Subsequent Development Of Heart Failure Research Articles

Chronic Neuregulin-1β Treatment Mitigates the Progression of Postmyocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus by Suppressing Myocardial Apoptosis, Fibrosis, and Key Oxidant-Producing Enzymes

BackgroundType 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher cardiovascular morbidity and mortality compared to their nondiabetic counterparts owing to the more frequent development of subsequent heart failure (HF). Neuregulin (NRG)-1β is released from cardiac microvascular endothelial cells and acts as a paracrine factor via the ErbB family of tyrosine kinase receptors expressed in cardiac myocytes to regulate cardiac development and stress responses. Because myocardial NRG-1/ErbB signaling has been documented to be impaired during HF associated with type 1 DM, we examined whether enhancement of NRG-1β signaling via exogenous administration of recombinant NRG-1β could exert beneficial effects against post-MI HF in the type 1 diabetic heart. Methods and ResultsType 1 DM was induced in male Sprague Dawley rats by a single injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, rats underwent left coronary artery ligation to induce MI. STZ-diabetic rats were treated with saline or NRG-1β (100 µg/kg) twice per week for 7 weeks, starting 2 weeks before experimental MI. Residual left ventricular function was significantly greater in the NRG-1β–treated STZ-diabetic MI group compared with the vehicle-treated STZ-diabetic MI group 5 weeks after MI as assessed by high-resolution echocardiography. NRG-1β treatment of STZ-diabetic MI rats was associated with reduced myocardial fibrosis and apoptosis as well as decreased gene expression of key oxidant–producing enzymes. ConclusionsThese results suggest that recombinant NRG-1β may be a promising therapeutic for HF post-MI in the setting of type 1 DM.

Angiotensin Receptor Blockers Do Not Reduce Risk of Myocardial Infarction, Cardiovascular Death, or Total Mortality: Further Evidence for the ARB-MI Paradox.

Opposing Viewpoint, see p 2085 Individual trials of angiotensin II receptor blockers (ARBs) and systematic meta-analyses have repeatedly demonstrated the ARB class to significantly reduce systemic blood pressure, stroke, and the subsequent development of heart failure and diabetes mellitus.1 However, no individual trial or meta-analysis has observed an impact of ARB treatment on the incidence of myocardial infarction (MI), cardiovascular mortality, or all-cause mortality (Table). All-cause mortality is the most comprehensive summary indicator of cardiovascular benefit of treatment2 and, consequently, it is surprising that ARBs have no impact given the other clinical benefits we have just acknowledged. View this table: Table. Risk of Myocardial Infarction, Cardiovascular Mortality, and All-Cause Mortality in Parallel Meta-Analyses of Placebo-Controlled Trials of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers A systematic review/meta-analysis conducted by Bangalore et al3 demonstrated that in 20 trials of ARB versus placebo (n=66 282) and 21 trials of ARB versus active comparator (n=39 738), ARB in no individual trial improved all-cause mortality. Furthermore, when the trials were analyzed in combination, the impact of ARB on mortality was precisely zero compared with placebo (odds ratio, 1.01; 95% confidence limit, 0.96–1.06) and virtually zero compared with an active comparator (odds ratio, 0.99; 95% confidence limit, 0.95–1.03). Placebo-controlled trials are the most rigorous method of assessing treatment efficacy (as well as harm), and, consequently, it is concerning that other meta-analyses of ARBs versus …

Mitochondrial Complex Dysfunction May Predict Subsequent Development of Heart Failure in Pressure Overload

Mitochondrial Complex Dysfunction May Predict Subsequent Development of Heart Failure in Pressure Overload

Three-dimensional myocardial scarring along myofibers after coronary ischemia-reperfusion revealed by computerized images of histological assays.

