Background. Orthotopic lung transplantation is now widely performed in patients with advanced lung disease. Patients with moderate or severe ventricular systolic dysfunction are typically excluded from lung transplantation; however, there is a paucity of data regarding the prognostic significance of abnormal left ventricular diastolic function and elevated pretransplant pulmonary pressures. Methods. We reviewed the characteristics of 111 patients who underwent bilateral and unilateral lung transplants from 200 to 2009 in order to evaluate the prognostic significance of preoperative markers of diastolic function, including invasively measured pulmonary capillary wedge pressure (PCWP) and echocardiographic variables of diastolic dysfunction including mitral A > E and A′ > E′. Results. Out of 111 patients, 62 were male (56%) and average age was 54.0 ± 10.5 years. Traditional echocardiographic Doppler variables of abnormal diastolic function, including A′ > E′ and A > E, did not predict adverse events (P = 0.49). Mildly elevated pretransplant PCWP (16–20 mmHg) and moderately/severely elevated PCWP (>20 mmHg) were not associated with adverse clinical events after transplant (P = 0.30). Additionally, all clinical endpoints did not show any statistical significance between the two groups. Conclusions. Pre-lung transplant invasive and echocardiographic findings of elevated pulmonary pressures and abnormal left ventricular diastolic function are not predictive of adverse posttransplant clinical events. Nearly three decades have passed since the first successful clinical lung transplant was performed and has become the preferred treatment option for a variety of end-stage pulmonary parenchymal or pulmonary vascular disorders. Due to the shortage of available organs as well as the advancement of disease in most transplant candidates, a full array of preoperative tests is needed in order to consider these patients appropriate applicants. As part of the preoperative workup of these patients, investigation of cardiac function with echocardiography and catheterization has been long considered the norm, yet predictors of outcome from these tests are not well defined. The risk posed by cardiac dysfunction must be assessed individually based on severity of disease, presence of end-organ damage, and ease of control with standard therapies . PatientA′ > E′ and A > E. Criteria for LV diastolic dysfunction were obtained from the 2009 ASE guidelines [The study was approved by the University of California, Los Angeles (UCLA) Institutional Review Board. All patients who underwent a bilateral or unilateral lung transplant at UCLA Medical Center from 2002 to 2009 were analyzed (394 patients) by chart review in order to evaluate the prognostic significance of preoperative markers of diastolic function, including invasively measured pulmonary capillary wedge pressure (PCWP) and echocardiographic variables of diastolic dysfunction. Diastolic dysfunction was assessed by traditional echocardiographic variables of abnormal diastolic function, including Exclusion criteria included any patients undergoing re-transplant, patients with lack of presurgical echocardiographic or catheterization data performed at UCLA, and patients with systolic left ventricular function less than 40% were excluded. We identified 111 patients who had pretransplant echocardiographic as well as catheterization data performed at UCLA Medical Center. Echocardiographic information was rereviewed by a blinded cardiologist (JA) to ensure the accuracy of the reports. Additionally, pulmonary artery pressures from preoperative catheterizations were analyzed to assess adverse clinical events posttransplant. P values were computed utilizing Cox Proportional Hazards models. For comparing differences between the nondiastolic dysfunction and diastolic dysfunction groups, P values were calculated using the t-test for quantitative variables or chi-square test for categorical predictors. If the sample size was too small for the chi-square approximation to be accurate, Fisher's exact test was used instead. The same methods were used for comparing differences among the mean PCWP thresholds. Logistic regression was used to see if clinical endpoints were associated with demographic variables. Error bars were calculated as a 95% confidence interval for proportions. The Kruskal-Wallis test was used for subgroup analysis of primary lung pathology due to the skewed distribution of these variables. If a significant effect was observed, follow-up pairwise Wilcoxon Rank Sum tests with Dunn-Sidak adjusted P values were used to test for specific differences between groups. P values less than 0.05 were considered statistically significant. All statistical analyses and plots were performed using R (Version 2.13.1) and IBM SPSS (Version 19).For comparing time until each clinical endpoint between groups, Subjects ranged from 22 to 70 years of age  and were transplanted for a variety of disease processes including forty-three cases of idiopathic pulmonary fibrosis, twenty-two of chronic obstructive pulmonary disease, twelve of scleroderma, eight of sarcoidosis, eight of usual interstitial pneumonia, eight of isolated pulmonary hypertension, four of cystic fibrosis, four of various rare etiologies, and two of alpha-1 antitrypsin deficiency cases. In all, 29 (26.1%) patients met criteria for diastolic dysfunction. P = 0.30) (P = 0.77), diastolic pulmonary artery pressures (dPAP) (P = 0.68), mean pulmonary artery pressures (mPAP) (P = 0.84), mean PCWP (P = 0.17), cardiac output (P = 0.23), cardiac index (P = 0.21), and left ventricular ejection fraction (P = 0.99) (P = 0.176) (P = 0.05).Catheterization data was reviewed and based upon this information, 20 (19.8%) patients were categorized into mildly elevated PCWP (16–20 mmHg) and 9 (8.9%) patients with moderate/severely elevated PCWP (>20 mmHg) . The sam = 0.30) . Additio = 0.99) . Lastly,= 0.176)   . Based uOver the last twenty years, there has been a steady growth in the number of lung transplant operations performed worldwide with concurrent improvement in both short-and long-term outcomes . VariousOverall, many guidelines have been developed to help risk-stratify candidacy of potential transplant recipients; however, there has been a lack of data regarding short- and long-term outcomes of left ventricular diastolic dysfunction as well as elevated PCWP. Given the scarcity of organs as well as the fact that nearly 20% of lung transplant recipients die within the first year of transplantation, we may be failing to identify those at high risk for severe early complications . E velocity (E) represents the early mitral inflow velocity and is influenced by the relative pressures between the left atrium (LA) and LV, which, in turn, are dependent on multiple variables including LA pressure, LV compliance, and the rate of LV relaxation. The A velocity (A) represents the atrial contractile component of mitral filling and is primarily influenced by LV compliance and LA contractility. In a less compliant heart, a greater proportion of this blood is pushed into the ventricles during atrial systole. In this scenario, the emphasis of ventricular filling during late diastole increases the (A) component of the E/A ratio causing a reversal of the ratio, hence an indication of diastolic dysfunction. Left atrial volume has also been described as an excellent biomarker of the chronicity of diastolic dysfunction and of cardiovascular disease risk [E prime (e′), the e′ to late diastolic filling (A′) ratio (e′/A′), and the transmitral to mitral annular early diastolic velocity ratio (E/e′) [e′) reflects the rate of myocardial relaxation. When combined with measurement of the early transmitral flow velocity (E), the resultant ratio (E/e′) correlates well with mean left ventricular end-diastolic pressure [Some studies have described this dysfunction in nearly 25% to 30% of individuals greater than 45 years of age , 10. On ase risk . Parameto (E/e′)  have allo (E/e′) , 14. Thepressure , hence aLeft ventricular diastolic dysfunction is a relatively common finding seen on Doppler echocardiography; while multiple studies demonstrate abnormal diastolic function assessment to be associated with increased cardiovascular comorbidity, it can hold varying prognostic significance depending on underlying cardiac ventricular function. It has been shown that mortality is higher in hospitalized patients with depressed left ventricular ejection fractions of less than 39% . AdditioThis association between echocardiographic markers of abnormal relaxation and decreased survival, even in those with no history of CHF, suggests that echocardiography may help identify those who are predisposed to adverse outcomes . Given tThere has been much investigation into Doppler echocardiography and comparison with Swan-Ganz catheterization measurements. Studies have shown that hemodynamic data acquired by echocardiography, including estimation of right atrial, pulmonary artery systolic, and PCWPs; cardiac output; and pulmonary vascular resistance, correlate to those of invasive catheterization values , 28. AltTransplantation remains the only therapeutic option for selected patients with advanced pulmonary arterial hypertension (PAH) who continue to deteriorate despite optimal medical therapy. Given the current shortage of donor organ availability worldwide, there is a need for inclusion of more discriminatory markers of PAH prognosis in donor-lung allocation scores to identify patients at risk and optimize survival to transplantation . Bando eNo optimal treatment of diastolic dysfunction exists. The objectives of therapy for left ventricular diastolic dysfunction include improvement of preload and afterload hemodynamics . Ace inhOur study has several limitations. This is a retrospective single-center review and has inherent limitations associated with all retrospective studies. The lung transplant patients are also highly selected in accordance with our selection protocol. As a result, there may have been a selection bias as the study does not include recipients and experience from other centers. In summary, there are many different factors that need to be accounted for when deciding to evaluate and list patients for lung transplantation. A team approach incorporating the surgeon, pulmonologist, and cardiologist is necessary to ensure optimum outcomes in this difficult and challenging group of patients. Pretransplant recipient variables significantly influence early and late survival following lung transplantation, suggesting that some patients face a higher than average risk of mortality during the first year after transplant, as well as severely diminished longer-term survival, that challenges the goals of equitable organs allocation. Further investigation regarding transplant variables are needed to help develop better guidelines, which will ultimately help with optimal utilization of these scarce organs.The present study demonstrates that prelung transplant invasive and echocardiographic findings of elevated pulmonary pressures, and abnormal left ventricular diastolic function are not predictive of adverse posttransplant clinical events.


Recent published literature has validated the use of transcatheter aortic valve implantation (TAVI) in high-risk patients with aortic stenosis. These trials and registries have largely focused on combined morbidity and mortality outcomes with little focus given to impact on early myocardial function. We assessed effects on myocardial function, reversible and irreversible myocardial injury of both transcatheter and open aortic valve replacement utilizing multi-parametric CMR.We conducted a prospective comparative study of 38 patients  with confirmed severe aortic stenosis undergoing either transcatheter valve replacement (20 patients) or high risk (euroSCORE >12) open AVR. CMR was carried out pre-operatively and within two weeks post-operatively. All scans used a Siemens Aera 1.5T system . ). Images obtained included a standard LV long and short axis SSFP imaging, T2 weighted images using LV basal, mid and apical SA slices and late gadolinium enhanced (LGE) images (Gadovist 0.1mg/kg) in standard LV long and SA planes.There was no difference in log euroSCORE's between the groups pre-operatively. Post-operative CMR was conducted at a median of 6.0 days for TAVI and 7.3 days for Open (p>0.05). Mean preoperative LV ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) was similar in the 2 groups . Post-operatively LVEF was preserved in both groups. In contrast, RVEF decreased significantly in the TAVI group when compared to the open group (58.3% to 49.4% vs 58.1% to 56.0% p= 0.02). This was largely driven by reduced RVESV in the open group and increased RVESV in the TAVI group (p = 0.04). The open AVR group demonstrated a trend towards increased early LV mass regression compared to the TAVI group (p = 0.08). Myocardial injury assessed biochemically using HS troponin and area under the curve showed significantly greater injury in the open cohort (p=0.001). A total of 3 patients in TAVI group and 2 patients in open AVR group demonstrated new LV irreversible injury (p>0.05).There is no significant difference in early left ventricular functional outcomes between Open and transcatheter techniques despite higher troponin in the open cohort. In the absence of new RV irreversible myocardial injury, it is likely that the RV dysfunction seen in the TAVI group is a result of rapid ventricular pacing during device insertion, resulting in myocardial stunning.Research grant from Flinders Cardiothoracic Research Fund.


