseline; diastolic blood pressure and heart rate decreased to a small degree. Verapamil may have therapeutic efficacy in patients with CHF, preserved systolic function and impaired diastolic filling.