Adverse left ventricular (LV) remodeling after acute myocardial infarction is characterized by LV dilatation and development of a fibrotic scar, and is a critical factor for the prognosis of subsequent development of heart failure. Although myofiber organization is recognized as being important for preserving physiological cardiac function and structure, the anatomical features of injured myofibers during LV remodeling have not been fully defined. In a mouse model of ischemia–reperfusion (I/R) injury induced by left anterior descending coronary artery ligation, our previous histological assays demonstrated that broad fibrotic scarring extended from the initial infarct zone to the remote zone, and was clearly demarcated along midcircumferential myofibers. Additionally, no fibrosis was observed in longitudinal myofibers in the subendocardium and subepicardium. However, a histological analysis of tissue sections does not adequately indicate myofiber injury distribution throughout the entire heart. To address this, we investigated patterns of scar formation along myofibers using three‐dimensional (3D) images obtained from multiple tissue sections from mouse hearts subjected to I/R injury. The fibrotic scar area observed in the 3D images was consistent with the distribution of the midcircumferential myofibers. At the apex, the scar formation tracked along the myofibers in an incomplete C‐shaped ring that converged to a triangular shape toward the end. Our findings suggest that myocyte injury after transient coronary ligation extends along myofibers, rather than following the path of coronary arteries penetrating the myocardium. The injury pattern observed along myofibers after I/R injury could be used to predict prognoses for patients with myocardial infarction.

Transient receptor potential vanilloid 2 is a mediator of left ventricular hypertrophy (862.5)

Background: Impaired calcium handling has been implicated in the development of left ventricular hypertrophy (LVH) and subsequent development of heart failure (HF). We have recently shown that the calcium channel Transient Receptor Potential Vanilloid 2 (TRPV2) is present in cardiomyocytes and regulates contractility on a beat to beat basis. This study was performed to elucidate if TRPV2 also modulates the development of LVH in a pressure overload mouse model via transverse aortic constriction (TAC).Methods: WT and TRPV2‐/‐ mice were subjected to pressure overload via TAC and followed echocardiographically for 8 weeks. A subgroup of WT mice were treated with a nonspecific TRPV2 antagonist (tranilast) for the same amount of time. At the conclusion, the hearts were collected for molecular and histological analysis of hypertrophy.Results: There was significantly less hypertrophy in TRPV2‐/‐ and in the WT mice treated with tranilast (n=5 and 2) in comparison to untreated WT mice (n=7) as noted via heart weight: body weight ratio and LV mass via echocardiography (P<0.05; TRPV2 vs. untreated WT). Furthermore, there was a trend towards improved contractility and less LV cavity dilation in the TRPV2‐/‐ and the WT treated mice in comparison to untreated mice.Conclusions: We have shown that TRPV2 modulates the development of LVH and is a potential target for the prevention and treatment of LVH and development of HF.

SOLUBLE ST2 AND GALECTIN-3 ARE ASSOCIATED WITH SUBCLINICAL DIASTOLIC DYSFUNCTION IN OLDER ADULTS

Diastolic dysfunction (DD) is common in asymptomatic older adults and predicts the development of subsequent heart failure (HF). We examined the association of biomarkers of cardiac stress (soluble ST2 [sST2]) and fibrosis (Galecin-3 [Gal-3]) with DD in older adults. Gal-3 and sST2 were measured in

Quantitative profiling of the rat heart myoblast secretome reveals differential responses to hypoxia and re-oxygenation stress