Investigations and primary outcome measures; cardiac magnetic resonance (CMR) - left ventricular mass index (LVMI), MPR , late gadolinium enhancement (LGE); echocardiography - AS severity, tissue Doppler-derived diastolic function; symptom-limited bicycle ergometer cardiopulmonary exercise testing (CPEX) - peak VO2 are summarised in Table 2. The relationship between peak VO2 and MPR is shown, Figure Four patients with variable LVMI, LGE and MPR are shown, Figure 2 and is inversely related to NYHA functional class in severe AS. Microvascular dysfunction is determined by a combination of factors including AS severity, LVMI, diastolic perfusion time, myocardial fibrosis and LV filling pressure. Further work is required to determine the clinical significance of microvascular dysfunction in AS.MPR is a novel independent predictor of peak VO


Heart failure patients have inadequate nutritional intake and alterations in metabolism contributing to an overall energy depleted state. Left ventricular assist device (LVAD) support is a common and successful intervention in patients with end-stage heart failure. LVAD support leads to alterations in cardiac output, functional status, neurohormonal activity and transcriptional profiles but the effects of LVADs on myocardial metabolism are unknown. This study set out to measure cardiac metabolites in non-failing hearts, failing hearts, and hearts post-LVAD support.The study population consisted of 8 non-ischemic failing (at LVAD implant) and 8 post-LVAD hearts, plus 8 non-failing hearts obtained from the tissue bank at the University of Colorado. NMR spectroscopy was utilized to evaluate differences in myocardial energy substrates. Paired and non-paired t-tests were used to determine differences between the appropriate groups.Glucose and lactate values both decreased from non-failing to failing hearts and increased again significantly in the (paired) post-LVAD hearts. Glutamine, alanine, and aromatic amino acids decreased from non-failing to failing hearts and did not change significantly post-LVAD. Total creatine and succinate decreased from non-failing to failing hearts and did not change significantly post-LVAD.Measured metabolites related to glucose metabolism are diminished in failing hearts, but recovered their values post-LVAD. This differed from the amino acid levels, which decreased in heart failure but did not recover following LVAD. Creatine and the citric acid cycle intermediate succinate followed a similar pattern as the amino acid levels. Patients with chronic heart failure often have inadequate intake of calories and protein and diminished energy availability Left ventricular assist device (LVAD) placement is becoming increasingly common as a bridge to transplant and as destination therapy. These patients often suffer from significant malnutrition both pre- and post- device placement. These devices have been shown to improve quality of life and survival in patients with end-stage heart disease when compared to medical therapy. For some patients, unloading of the LV by LVAD placement leads to improved function of the native LV, known as reverse remodeling. Noted effects of reverse remodeling on the LV include reductions in mass, end-diastolic diameter, and ejection fraction compared to pre-LVAD implantation The aim of this study was to measure key metabolites related to nutrition and energy in the myocardium of patients suffering from heart failure, and compare these measures to the myocardial metabolism in healthy patients and in patients following LVAD therapy. Our hypothesis is that the failing heart will have lower levels of most key metabolites than the non-failing hearts; and some of these metabolites will return to healthy levels after LVAD placement. This study focuses on levels of metabolites that might be altered via nutritional intervention.Ethics Statement: The protocol for the collection, storage, and analysis of tissue for this study was approved by the Colorado Multiple Institutional Review Board and is outlined in a previous publication Retrospective review of medical records for demographic and clinical data was conducted by a trained physician. Time points for echocardiographic and hemodynamic data collection were chart entries closest to LVAD implantation and cardiac transplantation. Post-LVAD data reflect device settings clinically indicated and represent the combined effects of native LV function as well as LVAD-related unloading.2O) for hydrophilic extracts and with 1.5 ml of deuterated methanol/chloroform for lipids.0.1 to 0.4 g of snap-frozen cardiac tissue was weighed out from each patient sample and homogenized in a mortar grinder in the presence of liquid nitrogen. Ice cold perchloric acid  extraction was carried out as described previously allowing for protein precipitation and separation of hydrophilic and lipophilic metabolites 4 acid (0.6 mM/L)as an external standard. 1H chemical shifts of spectra were referenced to trimethylsilyl propionic-2,2,3,3,-d4 acid at 0 ppm.H-NMR was carried out as published previously in order to evaluate cardiac metabolism Metabolites in cardiac tissue were compared via t-test (for comparisons of non-failing and failing hearts) and paired t-test (for comparisons of pre-LVAD vs. post-LVAD samples) using SAS/STAT® software version 9.2, The SAS Institute, USA.Patient characteristics are found in Pre-LVAD, all patients in the failing/post-LVAD group were on intravenous inotropic agents and diuretics, 88% were on an aldosterone antagonist, 62% and intravenous vasodilator, and 25% an ACE inhibitor. During LVAD support 88% of patients in this group were on an aldosterone antagonist and/or an ACE inhibitor. 75% took a β-blocker and/or a diuretic prior to LVAD implantation . Seven o2 (sd 0.4) to 2.47 l/min/m2 (sd 0.7), (p = 0.016).Key differences in myocardial metabolism are described in Glucose was higher in non-failing hearts (1.49±0.54 µmol/g of tissue) than in failing hearts , and the level increased again significantly after LVAD support . Lactate also was higher in non-failing hearts (11.2±3.69 µmol/g of tissue) than in failing hearts ; and also increased again significantly after LVAD support .Total creatine was higher in non-failing (10.4±1.97 µmol/g of tissue) than failing hearts ; and creatine did not increase significantly after LVAD support . Succinate was significantly higher in non-failing (3.55±0.91 µmol/g of tissue) than failing hearts , and did not change significantly post-LVAD .Our data indicates that significant changes in myocardial metabolism occur in the failing heart and some, but not all of these changes, are improved by LVAD placement. The amino acid levels in this study indicate that these substrates decrease significantly in cardiac tissue from non-failing to failing hearts and they do not recover during LVAD support. These data seem to support the hypothesis that the heart is depleting its amino acid stores and that unloading the heart through LVAD support does not allow replenishment of these losses.in vitro in chick cardiomyocytes post ischemia/reperfusion (I/R) injury Select metabolites from each category are represented graphically in Substrates related to glucose metabolism showed a different pattern pre-/post-LVAD placement than the measured amino acid levels. Both glucose and lactate decreased in heart failure but increased again after LVAD support. It is known that during heart failure there is a switch in substrate preference from fatty acids (β-oxidation) to carbohydrates (glycolysis) as the primary fuel preference. This is part of the reversion to the fetal energy substrate pattern known to occur during heart failure Total creatine levels (creatine plus phosphocreatine) were measured in an attempt to determine relative energy availability in the cardiac tissues. The pattern of total creatine data looked much like the amino acid data as it decreased significantly from non-failing to failing hearts and remained low post-LVAD. This was interesting in light of our overall hypothesis, as there is a link in the literature between glutamine and creatine. In rat models of ischemia/reperfusion, glutamine supplementation leads to an increase in the creatine and phosphocreatine content of the myocardium 2 and the generation of NADH and FADH2 for the electron transport chain. Increasingly cardiovascular researchers are studying the role of ‘anapleurosis’ in the heart, meaning the process of replenishing depleted metabolic cycle intermediates (in this case CAC intermediates) Succinate levels were also measured in order to determine the function of the citric acid cycle (CAC) under the disease states studied. Levels of CAC intermediates are crucial for the oxidation of acetyl-CoA to COIncreasing anapleurotic flux in the setting of cardiac disease is considered beneficial In conclusion, these data show that cardiac tissue amino acid stores are depleted in heart failure and they do not recover after LVAD support. This is of particular interest for the amino acid glutamine since it is known to have cardioprotective effects. Total creatine and succinate (a CAC intermediate) follow the same pattern as amino acids, while metabolites related to glycolytic metabolism recover their levels after LVAD implantation. It is known that individuals who have lower BMI's (and thus less lean body mass) have higher mortality from heart failure. In light of the obesity paradox and the cardiac data presented here, a clinical trial of targeted amino acid supplementation in patients with heart failure should be considered.There are several limitations to this study. A disadvantage of measuring metabolites only in cardiac tissue is the inability to obtain samples from the vast majority of patients with heart failure. Our study is confined to patients with advanced disease who received mechanical cardiac support. We did not prospectively collect peripheral blood on these patients so it is unknown if these changes in tissue metabolic substrates correlate with peripheral abnormalities. It is also unknown if these changes effect patients with less severe disease. It is interesting to note that data from the Framingham study has recently shown that higher peripheral glutamine is strongly associated with reduced cardiovascular risk. SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc. in the USA and other countries.


Interstitial myocardial fibrosis is a histological hallmark of non-ischemic dilated cardiomyopathy (DCM), and may play an important role in adverse remodelling and progressive systolic dysfunction. T1-mapping enables non-invasive assessment of diffuse fibrosis by quantification of myocardial extracellular volume fraction (ECV). We hypothesized that CMR would identify a raised ECV in DCM which would correlate with the degree of systolic dysfunction.Consecutive DCM patients referred for CMR and age/sex-matched healthy controls were prospectively enrolled. Exclusion criteria included a history of recent myocarditis, ischemic heart disease, diabetes, severe hypertension and primary valvular disease. All subjects underwent CMR  according to a standardized protocol which included T1-mapping and late gadolinium enhancement (LGE) imaging. Mid-ventricular short-axis T1-maps were acquired using a Modified Look-Locker Inversion recovery sequence prior to contrast and 20 minutes after gadolinium administration (Gadovist 0.1mmol/kg). The pre- and post-contrast T1-maps were co-registered and used with the patient's hematocrit to generate an ECV map.In total, 85 patients  and 35 controls  were studied. Baseline clinical and CMR characteristics for the cohort are summarized in Table ECV is expanded in DCM in proportion to the degree of LV systolic dysfunction. An increased ECV in sections of the heart without clinically obvious LGE suggests the presence of low level myocardial fibrosis or possibly myocardial edema. This technique offers potential for the evaluation of interstitial fibrosis in DCM, although important challenges include the substantial overlap of ECV values between patients and normals. Further work should aim to corroborate these findings with histological validation.This project was supported by the NIHR Cardiovascular Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust, the British Heart Foundation, and CORDA (research charity).Dr Peter Kellman and Dr Andrew Arai are funded by the National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.


Our manuscript addresses the reliability of cardiac CT as an alternative for cardiac MRI in patients with a systemic right ventricle. Currently, cardiac MRI is considered the gold standard for volumes and function measurements of the systemic right ventricle. However, 20% of patients with a systemic right ventricle is pacemaker dependent, and therefore unsuitable to undergo MRI. To our knowledge, this is the first study to evaluate whether cardiac CT provides a reliable alternative for volumes and function measurements of the systemic RV, which is morphologically very different from the subpulmonary RV. We found that cardiac CT provides a reliable alternative for cardiac MRI for volumes and function measurements of the systemic RV, although larger variability between measurements should be taken into account. However, we recommend restrictive patient selection, to avoid unnecessary exposure to radiation and contrast agents.Cardiovascular Magnetic Resonance (CMR) imaging is considered the gold standard for volumes and function measurements of the systemic right ventricle (RV). However, 20% of patients with a systemic RV is pacemaker dependent, and unsuitable to undergo CMR. Multidetector Row Computed Tomography (MDCT) could provide a reliable alternative for CMR in these patients. The aim of this study was to compare variability of MDCT with CMR measurements.Thirty-five patients  underwent MDCT , or CMR . Systemic RV end diastolic volume, end systolic volume, stroke volume, and ejection fraction were obtained.RV evaluation was done 3 times by 2 independent observers . The first observer analyzed all scans twice, with a minimal interval of 2 weeks between the first and second scan analysis, and blinded to the previous results. The second observer analyzed the scans once, blinded to the results of the first observer. The intra- and inter-observer variability for both modalities were assessed and compared.The Intra- and inter-observer variability data are summarized in Table MDCT provides a reliable alternative for CMR for volumes and function assessment in patients with a systemic RV, although larger variability between measurements should be taken into account. However, patient selection should be restrictive, to avoid unnecessary exposure to radiation and contrast agents.Financial disclosures: This study was supported by an unrestricted educational grant from Novartis Pharma B.V.


Right ventricular (RV) failure is a major cause of mortality in acute or chronic lung disease and left heart failure. The objective of this study was to demonstrate a percutaneous approach to study biventricular hemodynamics in murine models of primary and secondary RV pressure overload (RVPO) and further explore biventricular expression of two key proteins that regulate cardiac remodeling: calcineurin and transforming growth factor beta 1 (TGFβ1).Adult, male mice underwent constriction of the pulmonary artery or thoracic aorta as models of primary and secondary RVPO, respectively. Conductance catheterization was performed followed by tissue analysis for changes in myocyte hypertrophy and fibrosis.max) and end-systolic elastance (Ees) were preserved in both groups compared to controls. In contrast, left ventricular (LV) dP/dtmax and LV-Ees were unchanged by primary, but reduced in the secondary RVPO group. The ratio of RV:LV ventriculo-arterial coupling was increased in primary and reduced in secondary RVPO. Primary and secondary RVPO increased RV mass, while LV mass decreased in primary and increased in the secondary RVPO groups. RV fibrosis and hypertrophy were increased in both groups, while LV fibrosis and hypertrophy were increased in secondary RVPO only. RV calcineurin expression was increased in both groups, while LV expression increased in secondary RVPO only. Biventricular TGFβ1 expression was increased in both groups.Both primary and secondary RVPO decreased biventricular stroke work however RV instantaneous peak pressure (dP/dtThese data identify distinct effects of primary and secondary RVPO on biventricular structure, function, and expression of key remodeling pathways. Right ventricular (RV) failure is a major determinant of morbidity and mortality for millions of individuals worldwide who suffer from pulmonary hypertension (PH) due to acute and chronic lung disease, or left heart failure Ventriculo-arterial coupling describes the impact of arterial loading conditions on ventricular function. Under any given condition, optimal pump efficiency is achieved if ventricular function, or end-systolic elastance (Ees), is matched by vascular load, known as arterial elastance (Ea) As the thin-walled RV dilates in the setting of pressure overload, increased RV wall stress activates signaling cascades that promote cardiac hypertrophy and fibrosis including the transforming growth factor beta-1 (TGFβ1) and calcineurin pathways. TGFβ1 is a powerful pro-fibrogenic cytokine that signals through a heteromeric receptor complex comprised of a Type II ligand-binding receptor, Type I activin like kinase (ALK) signaling receptors, and the Type III accessory co-receptor, Endoglin. Upon TGFβ1 activation, this receptor complex phosphorylates downstream effector proteins known as Smads  or mitogen activated protein kinases, like extracellular regulated kinase  Given the increasing use of murine models of left heart failure and PH, the objective of this study was to demonstrate a novel percutaneous approach to study biventricular hemodynamics in clinically relevant murine models of primary and secondary RVPO and further explore biventricular expression of two key proteins that regulate cardiac remodeling: calcineurin and TGFβ1.Animals were treated in compliance with the Guide for the Care and Use of Laboratory Animals , and protocols were approved by the Tufts Medical Center Institutional Animal Care and Use Committee. Adult, 12–14 week-old male C57/Bl6 mice (n = 12/group) underwent constriction of the pulmonary artery or thoracic aorta as previously described to generate models of acute primary and progressive secondary RVPO respectively All animals underwent terminal hemodynamic evaluation. Biventricular catheterization was performed at the time of sacrifice in all animals. Mice were anesthetized with 2.0% isoflurane administered via a non-invasive nose-cone. Body temperature was monitored by a rectal thermistor probe and maintained at 37.5°C with heating pads and a cycling heat lamp. In the supine position, the right common carotid and right external jugular vein were surgically isolated. Silk ties were placed at the distal ends of both vessels while overhand loops were placed at the proximal ends with 7-0 nylon. Millar PVR-1035 and PVR-1045  mouse conductance catheters and independent consoles were used for right and left ventricular recordings respectively. Prior to insertion, conductance catheter calibration was performed using the cuvette method with freshly heparinized warm blood as previously described 0 is a theoretical estimate of volume at zero pressure For the primary  and secondary  RVPO groups, mortality was 50%, therefore 6 mice/group underwent analysis. All mice (n = 4/4) survived in the 7 day secondary RVPO (TAC) group and underwent analysis. Mortality approached 85% (n = 10/12) in the 3 week primary RVPO (PAC) group, which precluded further analysis. Once hemodynamic stability was achieved, steady-state baseline conditions were recorded from the RV first. To minimize interference due to local electric field distributions from two catheters in close proximity, the console for the RV conductance catheter was paused and steady-state baseline conditions were immediately recorded from the LV conductance catheter and console. The RV catheter was then re-activated and data was acquired sequentially from the RV, then LV during occlusion of the inferior vena cava (IVC). For IVC occlusion, a small incision inferior to the xyphoid was made and blunt dissection was used to visualize the IVC. Transient occlusion of the IVC was performed with a micro-vascular clip. Using the multiple beat method with variable preload, end-systolic elastance (Ees) was defined as P(t)[V(t)-V0], where P(t) is instantaneous pressure, V(t) is instantaneous volume, and VRV and LV collagen abundance by picrosirius red staining were quantified as percent fibrosis of the total RV and LV respectively. Cardiomyocyte cross-sectional area was quantified as previously described For RT-PCR, total RNA was extracted from RV and LV tissues directly using Trizol (Invitrogen), converted to cDNA using a High Capacity cDNA Reverse Transcription Kit (Applied Biosystems). For all RT-PCR experiments, samples were quantified in triplicate using 40 cycles performed at 94°C for 30 sec., 60°C for 45 sec, 72°C for 45 sec using an ABI Prism® 7900 Sequence Detection System using appropriate primers as previously described Total protein was extracted and quantified from tissue homogenates as described (28–30). Immunoblot analysis was then performed as previously described using antibodies for mouse targeted proteins including: Type I collagen (Santa Cruz Inc), calcineurin , pERK (Millipore), total ERK , pSmad-3 (Santa Cruz Inc), and total Smad-3 .Results are presented as mean ± standard deviation. Intergroup comparisons were made with a Student’s t-test and two-factor ANOVA. All statistical analyses were performed using SigmaStat Version 3.1 . An alpha level of P<0.05 was considered to indicate a significant effect or between-groups difference.To explore the impact of primary and secondary RVPO on biventricular function, steady-state hemodynamic analysis was performed using conductance catheterization in closed-chest, non-invasively ventilated mice . In shammax was decreased in 10-week secondary RVPO only but remained higher than RV dP/dtmax in each group. Similarly, LV stroke work was decreased in the 7-day primary and 10-week secondary RVPO compared to sham controls but remained higher than RV stroke work in each group.Compared to sham controls and 7-day primary RVPO, peak LV systolic pressure was increased in the 10-week secondary RVPO group . In contTo further study the impact of RVPO on biventricular function, ventriculo-arterial coupling (VAC) ratios of arterial elastance:end-systolic elastance (Ea:Ees) were measured for each ventricle. The ratio of RV-VAC to LV-VAC was defined as the BiV-VAC ratio . In the Compared to sham-operated controls, total body weight was significantly reduced after 7-days of primary RVPO only . In the 2+ATPase (SERCa) gene was reduced by 7-day primary RVPO only. LV SERCa gene expression was reduced in the 10-week secondary RVPO group only. No significant increase in calcineurin mRNA expression was observed in the RV after 7-days of secondary RVPO  ratio in the context of biventricular function. We observed that in both models of RVPO, RV contractile function was recruited to maintain ventriculo-arterial coupling, however with suboptimal efficiency. By measuring ratios of RV-VAC to LV-VAC