Secretion of bioactive mediators regulates cell interactions with the microenvironment in tissue homeostasis and wound healing processes. We assessed the cardiomyocyte secretory response to hypoxia with the aim of identifying key mediators of tissue pathology and repair after ischemic heart attack. We profiled the secretome of rat H9C2 cardiomyoblast cells subjected to 16h hypoxia followed by 24h re-oxygenation using iTRAQ and label-free quantitative proteomics. A total of 860 and 2007 proteins were identified in the iTRAQ and label-free experiments respectively. Among these proteins, 1363 were identified as being secreted proteins, including mediators of critical cellular functions that were modulated by hypoxia/re-oxygenation stress (SerpinH1, Ppia, Attractin, EMC1, Postn, Thbs1, Timp1, Stip1, Robo2, Fat1). Further analysis indicated that hypoxia is associated with angiogenesis, inflammation, and remodeling of the extracellular matrix (ECM), whereas subsequent re-oxygenation was instead associated with modified secretion of proteins involved in suppression of inflammation, ECM modification, and decreased output of anti-apoptosis proteins. These data indicate that hypoxia and subsequent re-oxygenation modify the cardiomyocyte secretome in order to mitigate cellular injury and promote healing. The identified changes in cardiomyocyte secretome advance our current understanding of cardiac biology in ischemia/reperfusion injury and may lead to the identification of novel prognostic biomarker. Cardiovascular diseases (CVDs) are the leading cause of death globally. Myocardial infarction (MI) resulting from ischemic heart disease represents a substantial component of CVD-associated mortality, and is associated with obstruction of blood flow to the myocardium. Restoration of blood flow through the occluded coronary artery is the current most effective therapy to limit infarct size and preserve cardiac function after acute myocardial infarction. However, this treatment does not prevent subsequent development of heart failure in some patients. Reperfusion following ischemia causes additional cell death and increase in infarct size, a phenomenon called myocardial ischemia/reperfusion (I/R) injury. In order to advance our current understanding of cardiac biology in ischemia/reperfusion injury, we assessed the cardiomyocyte secretory response to hypoxia with the aim of identifying key mediators of tissue pathology and repair after ischemic heart attack. We profiled the secretome of rat H9C2 cardiomyoblast cells subjected to 16h hypoxia followed by 24h re-oxygenation using LC-MS/MS-based iTRAQ and label-free quantitative proteomics approaches. We identified many secreted proteins as mediators of critical cellular functions that were modulated by hypoxia and re-oxygenation stress. Further analysis of these modulated secretory proteins indicated that hypoxia is associated with angiogenesis, inflammation, and remodeling of the extracellular matrix (ECM), whereas subsequent re-oxygenation/reperfusion was instead associated with modified secretion of proteins involved in suppression of inflammation, ECM modification, and decreased output of anti-apoptosis proteins. These data indicate that hypoxia and subsequent re-oxygenation modify the cardiomyocyte secretome in order to mitigate cellular injury and promote healing. The identified changes in cardiomyocyte secretome may lead to the identification of novel prognostic biomarkers secreted from injured heart tissues into the circulation of patients with cardiovascular disease.

Serial echocardiographic left ventricular ejection fraction measurements: A tool for detecting thalassemia major patients at risk of cardiac death

Cardiac damage remains a major cause of mortality among patients with thalassemia major. The detection of a lower cardiac magnetic resonance T2* (CMR-T2*) signal has been suggested as a powerful predictor of the subsequent development of heart failure. However, the lack of worldwide availability of CMR-T2* facilities prevents its widespread use for follow-up evaluations of cardiac function in thalassemia major patients, warranting the need to assess the utility of other possible procedures. In this setting, the determination of left ventricular ejection fraction (LVEF) offers an accurate and reproducible method for heart function evaluation. These findings suggest a reduction in LVEF≥7%, over time, determined by 2-D echocardiography, may be considered a strong predictive tool for the detection of thalassemia major patients with increased risk of cardiac death. The reduction of LVEF≥7% had higher (84.76%) predictive value. Finally, Kaplan-Meier survival curves of thalassemia major patients with LVEF≥7% showed a statistically significant decreased probability of survival for heart disease (p=0.0022). However, because of limitations related to the study design, such findings should be confirmed in a large long-term prospective clinical trial.

1593P - Influence of Baseline Oxidative Stress Level on Changes in Left Ventricle Echocardiographic Parameters in Patients with Breast Cancer Receiving Anthracycline Chemotherapy

ABSTRACT Introduction Breast cancer (BC), like other malignancies, is associated with chronic increase of oxidative stress (OS). Anthracyclines (ANTS), potent inductors of OS, represent first-line therapy of advanced BC. OS induction by ANTS is believed to be the key factor in ANTS- related left ventricle dysfunction and the subsequent development of heart failure, which are major complications of ANTS therapy. The aim of the present study is to establish the role of malignancy-related OS present before ANTS therapy in the development of changes in echocardiografic (ECHO) parameters after chemotherapy in patients with breast cancer. Patients and methods The study population consists of 99 adult female suffering from breast cancer (mean age 52 ± 12 years) receiving ANTS chemotherapy. Catalase (CAT) activity as a surrogate marker of OS level and ECHO examination were established at the baseline in all patients. Follow-up ECHO examinations were performed at the end of therapy and again one year after the start of therapy. The correlations between baseline CAT activities and changes in ECHO parameters were evaluated. Results Statistically significant correlation between baseline CAT activity and unfavorable change in end-diastolic left ventricle diameter ( r = 0.24; p = 0.02) was observed soon after the ANTS therapy. Statistically significant correlation between baseline CAT activities and unfavorable change in end-diastolic left ventricle diameter (r = 0.30;p = 0.003) was found at one year following the start of ANTS therapy. Conclusion The results of our study suggest a possible correlation between baseline OS level and the future development of morphological cardiac changes after ANTS chemotherapy in patients with breast cancer. Whether pre-treatment levels of OS can predict ANTS induced left ventricle dysfunction and/or the development of heart failure will be shown by a further follow-up of the study population. The study was supported by the grant awarded by Ministry of Health, Czech republic, IGA MZ CR NS 9774-4 Disclosure All authors have declared no conflicts of interest.