as an indicator of ’biventricular efficiency’, we first confirmed that the BiV-VAC ratio was approximately 1.0 in sham controls, which is consistent with optimal uni-ventricular efficiency. Surgical constriction of the pulmonary artery and thoracic aorta yielded an expected increase in end-systolic pressure coupled with reduced stroke volume, and thereby resulted in a net increase in arterial elastance (Ea). RV-Ea was similar in both acute, primary and chronic, secondary RVPO. In both models, load-dependent (dP/dtmax) and –independent (Ees) indices of RV contractile function were preserved, while RV ejection fraction was significantly reduced. As a result, distinct BiV-VAC ratios were observed in primary and secondary RVPO. Taken together, these findings suggest that increased afterload alone may not fully account for RV failure associated with pulmonary hypertension or left ventricular failure. Our findings are consistent with studies that have observed a similar degree of ‘RV resilience’ in the setting of pressure and volume overload We next examined the impact of RVPO on ventricular mass and first observed that total body weight was significantly reduced in primary RVPO, not secondary RVPO. Despite this profound difference in total body weight, RV mass increased to the same degree in both models of RVPO while LV mass was reduced in primary RVPO, but increased in secondary RVPO. Changes in cardiomyocyte cross-sectional area were consistent with changes in ventricular mass. Importantly, seven days of LV pressure overload increased LV mass, but did not affect RV mass, thereby suggesting that RV remodeling is a later consequence of LV pressure overload. A recent clinically study reported a similar pattern of atrophic remodeling of the LV in pulmonary hypertension that may be reversible in conditions such as chronic thromboembolic pulmonary hypertension Next, we explored two central pathways that mediate cardiac remodeling, namely, signaling via calcineurin and TGFβ1. Based on numerous studies of left heart failure, calcineurin has been identified as regulator of cardiac hypertrophy, fetal gene expression, and fibrosis TGFβ1 is a ubiquitously expressed master switch that induces the fibrotic program in various cell types including cardiac fibroblasts and has been implicated in multiple fibroproliferative diseases including: glomerulosclerosis, ulcerative colitis, hepatic fibrosis, glaucoma, and scleroderma There are several limitations to this study. First, since we used a retrograde approach to the LV and RV from the carotid artery and internal jugular vein, small changes in ventricular volumes may be due to aortic or tricuspid regurgitation. Second, simultaneous recordings of RV and LV loops were not currently feasible due to far-field and near-field interactions from the two conductance catheters despite the use of dual frequency modes. This was resolved by acquiring RV and LV PV loops in rapid sequence during the same setting. Third, cardiac dimensions were not quantified in this study. Finally, future studies employing other time points of RVPO and murine models of primary pulmonary hypertension will be necessary to further define the course of RV remodeling in response to primary and secondary RVPO.A primary cause of death for individuals with acute or chronic pulmonary hypertension and left heart dysfunction is RV failure which is a directly related to abnormally high pulmonary pressures Figure S1Biventricular remodeling after 7 days of secondary RVPO due to thoracic aortic constriction (TAC). A) Compared to sham controls, LV systolic pressure was increased  and RV systolic pressure unchanged  after 7 days of thoracic aortic constriction. B) Compared to sham controls, LV mass normalized to tibia length was increased  and normalized RV mass unchanged  after 7 days of thoracic aortic constriction. C) Calcineurin mRNA expression was not significantly increased in the RV or LV after TAC. D) TGFβ1 mRNA expression was increased in the LV (p = 0.03), not RV after TAC.(TIF)Click here for additional data file.Table S1Steady State Hemodynamics in a mouse model of primary RVPO (n = 6/group).(DOC)Click here for additional data file.Table S2Steady State Hemodynamics in a mouse model of secondary RVPO (n = 6/group).(DOC)Click here for additional data file.


There is strong evidence that left atrial (LA) size is a prognostic marker in a variety of heart diseases. Recently, real-time three-dimensional echocardiography (RT3DE) has been reported as a useful tool for studying the phasic changes of the left atrial volumes. The aim of this study was to investigate the performance of the left atrium in beta-thalassemic patients with preserved left ventricular ejection fraction (EF) and no iron overload, using RT3DE.Twenty-eight asymptomatic b-thalassemic patients  who were on iron chelating therapy, as well as 20 age- and sex-matched healthy controls underwent transthoracic RT3DE. The patient group had normal echocardiographic systolic and diastolic indices, while there was no myocardial iron disposition according to MRI. Apical full volume data sets were obtained and LA volumes were measured at 3 time points of the cardiac cycle: (1) maximum volume (LAmax) at end-systole, just before mitral valve opening; (2) minimum volume (LAmin) at end-diastole, just before mitral valve closure; and (3) volume before atrial active contraction (LApreA) obtained from the last frame before mitral valve reopening or at time of the P wave on the surface electrocardiogram. From the derived values, left atrial active and passive emptying volumes, as well as the respective emptying fractions were calculated.3, LAmin:(16.0 ± 6.0 vs. 13.5 ±4.2)cm3, and LApreA:(25.4 ± 9.8 vs. 24.3 ± 7.2)cm3. However, left atrial active emptying fraction was reduced in the patient group as compared to the healthy population .Left ventricular EF (59.2 ± 2.5% patients vs. 60.1 ± 2.1% controls), E/A, E/E' were similar between the two groups. Differences in the LAmax, LAmin and LApreA between b-thalassemic patients and controls were non-significant, LAmax:(35.5 ± 13.4 vs 31.8 ± 9.8)cmRT3DE may be a novel technique for the evaluation of LA function in asymptomatic patients with b-Thalassemia Major. Among three-dimensional volumes and indices, left atrial active emptying fraction may be an early index of LA dysfunction in the specific patient population. Cardiac involvement represents an important complication of b-thalassemia major, and results in increased mortality and morbidity rates. Disease mechanisms implicate iron infiltration of the heart structures due to frequent blood transfusions. Transfusion-dependent patients receive 20 times the normal intake of iron, which leads to iron accumulation and damage in the liver, heart, and endocrine organs . AlthougOn the other hand, left atrial (LA) enlargement plays a pivotal role in the prognosis and management of various cardiovascular diseases, including coronary artery disease and heart failure ,4. RecenThe aim of the current study is to investigate the performance of the left atrium in b-thalassemic patients with preserved left ventricular ejection fraction (EF) and no myocardial iron overload employing RT3DE.Twenty-eight consecutive asymptomatic patients  with b-Thalassemia major were retrospectively studied, compared to twenty healthy age, sex- and BMI- matched controls. Thalassemic patients were on intense chelating therapy with deferipone (p.os) and desferioxamine (i.v/s.c). All patients were on sinus rhythm. Exclusion criteria included a medical history of smoking, arterial hypertension, diabetes mellitus, as well as the presence of heart failure and pulmonary hypertension symptoms (NYHA> Stage I). Structural and valvular heart diseases were also within the exclusion criteria. Additionally, patients with CMR-detected myocardial iron overload during the previous six-month scan were excluded from the study. A critical iron loading was defined as a T2* value less than the threshold of 20 ms , were measured using pulsed Doppler echocardiography from the apical 4-chamber view by positioning the sample volume at the tips of the mitral valve, and the E/A ratio was subsequently calculated. The early diastolic mitral annular velocity (E') was measured at the septal side of the mitral annulus using tissue Doppler imaging in the apical 4-chamber view. The ratio E/E' was estimated as a non-invasive LV filling pressure index.Real-time 3-dimensional echocardiography imaging was performed from the apical window using a commercial scanner equipped with a fully sampled matrix array transducer x3-1), in the harmonic mode. Two full-volume data sets were acquired from an apical window over seven cardiac cycles, with a breath hold. The 3-dimensional data sets were transferred to a Q-Lab system  for off-line analysis. Analysis of 3-dimensional images was based on a 2-dimensional approach, which relied on obtaining images from an apical 4-chamber view  maximum volume (Vmax) at end-systole, just before mitral valve opening; (2) minimum volume (Vmin) at end-diastole, just before mitral valve closure; and (3) volume before atrial active contraction (VpreA) obtained from the last frame before mitral valve reopening or at time of the P wave on the surface electrocardiogram.All 3D LA volumes were independently assessed by two echocardiographers (C.A and I.F).LA passive emptying volume (PAEV) was defined as the maximum LA volume minus the LA volume before atrial contraction (PAEV = Vmax-VpreA). LA active emptying volume (AAEV) was defined as the LA volume before atrial contraction minus the minimum LA volume (AAEV = VpreA-Vmin). For the assessment of the LA function the following indicators derived from volumes were used: left atrium active emptying fraction defined as (AAEF) = (VpreA-Vmin)/VpreAx100; and LA passive emptying fraction (PAEF) = (Vmax-VpreA)/Vmax100.Continuous variables are presented as mean ± standard deviation of the mean or as percentage where appropriate. Data were tested for normality by Kolmogorov-Smirnov test. The means of normally distributed data were compared using independent Student's t-test. A value of p < 0.05 was considered significant in all cases. All tests were two-tailed. Intra- and inter-observer agreement was assessed with the kappa statistic. Kappa statistic values are expressed as k ± std. error. Intervals of agreement are denoted as: kappa value greater than 0.800 denotes excellent agreement, 0.601-0.800 good agreement, 0.401-0.600 moderate agreement, 0.400 or less poor agreement. Data analysis was performed using the SPSS 17.0 statistical package for Windows .Twenty eight patients  as well as twenty healthy controls  were enrolled in the study. All patients with beta- thalassemia were on chelating therapy and had no myocardial iron according to CMR. Patient demographics are illustrated in Table Measurements regarding conventional two-dimensional echo as well Doppler indices were similar between the 2 groups tables . The aveRT3DE reported no differences with regards to the phasic changes of atrial volumes Table . The meaThe agreement between the two readers was 0.918 ± 0.012 (0.894-0.942 95% C.I). Intra-observer agreement was 0.892 ± 0.017 .According to our knowledge, this is the first study that attempts to assess phasic changes of LA volumes in asymptomatic patients with b-thalassemia major by employing RT3D technology. As indicated by RT3D volumetric measurements, AAEF appears reduced in the patient population. This reflects abnormal systolic function of the LA, even in the absence of other affected echocardiographic parameters. This in turn could be explained by the fact that our patients were on intense chelating therapy, which maintained tissue iron levels within normal range (as illustrated by serum ferritin levels); therefore no iron accumulation was reported in the CMR evaluation. Indeed, studies have demonstrated that intense chelating therapy may prevent myocardial systolic function deterioration or even improve it . Moreoveal. [al. [Iron toxicity is a major determinant of disease prognosis in b-thalassemic patients . Althougal. , diastolal.  illustraal. [al.  have sugal. have illustrated that LAEF was reduced in well-preserved thalassemic patients, a finding that was verified by our results. According to the same authors, this reduction was associated with reduced exercise capacity [On the other hand, left atrial volumetric assessment employing RT3D seems to offer an alternative approach as it can provide useful clinical information in early disease states, regardless of the left ventricular ejection fraction . In our capacity .The echocardiographic evaluation of LA dimensions and performance is a matter of intense research. LA diameters as measured with 2D and M-Mode from the parasternal view tend to underestimate the true atrial dimensions, although they are useful and widely available . EnlargeMore recently, LA volume has been measured using real-time 3D echocardiography that has shown good agreement with other imaging modalities including magnetic resonance imaging ,23. AddiHowever, studies on 3D echo measurement of LA volume have been limited, and there is no consensus on the methods or comparisons with established normal values. In addition, the low frame-rates achieved by the X3-1 transducer constitute a major limitation. Furthermore, we did not employ strain and strain rate measurements, which could provide information on early atrial involvement in our study population ,27. BiocReal-time 3D seems to be a novel method for the accurate assessment of LA phasic changes in asymptomatic patients with b-thalassemia major. Additionally, AAEF may represent an early index of impaired left atrial performance in the specific population. In turn, left atrial dysfunction could be related to the increased incidence of arrhythmias and reduced functional capacity during exercise in thalassemic patients. Our results imply that left atrial function should be thoroughly investigated by clinicians.LA: left atrial; CMR: cardiac magnetic resonance; 2D: two-dimensional; RT3D: real-time three-dimensional; AAEV: active atrial emptying volume; PAEV: passive atrial emptying volume; AAEF: active atrial emptying fraction; PAEF: passive atrial emptying fraction.The authors declare that they have no competing interests.CA and IF in the data collection, CA in the laboratory analysis, EP and AA in statistical analysis, IF drafted the manuscript, CS provided critical review of the manuscript. All authors read and approved the final manuscript.3D full-volume dataset of a thalassemic patient, cropped to illustrate the 4-chamber view.Click here for file


Primary aldosteronism (PA) is a most common cause of secondary hypertension. In PA, left ventricular hypertrophy (LVH) is more progressive than in any other cause of hypertension. Aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) are major subtypes of PA. However there is little information concerned with differences of cardiac structures between these two subtypes.We reviewed echocardiographic findings in 46 patients with PA. All patients had a positive screen test and subtypes of PA were confirmed by adrenal vein sampling. Subjects consisted of 20 patients with APA  and 26 patients with IHA . We investigated differences of cardiac structures and functions in the left atrium and ventricle between the APA group and IHA group.In terms of clinical characteristics, the height and duration of hypertension were greater and serum potassium concentration and BMI were lower in the APA group than in the IHA group. Plasma aldosterone concentration (PAC) and PAC to plasma renin activity ratio were higher in the APA group than in the IHA group. In echocardiographic assessment, the left atrial volume, left ventricular end-diastolic and end-systolic diameters, left ventricular mass (LVM), and prevalence of LVH were greater in the APA group than in the IHA group. Multiple linear regression analysis revealed that the diagnosis of APA independently correlated with left atrial volume, left ventricular end-diastolic diameter, and LVM.We demonstrated that differences of cardiac structures between the APA group and IHA group existed. In APA, left atrial enlargement and LVH were more prominent than in IHA. Primary aldosteronism (PA) is a common cause of secondary hypertension. Aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) are major subtypes of PA . DistincLeft ventricular hypertrophy (LVH) is one of the most important predictors of cardiovascular events. Previous studies reported that, in patients with PA, LVH preceded other organ damage  and was We investigated 46 consecutive hypertensive patients with a positive screening test for PA who were referred to our department for AVS from February 2009 to January 2012. All these patients were suspected of having secondary hypertension. Echocardiographic assessment was performed in all patients on their first visit. Blood pressure (BP) and heart rate (HR) were measured at the time of echocardiographic examination without the cessation of antihypertensive agents. The hormonal evaluation was conducted within 2 months after the echocardiographic assessment. No patient had a history of ischemic heart disease, valvular heart disease, or any other cardiomyopathies. Subjects consisted of 20 patients with APA (APA group) and 26 patients with IHA (IHA group).The aldosterone receptor blockers, angiotensin receptor blockers, and β-blockers were withdrawn and changed to long-acting calcium channel blockers, if needed, at least 2 weeks before the hormonal evaluation. Administration of long-acting calcium channel blockers had been continued. The PAC (in ng/dl) and the plasma renin activity (PRA) (in ng/ml/h) were measured after overnight fast and 30 min rest. A positive screening test for PA was defined as a PAC value greater than 15 ng/day and a PAC/PRA ratio (ARR) greater than 20 in accordance with the Japanese Society of Hypertension’s guideline for the management of hypertension 2009. The AVS protocol and diagnostic criteria were in accordance with the guideline of the Japan Endocrine Society [2 in men and greater than 95 g/m2 in women. Other echocardiographic parameters were normalized for body surface area if needed. LV diameters and LV posterior wall thickness (LVPWT) and interventricular septal thickness (IVST) were measured at the level of the tip of the mitral valve leaflet using B-mode images. Relative wall thickness (RWT) was calculated according to the following equation: RWT = (IVST + LVPWT)/left ventricular end-diastolic diameter.Comprehensive echocardiographic assessment was conducted by three experienced sonographers, who had no knowledge of the clinical data, using high-quality commercially available ultrasound systems . All echocardiographic parameters were measured according to the recommendation of the American Society of Echocardiography , 15. ImaStroke volume was determined as the product of the time–velocity integral measured at the left ventricular outflow tract and the cross-sectional area of the aortic annulus.E), peak flow velocity at atrial contraction (A), E/A ratio, and deceleration time of E (Dct). Mitral annular velocity was measured using pulsed wave tissue Doppler imaging (TDI). Early diastolic peak velocity (e′), late diastolic velocity (a′), and systolic velocity (s′) were measured at the septal and lateral sides of the mitral annulus from the apical four-chamber view. Systolic pulmonary artery pressure (SPAP) was estimated using continuous wave Doppler by calculating the right ventricular to right atrial pressure gradient during systole, approximated by the modified Bernoulli equation as 4v2, where v is the tricuspid regurgitation velocity. Right atrial pressure was estimated on the basis of echocardiographic assessment of the inferior vena cava and added to the calculated gradient to give the SPAP.Transmitral flow velocity was measured using pulsed wave Doppler from the apical long axis view at the end of expiration. The sample volume was positioned between the tips of the mitral leaflet maintaining the ultrasonic beam parallel to the direction of blood flow. The following parameters were obtained: early diastolic peak flow velocity .Data are expressed as mean ± SD or median (interquartile range) as indicated and the comparison between groups was performed with Student’s Clinical characteristics in the APA group and IHA group are summarized in Table E, were similar between the two groups. E was higher in the APA group than in the IHA group. E/A ratio was similar between the two groups. Mitral annular velocities and E/e′ were similar between the two groups. Tricuspid regurgitation velocity and SPAP were similar between the two groups.Echocardiographic parameters in the APA group and IHA group are summarized in Table r = 0.66, p < 0.01), two independent models were tested. The diagnosis of APA was included in model 1 and log PAC was included in model 2. Multiple linear regression analysis revealed that the duration of hypertension independently correlated with LAVI in both models and LVDdI in model 1 , left ventricular end-diastolic diameter index (LVDdI), and LVMI Table . Systoli 1 Table . The diaIn the present study, we reviewed echocardiographic data to investigate the difference of cardiac structure between APA and IHA. In the APA group, left atrium volume and left ventricular diameters and LVMI were greater than in IHA. Multiple linear regression analysis revealed that the diagnosis of APA and log PAC were predictors of LAVI, LVDdI, and LVMI. In the present study, we demonstrated that the morphological differences in the left atrium and left ventricle existed between the APA group and IHA group and that LVH was more progressive and common in the APA group than in the IHA group.The duration of hypertension and the number of antihypertensive agents used per patient were greater in APA than in IHA. These findings imply that hypertensive state was more severe in APA than IHA. It is well known that hypertension is one of the most important factors leading to LVH. In the present study, the duration of hypertension correlated with LVMI, although BP at the time of echocardiographic examination was similar between the two groups. These findings suggest that a more severe hypertensive status of APA in a prior period had contributed to the greater progression of LVH in APA than in IHA, although the duration of hypertension was not an independent predictor of LVMI in multiple linear regression analysis.Several lines of evidence have shown that excess aldosterone secretion promotes LVH. Brilla et al. , 6 demonExcess aldosterone secretion affects loading condition through sodium and water retention. Several studies reported that patients with APA had larger left ventricular dimensions compared to patients with other types of hypertension such as essential hypertension, pheochromocytoma, Cushing syndrome, and renovascular hypertension , 21, 22.In fact, in the present study, the prevalence of LVH in IHA was as high as 68 %. This high prevalence of LVH may play a role in the poor prognosis in patients with PA compared to other secondary hypertension and essential hypertension. However, it is unclear whether the difference in prognosis exists between APA and IHA. In addition, to our knowledge, there has been little information concerning the difference of left ventricular structures and function among subtypes of PA such as APA and IHA. In the present study, we demonstrated that the morphological differences in the left atrium and left ventricle existed between APA and IHA and that the degree of LVH progressed in APA compared to IHA, although it might be difficult to differentiate APA from IHA on the basis of the presence and degree of LVH. These findings may suggest the possibility of poor prognosis in patients with APA compared to IHA if they are untreated.E was significantly larger in APA than in IHA. This finding might indicate greater preload in APA than in IHA. The values of A, Dct, and E/A were similar between the two groups. In the tissue Doppler assessment of mitral annular velocities, the values of e′ and E/e′ in the septal and lateral sides of the mitral annulus were similar between the two groups. The values of Dct and e′ in both groups were below the normal range specified in the American Society of Echocardiography’s recommendation [e′ was a good predictor of left ventricular diastolic function, it was determined by several factors such as left ventricular relaxation, preload, systolic function, and left ventricular minimal pressure [In the Doppler assessment of transmitral flow velocities, the value of endation . These fpressure . Other epressure  reportedpressure  demonstrThere are a few limitations in this study. This was a cross-sectional study and the number of patients was small. We could not show whether the differences of cardiac structure between APA and IHA affect their prognosis or not. In this regard, a cohort study with larger numbers of patients is needed. In our study, some patients were taking antihypertensive medications. We continued these medications owing to ethical considerations when echocardiography was performed. The influence of antihypertensive drug on our results would be small because the use of antihypertensive drugs was similar between the two groups. Despite the progression of LVH in the APA group, we could not find a difference of left ventricular diastolic properties between the two groups. Additional but more precise evaluation such as the two-dimensional speckle tracking method may be useful to evaluate the difference between the two groups.In the present study, we demonstrated that the diagnosis of APA was an independent predictor of greater left atrial volume, left ventricular dimensions, and LVM. Excess aldosterone secretion in APA compared to IHA would play a role in the progression of LVH with larger left atrial and left ventricle. The difference of left ventricular diastolic properties was unclear. To determine the usefulness of this diagnostic and prognostic parameter, a prospective study with larger numbers of subjects is needed.