Abstract 352: Myocardial Neuregulin-1/ErbB Signaling Is Impaired in the Setting of Post--Myocardial Infarction Heart Failure Complicated by Type 1 Diabetes Mellitus

Background: Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) are at heightened risk for the subsequent development of heart failure (HF). Despite the worse outcomes, investigations into the pathophysiological mechanisms that contribute to the increased frequency of HF after MI in the type 1 DM heart remain scarce. Neuregulin-1 (NRG-1), along with the ErbB family of receptor tyrosine kinases through which NRG-1 ligands signal, have been shown to be intimately involved in mediating cardiac recovery after MI. However, the impact of type 1 DM on this signaling system post-MI remains to be elucidated. Therefore, in the present study, we examined myocardial NRG-1/ErbB signaling during post-MI HF in the presence of type 1 DM. Methods: Type 1 DM was induced in male Sprague-Dawley rats via a single intraperitoneal injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, MI was produced in DM and non-DM rats by ligation of the left anterior descending (LAD) coronary artery. Residual left ventricular (LV) function was assessed by echocardiography at 4 weeks post-MI. Following echocardiographic assessment, NRG-1, ErbB2, and ErbB4 protein expression was assessed in the remote, surviving LV myocardium of DM and non-DM rats using Western blot techniques. Results: LV Fractional Shortening (FS) and LV Ejection Fraction (EF) were significantly lower in the DM + MI group compared to the MI group ([LVFS: DM + MI, 17.9 ± 0.7 (n=6) vs. MI, 25.2 ± 2.2 (n=6), p <0.05; LVEF: DM + MI, 35.5 ± 1.4 (n=6) vs. MI, 47.5 ± 3.5 (n=6), p <0.05]), indicating an increased functional severity of HF in the diabetic post-MI group. The weight of myocardial scar caused by the infarction was not significantly different between the MI groups ([DM + MI, 0.19 ± 0.02 g (n=4) vs. MI, 0.20 ± 0.03 g (n=4), p =0.70]). ErbB2, ErbB4, and NRG-1 protein expression levels were all significantly lower in the DM + MI group compared to the MI group. Conclusions: These findings demonstrate that type 1 DM impairs myocardial NRG-1/ErbB signaling in response to MI, which may contribute to the accelerated progression of subsequent HF. Augmentation of NRG-1 or its downstream signaling pathways may represent a novel therapeutic strategy for ameliorating post-MI HF in the setting of type 1 DM.

New index for assessing the chronotropic response in patients with end-stage liver disease who are undergoing dobutamine stress echocardiography

The inability to achieve 85% of the maximum predicted heart rate (MPHR) on dobutamine stress echocardiography (DSE) is defined as chronotropic incompetence and is a predictor of major cardiac events after orthotopic liver transplantation (OLT). The majority of patients with end-stage liver disease (ESLD) receive beta-blockers for the prevention of variceal bleeding. In these patients, it is impossible to determine whether chronotropic incompetence is secondary to cirrhosis-related autonomic dysfunction or is merely a beta-blocker effect. We evaluated the usefulness of the maximum achieved heart rate (MAHR) and the heart rate reserve (HRR) in the detection of chronotropic incompetence in ESLD patients on beta-blocker therapy before DSE. We also evaluated the usefulness of a new index, the modified heart rate reserve (MHRR), in diagnosing chronotropic incompetence and predicting major cardiovascular adverse events after OLT. The study population consisted of 284 ESLD patients. The mean values of MAHR (expressed as a percentage of 85% of MPHR) and HRR were significantly lower for patients on beta-blockers versus patients off beta-blockers [97.1% versus 101.6% (t = 5.01, P < 0.001) and 71.7% versus 77.3% (t = 4.03, P < 0.001), respectively], whereas the values of MHRR were similar in patients on beta-blockers and patients off beta-blockers [102.3% versus 102.1% (t = 0.04, P = 0.97)]. A regression analysis showed a significant association of MAHR (P < 0.001) and HRR (P < 0.001) with beta-blockers, whereas MHRR was not associated with beta-blocker treatment (P = 0.92). MAHR and HRR were found to have no value for diagnosing chronotropic incompetence in ESLD patients. MHRR was not affected by beta-blocker therapy. Patients who developed heart failure (HF) and myocardial infarction (MI) after OLT had significantly lower MHRR values according to pretransplant DSE. MHRR was significantly associated with the subsequent development of HF (P = 0.01) and MI (P = 0.01) after OLT. MHRR may be useful for the determination of the target heart rate for stress testing, the diagnosis of chronotropic incompetence, and the prediction of adverse cardiac events after OLT.

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca(2+) sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca(2+) sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to β-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca(2+) sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice.

Usefulness of Plasma Brain Natriuretic Peptide Measurement and Tissue Doppler Imaging in Identifying Isolated Left Ventricular Diastolic Dysfunction Without Heart Failure

Left ventricular (LV) diastolic dysfunction carries a substantial risk for the subsequent development of heart failure and reduced survival, even when it is asymptomatic. Plasma brain natriuretic peptide (BNP) level and tissue Doppler imaging indexes provide powerful incremental assessment of LV diastolic function. Accordingly, the aim of this study was to clarify whether these methodologies could identify LV diastolic dysfunction without heart failure in 280 patients with preserved LV ejection fractions (> or =50%) who underwent echocardiography and cardiac catheterization for the evaluation of coronary artery disease. Patients were classified into 2 groups, those with diastolic dysfunction (tau > or =48 ms; n = 91) and those with normal diastolic function (tau <48 ms; n = 189). Plasma BNP > or =22.4 pg/ml, an unexpectedly low value, had sensitivity of 74.7% and specificity of 60.8% for identifying isolated LV diastolic dysfunction; the combined use of BNP > or =22.4 pg/mL and mitral annular velocity during early diastole <7.4 cm/s had relatively low sensitivity of 44.0% but high specificity of 86.8%. In conclusion, using plasma BNP level and with the combination of BNP level and mitral annular velocity during early diastole, invasively proved isolated LV diastolic dysfunction without heart failure could be identified in patients with coronary artery disease.

Examining the Jugular Vein Is Never in Vain

In this issue of Circulation: Heart Failure , Drazner et al1 report the findings of their study on the relationship of right and left ventricular (LV) filling pressures in patients with heart failure and preserved LV ejection fraction (HFPEF) (also referred to as heart failure with preserved systolic function, diastolic heart failure). They noted good concordance (79%) in this patient population between right atrial pressure (RAP), indicative of right ventricular filling pressure, and pulmonary artery occlusive pressure (pulmonary capillary wedge pressure [PCWP]), indicative of LV filling pressure. These pressures, modulated by various loading and unloading maneuvers, ranged from low to normal to high. Nonconcordance was noted in only 21% of the measurements, and, in these, the PCWP did not match the elevation of RAP. Article see p 202 The weaknesses and limitations of this study are overshadowed by its strengths. PCWP is not a direct measurement of left atrial pressure, and RAP and PCWP are not direct measurements of right and LV filling pressures, respectively. But their relationships (RAP to right ventricular filling pressure; PCWP to left atrial pressure and LV filling pressure) are closely linked, and correlations are generally quite high,2–5 such that RAP and PCWP are routinely used in clinical medicine as respective indicators of right and LV filling pressures. Only 11 patients with HFPEF were studied by Drazner et al.1 However, the study was performed in an experienced laboratory by seasoned investigators of human heart failure, using the standard techniques to generate a spectrum of ventricular-loading conditions. The lead author has a noteworthy record of studying fundamental hemodynamic questions in human heart failure.6–9 The question itself, namely the relationship between right and left heart filling pressures, had not been adequately examined in HFPEF. The favorable concordance of right and left heart filling pressures …