Some studies have suggested that diastolic dysfunction precedes the clinical manifestation of hypertension. Whether changes in cardiac structure and function predate the clinical manifestation of hypertension later in life is now being investigated. The aim of this study was to assess the differences in cardiac structure and function between the offspring of hypertensive and normotensive parents.Eighty normotensive offspring of hypertensive parents (OHyp)  and 62 normotensive offspring of normotensive parents (ONorm)  were recruited for echocardiography.p = 0.369). Other baseline parameters were comparable between the two groups. Septal wall thickness in systole was higher in the OHyp than the ONorm subjects . Indexed left ventricular mass  and relative wall thickness  were similar in the two groups. The offspring of hypertensives had lower deceleration time , prolonged duration of pulmonary A reverse flow , increased myocardial isovolumic relaxation time  and a lower myocardial Em  and myocardial Em/Am ratio  than the offspring of normotensives.The mean age was 25.0 (5.31) and 24.3 (3.60) years in the OHyp and ONorm participants, respectively (This study showed that offspring of OHyp subjects had early diastolic functional abnormalities when compared with offspring of ONorm participants. Longitudinal studies are needed to determine the implications of this finding in this African population. Worldwide, hypertension is an independent risk factor for cardiovascular morbidity and mortality.Studies on offspring of hypertensive patients have shown the significant roles of heredity, salt intake, increased peripheral vascular resistance, insulin resistance and increased left ventricular (LV) mass in the pathogenesis of hypertension.16Since most of these studies have been carried out in Europe and America, little is known about LV filling patterns in the offspring of hypertensive Nigerians, in a country with increasing prevalence of hypertension, as are most other African countries. This study therefore aimed to determine LV diastolic filling patterns in normotensive offspring of hypertensive Nigerians in comparison with normotensive control subjects without a family history of hypertension.The study was carried out at the cardiology unit of the Department of Medicine of the University College Hospital, Ibadan, Nigeria. Eighty normotensive offspring aged 18 to 40 years with hypertensive parents attending the cardiac clinic of the Hospital were recruited over a six-month period. Subjects were offspring of consecutive hypertensive parents seen at the medical outpatient department.Comparable control subjects were recruited among the children of normotensive hospital staff and relatives of patients on treatment for conditions other than hypertension or other chronic medical conditions. Ethical approval was obtained from the institutional ethics review board and informed consent was obtained from each participant.2 were excluded from the study. Other exclusion criteria were existing heart disease and diabetes mellitus.Blood pressure was measured with a mercury sphygmomanometer (Accosson) according to standard guidelines.r = 0.90),p = 0.93) in one study.21Echocardiographic examination was performed with the subjects in partial left lateral decubitus position using an Aloka SSD1700 machine  with a 3.5-MHz transducer. Two-dimensional guided M-mode measurements were obtained as recommended by the American Society of Echocardiography.2.7.2.7. Relative wall thickness (RWT) was calculated as 2RWTd/LVIDd .24LVM was indexed by the allometric power of height , early diastolic flow time (EDFT), late diastolic peak flow velocity (A), late diastolic flow time (ADFT), the deceleration time of early mitral velocity, and the ratio of E to A (E/A).Isovolumic relaxation time (IVRT) was measured with the pulse-wave Doppler beam intersecting the LV outflow and inflow tracts. EDFT was measured from the onset of diastolic flow to the intersection of a line extrapolated to the baseline, and ADFT was measured from the onset of late diastolic flow to the end of diastolic flow.25Pulmonary venous flow recordings were obtained from a four-chamber view directed at the right upper pulmonary vein. The sample volume was placed 1–2 cm into the pulmonary vein and the following measurement were recorded: peak S-wave velocity (peak systolic pulmonary venous inflow velocity during ventricular systole), peak D-wave velocity (peak diastolic pulmonary venous inflow velocity during early phase of diastole), peak AR-wave velocity , and duration of the reverse atrial contraction-induced diastolic flow.26Myocardial Doppler velocities were measured in the apical four-chamber view with the Doppler beam well aligned to the septum and the pulsed Doppler sample volume placed 1 cm apically from the mitral annulus in the interventricular septal myocardium. The following measurements were made: myocardial isovolumic contraction time, myocardial peak systolic velocity (Sm), myocardial contraction time, myocardial isovolumetric relaxation time, myocardial early diastolic relaxation velocity (Em), and myocardial late relaxation velocity (Am). Other measurements were the duration of the diastolic period and the durations of Em and Am. Measurements from three cardiac cycles were taken and averaged.The calculation of the sample size for this study was based on a difference of 0.2 in the mitral E/A ratio between the controls and the subjects, with a 90% power to detect the difference at a significance level of 0.05 in a two-tailed test. The estimated sample size was 63 subjects per group. 27t-test for independent groups. Where data were not normal, the Mann-Whitney test was used to compare the two groups. Data were adjusted for covariates using analysis of covariance. A two-tailed p-value < 0.05 was considered significant.All data generated were entered into a standard proforma. SPSS software, version 10.0  was used for statistical analysis. Continuous variables were expressed as mean (standard deviation). Differences in continuous variables between the groups were assessed with a The cardiac structure and systolic functional data are listed in p = 0.012]; posterior wall thickness in systole ; and deceleration time of the E wave .Among the male gender, statistical differences were found in only some echocardiographic parameters. Hypertensive vs normotensive offspring: left atrial diameter ; body surface area ; diastolic blood pressure ; mean arterial blood pressure ; duration of the medial annulus IVRT .On the other hand, among the females, statistical differences were found in some of the physical and echocardiographic parameters. Hypertensive vs normotensive offspring: height [1.64 (0.08) vs 1.60 (0.05) m, This study shows that normotensive offspring of hypertensive Nigerians had abnormal diastolic functional parameters compared with normotensive control subjects without a family history of hypertension. The changes in left ventricular filling dynamics and an increased left ventricular mass occurred early in the development of systemic hypertension. Increased left ventricular mass and diastolic dysfunction have been demonstrated in the early stages of hypertension, in the stage of prehypertension, and in hypertensive subjects without left ventricular hypertrophy.et al.In this study, the offspring of hypertensive subjects showed features of early diastolic dysfunction even in the absence of increased left ventricular mass. This was demonstrated by significantly higher deceleration time of E, as well as a prolonged diastolic period, assessed by tissue Doppler. Impaired relaxation is conventionally associated with increased A velocity, and reduced E/A ratio. Our finding was similar to the work of Graettinger Pulmonary vein flow parameters are useful non-invasive methods of assessment of LV diastolic function. The present study showed prolonged duration of the A reverse flow (Ar) in the offspring of hypertensives. Prolonged Ar duration is associated with impaired relaxation, as well as reduced preload.et al.Tissue Doppler imaging is a non-invasive and easily reproducible method of assessment of left ventricular function. The parameters are less influenced by preload changes compared with transmitral and pulmonary vein flow measurements and also believed to be more sensitive than the convectional Doppler methods. Our septal myocardial tissue Doppler measurements showed reduced Em and Em/Am ratio and increased IVRT in the offspring of hypertensives. These findings are indicative of diastolic dysfunction and were similar to those of Aeschbacher In an earlier study by the same group,Studies that did not demonstrate differences between diastolic function in the offspring of hypertensives and normotensives used only mitral inflow parameters, which are inadequate in assessing diastolic function, as the parameters are easily affected by loading conditions.et al,Our data suggest that diastolic dysfunction was present in offspring of hypertensive subjects despite the fact that they had similar baseline characteristics and left ventricular dimensions to the control group. Although the effect of the insignificantly higher blood pressure and LVM on the findings of diastolic function cannot be totally ruled out, our findings are similar to those of Aeschbacher et al.Gender differences noted in the analysis are not surprising. Other workers have reported gender differences in LV parameters, as well as parameters of LV diastolic function.Before changes in LV mass or hypertension become apparent, various changes occur at the cellular level that cause alterations in the myocardial architecture and collagen structure. Metabolic and neuro-endocrine changes also occur. Some studies have demonstrated acceleration of these factors in the offspring of hypertensives.The study had some limitations. We did not obtain information on and correct for factors such as socio-economic status, level of physical activity, diet or biochemical parameters, and this may have affected the results.Diastolic dysfunction has been shown to affect the quality of life of patients with advanced cardiac disease. Assessment of diastolic function is of paramount importance in the management of this disease. Early identification of subjects with or at risk for hypertension and diastolic dysfunction may help to stratify risk, guide therapy and prevent target-organ damage in these patients.The consistent independent effects of increased body weight and particularly male gender


MR imaging of the heart typically involves the acquisition of standard views aligned with the heart axes. Time-efficient and reproducible planning requires expertise in heart geometry and anatomy. In this study, we evaluate the ability of fully automatic heart view localization software to detect the long-axis views of the heart and compare the results both visually and geometrically with manual localization.27 patients (age range 9-70 years) undergoing CMR for a range of different indications  were examined on a 1.5 T MAGNETOM Avanto MR system . Following rough localization of the heart within the thorax, a stack of slices covering the entire heart was acquired in the approximate short-axis orientation using a single-shot TrueFISP sequence. This stack of slices was used as input to a machine learning-based algorithm [The automatic view-planning software detected the heart in all 27 cases. Visual agreement scores are summarized in Table We have demonstrated in a group of patients with a range of different cardiovascular pathologies that automatic planning of the long-axis views of the heart can be accomplished in the majority of cases with little or no clinically relevant difference compared with manual planning. Consistent with the visual assessment, the angular differences between the manually and automatically planned views increased with increasing visual difference.Siemens AG.