The Development of Heart Failure in Patients With Diabetes Mellitus and Pre-Clinical Diastolic Dysfunction: A Population-Based Study

The purpose of this study was to evaluate the outcomes of pre-clinical diastolic dysfunction in diabetic patients. Studies have reported a high prevalence of pre-clinical diastolic dysfunction among patients with diabetes mellitus. We identified all diabetic patients with a tissue Doppler imaging assessment of diastolic function in Olmsted County, Minnesota, from 2001 to 2007. Diastolic dysfunction was defined as a passive transmitral left ventricular (LV) inflow velocity to tissue Doppler imaging velocity of the medial mitral annulus during passive filling (E/e') ratio >15. The main outcome was the development of heart failure (HF). Secondary outcomes were the development of atrial fibrillation and death. Overall, 1,760 diabetic patients with a tissue Doppler echocardiographic assessment of diastolic function were identified; 411 (23%) patients had diastolic dysfunction. Using multivariable Cox's proportional hazard modeling, we determined that for every 1-U increase in the passive transmitral LV inflow velocity to tissue Doppler imaging velocity of the medial mitral annulus during passive filling (E/e') ratio, the hazard ratio (HR) of HF increased by 3% (HR: 1.03; 95% confidence interval [CI]: 1.01 to 1.06; p = 0.006) and that diastolic dysfunction was associated with the subsequent development of HF after adjustment for age, sex, body mass index, hypertension, coronary disease, and echocardiographic parameters (HR: 1.61; 95% CI: 1.17 to 2.20; p = 0.003). The cumulative probability of the development of HF at 5 years for diabetic patients with diastolic dysfunction was 36.9% compared with 16.8% for patients without diastolic dysfunction (p < 0.001). Furthermore, diabetic patients with diastolic dysfunction had a significantly higher mortality rate compared with those without diastolic dysfunction. We demonstrated that an increase in the passive transmitral LV inflow velocity to tissue Doppler imaging velocity of the medial mitral annulus during passive filling (E/e') ratio in diabetic patients is associated with the subsequent development of HF and increased mortality independent of hypertension, coronary disease, or other echocardiographic parameters.

Right Ventricular Septal Versus Right Ventricular Apical Pacing and Subsequent Development of Heart Failure—A Single Centre Experience

roof line was performed only if venous lesion sets were sufficiently close. Patients were cardioverted to SR, if required. Further linear ablation was only performed if SR could not be maintained. Antiarrhythmic drugs were continued if possible. Postprocedure, recurrent persistent atrial tachyarrrhythmias (AT) were cardioverted within 48h of detection. Redo catheter ablation was considered if arrhythmias were detected beyond 3 months. Results: Consecutive patients with persistent (29/47) or permanent (18/47) AF were included. Sixteen patients received a roof line and 1 a mitral isthmus line. 21/47 patients had recurrent early AT with 19/21 requiring cardioversions. At a follow-up time of 339± 160 days 96% (45/47) remain in SR with 66% free of AT including 79% (23/29) persistent and 44% (8/18) permanent. Redo ablations were performed in 1 persistent and 8 permanent patients. Linear ablation did not predict freedom from AT. Early arrhythmias did not predict late recurrence with 10/21 subsequently remaining arrhythmia-free. Conclusions: Pulmonary vein antral electrical isolation with antiarrhythmic drugs and timely cardioversions in the early post-procedural period may promote reverse atrial electrical remodelling in persistent forms of AF. Permanent AF was significantly more likely to require redo ablation. doi:10.1016/j.hlc.2010.06.926

Right Ventricular Septal Versus Right Ventricular Apical Pacing and Subsequent Development of Heart Failure—A Single Centre Experience

Background: Previous studies have demonstrated favourable haemodynamics with septal pacing compared to apical pacing. Ventricular dyssynchrony due to RVA pacing may contribute to heart failure following pacemaker implantation. Our aim was to study septal versus apical pacing and determine if an association with development of heart failure exists.