We combined transapical cannulation (TAC) and right axillary artery cannulation (RAAC) for the repair of AAAD to reduce mortality and morbidity when malperfusion risk existed. We evaluated early and mid-term outcomes of AAAD repair with TAC and RAAC.Between October 2009 and March 2012, 23 patients of AAAD received graft replacement with TAC and RAAC combination. Patients’ age was 54.3±13.5 years old. Preoperative malperfusion was presented in 16 patients (69.6%). CPB was initially started with RAAC through the right armpit and right atrial drainage, and then TAC was applied through apex. We retrospectively investigated mortality and morbidity, and cardiac functions by echocardiography during hospital stay and once a year after operation.Total arch replacement was performed in all patients. In-hospital mortality was 4.3%, and no patient developed intraoperative malperfusion. Intraoperative stroke occurred in 1 patient (4.3%), and 3 patients (13.0%) suffered from delayed stroke (10-24 days). These delayed strokes might be caused by cardiogenic thrombus, although no intracardiac thrombus was found. Mean ejection fraction was 66.1±10.9 % in early periods and 73.1±8.7% mid-term periods. There was no LV asynergy or intra-cardiac thrombus in echocardiography of both studies of early and mid-term period.TAC with RAAC is a safe and effective procedure to reduce the risk of operation in acute type A aortic dissection. TAC may not affect cardiac functions although it might have potential risk of delayed stroke.


P < 0.0005), aortic leaflet separation diameter , right ventricle diameter  and right ventricle systolic pressure . Model has good prognostic accuracy (AUROC = 0.84) and it retains good (AUROC = 0.78) when testing on the validation cohort. Risks for in-hospital mortality after PCI in ACS patients using echocardiographic measurements could be accurately predicted in contemporary practice. Incorporation of such developed model should facilitate research, clinical decisions, and optimizing treatment strategy in selected high risk ACS patients.Different ways have been used to stratify risk in acute coronary syndrome (ACS) patients. The aim of the study was to examine the usefulness of echocardiographic parameters as predictors of in-hospital outcome in patients with ACS after percutaneous coronary intervention (PCI). A data of 2030 patients with diagnosis of ACS hospitalized from December 2008 to December 2011 was used to develop a risk model based on echocardiographic parameters using the binary logistic regression. This model was independently evaluated in validation cohort prospectively (954 patients admitted during 2012). In-hospital mortality in derivation cohort was 7.73%, and 6.28% in validation cohort. Developed model has been designed with 4 independent echocardiographic predictors of in-hospital mortality: left ventricular ejection fraction (LVEF RR = 0.892; 95%CI = 0.854–0.932,  Despite the modern methods of diagnosis, advances in treatment over the last three decades, and the implementation of measures of primary and secondary prevention, ACS is still a major threat to the health and life of humans.Nowadays risk assessment is needed to guide triage and key management decisions. For decades scientists are trying to create ideal scores for predicting risk which is simple, fast, and applicable to everyday practice. Although number of risk scores have been developed to predict short and long term outcomes in patients with ACS –10, GRACEchocardiography, as one of most important modality in the acute setting, rapidly and widely available, has significant utility in the diagnosis and management, and is also used for risk stratification and prognosis of ACS patients. Estimated risk, based on echocardiographic predictors, is challenging but there has not been a widespread adoption in the contemporary practice, regardless of the potential benefits this could lead to.The aim of study was to examine the usefulness of echocardiographic parameters as predictors of in-hospital outcome in patients with ACS after PCI.The rest of the paper is organized as follows. A set of patient-related data is obtained from the hospital information system from Institute of Cardiovascular Diseases of Vojvodina, situated in Sremska Kamenica, Serbia, Europe.A total of 2030 patients (aged 61.29 ± 11.70 years) hospitalized for ACS and treated with PCI between December 2008 and December 2011 were assigned to a derivation cohort. Validation cohort contained 954 patients (aged 61.54 ± 11.91 years) hospitalized during 2012. All patients were examined by an experienced cardiologist immediately after admission.ACS is defined as “any group of clinical symptoms compatible with acute myocardial ischemia”, which includes unstable angina (UA) and myocardial infarction (MI), with or without ST-segment elevation according to American Heart Association . All patThe echocardiography examination was performed by a Vivid 7  with a phased-array 3.5-MHz transducer. All physicians who applied echocardiography routinely in the Institute were involved. A complete M-mode, two-dimensional and Doppler technique  examination was performed in all patients during hospitalization, according to the recommendations of the American Society of Echocardiography . PatientThe following 45 echocardiographic parameters (EP) were obtained in a study presented: IVSd , LVIDs , LVIDd , PLWd , AO (the aortic root diameter), AOvs (aortic leaflet separation diameter), LA , RV (right ventricular diameter), EDVLV (end-diastolic volume of the left ventricle), ESVLV (end-systolic volume of left ventricle), LVSV (left ventricular stroke volume), EDVLVI (end-diastolic volume of the left ventricle index), ESVLVI (end-systolic volume of the left ventricle index), LVSVI (left ventricular stroke volume index), LVEF (left ventricular ejection fraction), CO (cardiac output), LAab , RAab , LAll , RAll , LVOTd (left ventricular outflow tract diameter), MADd , MAAd , AscAO (ascending aorta diameter), DscAO (descending aorta diameter), ArchAO (arch aorta diameter), TrcPA , RVd (right ventricular diameter-diastole), RVs (right ventricular diameter-systole), AOmaxPG , AOmeanPG (transaortic mean gradient), AoVTI , MVmaxPG , MVmeanPG , MVVTI , PVmaxPG , PVmeanPG (transpulmonic mean gradient), PAVTI , AVA , MVA , RVSP (right ventricular systolic pressure), Emv , Amv , and Emv/Amv, MV Dct .t-test or Mann-Whitney test. To identify predictors of intrahospital mortality, the univariate binary logistic regression was used. Including all the variables with P < 0.05 the multivariate binary logistic regression gave the model for intrahospital mortality. Receiver operating characteristic (ROC) curve was generated and the area under the curve was calculated. This method was used to investigate the prognostic value of obtained model. Sensitivity and specificity for optimal cutoff were calculated. Differences were considered significant at P < 0.05.Statistical analysis was performed using SPSS Version 17. Continuous variables were presented as mean ± SD or median (25th percentile–75th percentile). Comparisons between groups were analyzed by unpaired The age distribution of 2030 patients belonging to derivation cohort is shown in As +, K+, and Total protein did not show significant difference between patient who survived and those who did not.As Each patient from derivation cohort was initially described with 45 echocardiographic parameters  which ar2), LAII (cm), RAab (cm), RAII (cm), MAAd (cm), MVmeanPG (mmHg), Emv (cm/sec.), Emv/Amv., RVs (cm), and RVSP (mmHg) compared with patients who survived. Survivors tended to have higher values of AOvs (cm), SVLV (mL), LVEF (%), LVOTD (cm), AOmaxPG (mmHg), AOVTI (cm), AVA (cm2), MVVTI (cm), PAmaxPG (mmHg), PAmeanPG (mmHg), PAVTI (cm) compared to those with an adverse outcome. Body weight (kg), Body height (cm), Body Surface Area (m2), LVIDd (cm), IVSd (cm), PLWd (cm), RV (cm), AO (cm), EDVLV (mL), EDVLVI (mL/m2), LVSVI (mL/m2), CO (L/min.), LAab (cm), AOmeanPG (mmHg), AscAO (cm), DscAO (cm), ArchAO (cm), MADd (cm), MVA (cm2), MVmaxPG (mmHg), Amv (cm/sec.), MV Dct. (msec.), RVd (cm), and TrcPA (cm) did not show significant difference between patients who died compared to survivors.As Using 19 echocardiographic parameters selected by univariate binary logistic regression, the multivariate binary logistic regression gave the model of 4 independent predictors of intrahospital mortality .Consider the following:tval=2.05ROC curves achieved on derivation and validation cohorts are presented in Figures Risk scores are useful tools for the assessment of risk in ACS patients and allow accurate estimations of ischemic and bleeding risk for individual patients. This information is now increasingly used for estimating the patient's risks with the expected benefits and risks associated with available therapies, hence facilitating individual tailoring of treatments.Nowadays most of predictive models were selected as independent risk factors: age, heart failure, ST segment deviation, and elevated cardiac biomarkers, while a variety of other factors are used in individual models. The most popular risk scoring systems in clinical practice TIMI  and the In coronary care units, echocardiography as a noninvasive and inexpensive method in comparison with other established methods has significant utility in the diagnosis and management of ACS patients. Echocardiography also has a crucial role in the daily work of clinicians in assessing the risk and prognosis after a coronary incident by evaluating systolic and diastolic left ventricular function. Except ejection fraction others echocardiographic parameters rarely appear as predictors in contemporary risk scores.P < 0.0005), AOvs—aortic leaflet separation diameter (P = 0.011), RV—right ventricle diameter (P = 0.028), and RVSP—right ventricle systolic pressure (P = 0.048).Presented study showed that four independent echocardiographic predictor factors have influence on in-hospital mortality: LVEF—left ventricular ejection fraction  have a worse prognosis compared to patients without structural disease of the aortic valve in presence of ACS . On the Pathophysiological explanation for RV and RVSP as predictors of mortality in patients with ACS could be interpreted in many ways. ACS leading to anterograde, LV failure, can have further influence on the pulmonary microcirculation (increased Pulmonary Capillary Wedge Pressure), and then retrograde may be influenced on the increase in RVSP. In study presented RVSP was significantly higher in patients who died. Another explanation is STEMI of the right ventricle, which leads to dilatation of the RV and consecutive increase in RVSP. Although we and others have shown that the presence of RV dysfunction immediately after an MI was an important prognostic factor –29, few Goal was to create a model with echocardiographic parameters as predictors which would be easy to use in everyday work, in all institutions, without limitations of preinstalled software of echocardiographic equipment.The developed echocardiographic model might prove to be very helpful in the decision-making process and optimizing treatment strategy in selected high risk patients presenting with ACS after invasive strategy. It is suitable for expert interpretation, yet relatively simple as it contains only 4 echocardiographic parameters as predictors. Although presented study has been done on a large number of patients and it faithfully illustrates the actual state of patient population of the region where it was developed, authors believe it may find their role in the daily work of clinicians worldwide.This is still unexplored area and further investigations are needed. For future work it would be interesting to deploy Data Mining techniques including machine learning algorithms in order to find new relationships in the cohorts and extract new useful knowledge.The study presented has some limitations. Lack of this study is that some parameters were missing in derivation cohort, like precise parameters of diastolic function, strain rate velocities, myocardial contrast echocardiography, and so forth. Achieved accuracy could be better, taking into account missing parameter and missing values for existing parameters.Finally, we developed the model for in-hospital mortality, but fatal outcome cannot be excluded after discharge, so the follow-up of this study would be needed.