The Development of Heart Failure in Diabetic Patients with Preclinical Diastolic Dysfunction: A Population Based Study

Background: Studies have reported a high prevalence of preclinical diastolic dysfunction among patients with diabetes mellitus (DM). However, there have been few studies to evaluate the outcomes of preclinical diastolic dysfunction in DM. The objective of our study is to determine if there is an association between diastolic dysfunction in DM patients and the subsequent development of heart failure (HF). Methods: We retrospectively identified all DM patients with a tissue Doppler assessment of diastolic function within the Olmsted County, MN population from September 2001 through June 2005. Patients with a diagnosis of HF prior to the echocardiogram were excluded as were patients with severe mitral or aortic valve regurgitation. Diastolic dysfunction was defined as a Doppler mitral E/e' ratio ≥ 15 as previously described. The main outcome was the development of HF. Results: Overall, 1924 diabetic patients with a tissue Doppler echocardiographic assessment of diastolic function were identified of which 505 patients (26%) had diastolic dysfunction as defined above. Average time from echocardiogram to HF or latest follow-up was 2.52±1.77 years. Using Cox's proportional hazard modeling we determined that for every 1 unit increase in the mitral E/e' ratio the hazard of HF increases by 4% (HR=1.04, 95% CI=1.02–1.05; p<0.001) and that diastolic dysfunction was associated with the subsequent development of HF (HR=1.76, 95% CI=1.40–2.23; p<0.001) after adjustment for age, sex, body mass index, hypertension, coronary disease, ejection fraction, left atrial volume and deceleration time. Conclusion: This study confirms that preclinical diastolic dysfunction is prevalent in DM patients. More importantly, we demonstrated that an increase in the E/e' ratio in DM patients is associated with the subsequent development of HF independent of hypertension, coronary disease or other echocardiographic parameters. Background: Studies have reported a high prevalence of preclinical diastolic dysfunction among patients with diabetes mellitus (DM). However, there have been few studies to evaluate the outcomes of preclinical diastolic dysfunction in DM. The objective of our study is to determine if there is an association between diastolic dysfunction in DM patients and the subsequent development of heart failure (HF). Methods: We retrospectively identified all DM patients with a tissue Doppler assessment of diastolic function within the Olmsted County, MN population from September 2001 through June 2005. Patients with a diagnosis of HF prior to the echocardiogram were excluded as were patients with severe mitral or aortic valve regurgitation. Diastolic dysfunction was defined as a Doppler mitral E/e' ratio ≥ 15 as previously described. The main outcome was the development of HF. Results: Overall, 1924 diabetic patients with a tissue Doppler echocardiographic assessment of diastolic function were identified of which 505 patients (26%) had diastolic dysfunction as defined above. Average time from echocardiogram to HF or latest follow-up was 2.52±1.77 years. Using Cox's proportional hazard modeling we determined that for every 1 unit increase in the mitral E/e' ratio the hazard of HF increases by 4% (HR=1.04, 95% CI=1.02–1.05; p<0.001) and that diastolic dysfunction was associated with the subsequent development of HF (HR=1.76, 95% CI=1.40–2.23; p<0.001) after adjustment for age, sex, body mass index, hypertension, coronary disease, ejection fraction, left atrial volume and deceleration time. Conclusion: This study confirms that preclinical diastolic dysfunction is prevalent in DM patients. More importantly, we demonstrated that an increase in the E/e' ratio in DM patients is associated with the subsequent development of HF independent of hypertension, coronary disease or other echocardiographic parameters.

Mortality in patients with atrial fibrillation: improving or not?

This editorial refers to ‘Mortality in patients with atrial fibrillation has significantly decreased during the last three decades: 35 years of follow-up in 1627 pacemaker patients’ † by S. Asbach et al. on page 391 Atrial fibrillation (AF) is the commonest sustained arrhythmia, with an increasing incidence. 1 With the increasing elderly population, the prevalence of AF is estimated to rise, conferring a significant mortality and morbidity. In the Framingham study, the presence of AF independently increased mortality in men by 1.5-fold and in women by 1.9-fold. 2 Given that the average lifetime risk of developing AF is 25% 3 and the high economic cost associated with AF, 4 it is clear that we are dealing with a condition with major public health implications. The mortality and morbidity associated with AF are probably not homogeneous when taking into consideration related co-morbidities, complications, and treatment strategies. The lowest risk group is probably that with the so-called ‘lone AF’, which is essentially a diagnosis of exclusion, where AF is associated with no obvious pre-disposing factor on thorough clinical history and examination, with a structurally normal heart on echocardiography, normal ECG (except for AF), normal blood tests, and normal chest X-ray. 5 As we recently highlighted, some series even report an increased mortality with lone AF patients. 6 This may reflect how hard we look for associated co-morbidities, and furthermore, as patients get older, new co-morbidities will intervene. 5 At the other extreme, the presence of AF in patients with acute coronary syndromes, 7 congestive cardiac failure, and in the post-operative setting conditions associated with greater risk of adverse events. For example, an analysis from the TRAndolapril Cardiac Evaluation (TRACE) 7 study reported AF to increase total mortality by 33%, with a risk ratio for sudden cardiac death (SCD) of 1.31 (95% CI: 1.07– 1.60; P , 0.009). Furthermore, the adjusted risk ratio of AF for non-SCD was 1.43 (95% CI: 1.21–1.70; P , 0.0001). Similarly, data from the Framingham Heart Study 8 reported that AF associated with the subsequent development of heart failure resulted in an increased mortality [men: hazard ratio (HR) 2.7, 95% CI: 1.9–3.7 and women: HR 3.1, 95% CI: 2.2–4.2]. Clearly, AF in association with heart disease is not a good combination. Perhaps what has attracted much interest in AF is the morbidity and mortality associated with stroke and thrombo-embolism. 9 Overall, AF increases the risk of stroke by up to 5-fold, but this risk is not homogeneous. 9,10 Stroke risk in AF is increased with the presence of associated stroke risk factors such as previous stroke, increasing age, hypertension, diabetes mellitus, and so on—with the risk being cumulative with increasing co-morbidities. 11,12 For example, this risk increases with age, with stroke occurring in 1.5% of the under 60 year olds and rising to 23.5% in the over 80s 11 and is further increased (for example) by concomitant hypertension. Given the improvements in the recognition and management of the co-morbid conditions associated with AF— especially hypertension, heart failure, and coronary artery disease—one would expect an improvement in the clinical outcome and prognosis of this arrhythmia. Is this really the case?

Assessment of Left Ventricular Diastolic Function and Recognition of Diastolic Heart Failure

Left ventricular (LV) diastolic dysfunction, as occurs in patients with hypertension, diabetes mellitus, and/or aging, carries a substantial risk of the subsequent development of heart failure and reduced survival, even when it is asymptomatic or “preclinical.”1–4 Diastolic dysfunction is defined as functional abnormalities that exist during LV relaxation and filling. When such abnormalities cause or contribute to the clinical syndrome of heart failure with a normal LV ejection fraction, it is appropriate to describe the condition as diastolic heart failure. This diagnosis carries a mortality rate that is similar to that seen in systolic failure, approaching 15% per year in patients older than 65 years.5,6 Over the past 20 years, the survival of patients with systolic heart failure has improved, whereas the prognosis of diastolic heart failure has not changed.5 Diagnostic echocardiographic and Doppler techniques have improved,7 and criteria for the diagnosis of diastolic heart failure have been developed,8,9 but the evolution of therapeutic strategies has not kept pace with this growing public health problem. Improved therapy will depend on basic research directed at mechanisms of disease, coupled with clinical investigations directed at diagnosis and therapy. Article p 637 The article published by Kasner et al10 in this issue of Circulation consists of an exhaustive evaluation of invasive hemodynamic and noninvasive conventional and tissue Doppler echocardiographic parameters to search for the optimal method(s) for the evaluation of LV diastolic function. They studied 43 patients with definite and reliable evidence of diastolic dysfunction obtained during cardiac catheterization. The patients exhibited exercise intolerance, all were in New York Heart Association functional class II or III, and the level of the N-terminal pro B-type natriuretic peptide was elevated. The authors do not mention the physical examination, but presumably, the patients had been treated and signs of congestion …