The purpose of this study was to determine if anodal stimulation accounts for failure to benefit from cardiac resynchronization therapy (CRT) in some patients.Approximately 30-40% of patients with moderate to severe heart failure do not have symptomatic nor echocardiographic improvement in cardiac function following CRT. Modern CRT devices allow the option of programming left ventricular (LV) lead pacing as LV tip to right ventricular (RV) lead coil to potentially improve pacing thresholds. However, anodal stimulation can result in unintentional RV pacing (anode) instead of LV pacing (cathode).Patients enrolled in our center's CRT registry had an echocardiogram, 6-minute walk (6MW), and Minnesota Living with HF Questionnaire (MLHFQ) pre-implant and 6 months after CRT. Electrocardiograms (12 lead) during RV, LV, and biventricular (BiV) pacing were obtained at the end of the implant in 102 patients.  Anodal stimulation was defined as LV pacing QRS morphology on EKG being identical to RV pacing or consistent with fusion with RV and LV electrode capture. LV end systolic volume (LVESV) was measured by echo biplane Simpson's method and CRT responder was defined as 15% or greater reduction in LVESV.Of the 102 patients, 46 (45.1%) had the final LV lead pacing configuration programmed LV (tip or ring) to RV (coil or ring).  3 of the 46 subjects (6.5%) had EKG findings consistent with anodal stimulation, not corrected intraoperatively.  All anodal stimulation patients were nonresponders to CRT by echo criteria  compared to 46% responders for those without anodal stimulation, . None of the anodal stimulation patients were responders for the 6 minute walk, compared to 32 of 66 (48%) of those without anodal stimulation.Anodal stimulation is a potential underrecognized and ameliorable cause of poor response to CRT. Heart failure is a significant cause of morbidity and mortality affecting nearly five million people in the United States, with approximately 500,000 newly diagnosed cases each year ,2. CardiStandard bipolar pacing is between two closely spaced electrodes, such as left ventricular (LV) lead tip electrode to LV ring electrode. Capture typically occurs at the cathode. Modern CRT devices allow the option of programming LV lead pacing as LV tip electrode (cathode) to right ventricular (RV) lead coil or ring (anode) as an alternative to improve pacing thresholds. Anodal stimulation  is definPatients who underwent clinically indicated biventricular pacemaker implantation (with or without defibrillator) at our institution between September 2005 and October 2007 were offered the opportunity to enroll in the cardiac resynchronization therapy registry. Of the 185 patients enrolled in the registry, there were 102 patients with comprehensive RV, LV, and BiV pacing EKG data which were included in this study. The study was approved by the Institutional Review Board.Commercially available CRT devices and leads were used. Standard settings included atrioventricular delay of 100 ms (sensed) and 130 ms (paced), interventricular delay of 0 ms with DDD or DDDR mode and standard lower (50-60 beats/min) and upper (120-130 beats/min) pacing rates. At the time of CRT implant, LV lead thresholds were tested LV tip to LV ring, and LV tip or ring to RV coil or ring, depending on the CRT device pacing configuration options. The final programmed setting was the LV pacing configuration that resulted in the lowest pacing threshold.This single center registry of prospectively collected data included baseline characteristics, extensive echocardiography data, device implant data, and lead position data.  Patient data was collected prior to CRT implantation and at 6 month follow-up.  At baseline and the time of each follow-up, patients underwent laboratory testing, comprehensive echocardiograms, device interrogation, 6 minute walk, oxygen consumption exercise treadmill testing, completion of Minnesota Living with Heart Failure Questionnaire, and evaluation of NYHA class. Left ventricular end systolic volume (LVESV) and left ventricular ejection fraction (LVEF) were measured by echo biplane Simpson's method .  A CRT Electrocardiograms (12 lead) were obtained on a digital recording system at an increased sweep speed of 100 mm/sec during LV, RV, and biventricular (BiV) pacing at the end of CRT implant. All tracings were reviewed independently by 2 physicians (KDF and BDP). Anodal stimulation was defined as LV pacing QRS morphology on EKG being consistent with partial or complete RV coil or ring capture.  This was defined as LV pacing either 1. Being identical to RV pacing QRS morphology, or 2. Fusion of RV and LV electrode capture based on LV pacing QRS vectors being inconsistent with anticipated EKG morphology for an LV lead pacing location .  Chest x-rays were reviewed for LV lead position to exclude closely placed LV and RV leads (within 2 cm) as the reason for the same EKG morphology.Of the 102 patients, 46 (45.1%) had the final LV lead pacing configuration programmed LV (tip or ring) to RV (coil or ring). Three of the 46 subjects (6.5%) were confirmed to have anodal stimulation, not corrected intraoperatively. Baseline characteristics showed the anodal stimulation group to have a higher rate of ischemic cardiomyopathy, higher LVESV and 6MW, and a lower LVEF.  Full Baseline characteristics are listed in Anodal stimulation patient #1 was an 81 year old male with ischemic cardiomyopathy (LVEF 16%), QRS duration of 186ms, and NYHA class III functional status on maximal medical therapy.  A Guidant H170 CRT-D pulse generator was placed. He had a Medtronic 6949 Sprint Fidelis RV defibrillator lead positioned in the RV apex. The LV lead (Boston Scientific Easy Track 2) was placed in an anterolateral vein branch of the coronary sinus. LV lead was programmed LV ring to RV coil at a pacing output of 2.6 Volts, 0.50 msec. Lead position and EKG tracings are shown in Anodal stimulation patient #2 was a 68 year old male with ischemic cardiomyopathy (LVEF 23%), QRS duration 138ms, and NYHA class III functional status on maximal medical therapy. A Medtronic 7991 ID pulse generator was placed.  He had a Medtronic 6947 Sprint Quattro Secure RV defibrillator lead positioned in the RV apex. The LV lead (Boston Scientific Easy Track 2) was positioned in the basal lateral location.  LV lead minimum threshold after testing various pacing configurations was 2.4 Volts at 0.50 msec and was with pacing LV tip to RV coil.  The final LV pacing output was programmed LV tip to RV coil at 5.0 Volts, 0.50 msec. Lead position and EKG tracings are shown in Anodal stimulation patient #3 was a 61 year old male with ischemic cardiomyopathy (LVEF 19%), QRS duration 96ms, and NYHA class II functional status.  He required pacemaker placement following planned AV node ablation for symptomatic atrial fibrillation.  Although his pre-ablation QRS was narrow he underwent CRT-D placement as it was known he would have post-ablation continuous ventricular pacing in the setting of a low LVEF and heart failure.  A Guidant H217 pulse generator was placed. A Medtronic 6949 Sprint Fidelis lead was positioned in the RV apex.  A Boston Scientific Easy Track 2 lead was placed in the anterior interventricular vein after inadequate thresholds and/or phrenic nerve stimulation were found at more lateral sites.  LV lead was programmed LV tip to RV coil at a pacing output of 5.0 Volts, 0.50 msec.  In spite of LV pacing from an anterior location, the QRS vector was negative in leads II, III, and aVF, consistent with anodal stimulation. At 6 month follow-up EF was slightly decreased from 26% to 22%, NYHA class was unchanged at III, 6MW decreased from 530m to 476m, and MLWHF score increased from 16 to 28.The main findings from this study are the following:  1. Anodal stimulation is underrecognized and was found in 6.5% of patients programmed LV tip to RV coil or ring, 2. Patients with anodal stimulation have a decreased response to CRT.Past studies have reported a 60-70% response rate to CRT -5. The lThe incidence of anodal stimulation has not been documented in prior CRT studies. Anodal stimulation was recognized and corrected intraoperatively in some patients included in this study's control group. In spite of that, anodal stimulation went unrecognized in 6.5% of CRT implants with LV pacing configuration of LV to RV in this study.  Pacing LV tip or ring to RV coil or ring is often used due to lower pacing thresholds in some patients (45% of this study population). These pacing configurations can lead to clinically significant anodal stimulation resulting in RV capture during attempted LV pacing.Poor CRT response when anodal stimulation is present is consistent with physiologic principles of ventricular synchrony. The benefit from CRT is believed to occur through improvement in left ventricular late depolarization in patients with left bundle branch block . CRT witAnodal stimulation is more likely to occur if:1. Pacing from an LV lead electrode to a dedicated bipolar RV lead.2. Pacing at high outputs.3. Clinically relevant if pacing from an LV electrode to a distant RV coil or ring.Prior studies have suggested that anodal stimulation is more common in dedicated than integrated bipolar defibrillation leads ,16. The The incidence of anodal stimulation that was corrected at the time of device implant is not known.  This study demonstrated the incidence of undetected anodal stimulation and subsequent patient outcomes. Some patients were excluded due to incomplete follow-up data. Response rates of the overall CRT group are lower than some other reported trials. This may be secondary to the greater percentage of patients with ischemic cardiomyopathy in this study, and may be related to the cut-off values used for defining CRT response. Due to size limitation of the study it is difficult to interpret the significance of baseline characteristic differences between groups.  We cannot rule out confounding variables that may play a role in poor response to CRT.  Suboptimal LV lead position is one potential confounding variable contributing to poor response.Anodal stimulation is a potential underrecognized and ameliorable cause of poor response to CRT. Increased awareness of this phenomenon and correction at the time of implant and follow-up may lead to a greater number of patients benefiting from CRT.