Kavit A. Desouza

Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials

Objective To compare the long term efficacy and adverse events of dual blockade of the renin-angiotensin system with monotherapy. Design Systematic review and meta-analysis. Data sources PubMed, Embase, and the Cochrane central register of controlled trials, January 1990 to August 2012. Study selection Randomised controlled trials comparing dual blockers of the renin-angiotensin system with monotherapy, reporting data on either long term efficacy (≥1 year) or safety events (≥4 weeks), and with a sample size of at least 50. Analysis was stratified by trials with patients with heart failure versus patients without heart failure. Results 33 randomised controlled trials with 68 405 patients (mean age 61 years, 71% men) and mean duration of 52 weeks were included. Dual blockade of the renin-angiotensin system was not associated with any significant benefit for all cause mortality (relative risk 0.97, 95% confidence interval 0.89 to 1.06) and cardiovascular mortality (0.96, 0.88 to 1.05) compared with monotherapy. Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to hospital for heart failure (0.82, 0.74 to 0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalaemia (P<0.001), a 66% increase in the risk of hypotension (P<0.001), a 41% increase in the risk of renal failure (P=0.01), and a 27% increase in the risk of withdrawal owing to adverse events (P<0.001). Efficacy and safety results were consistent in cohorts with and without heart failure when dual therapy was compared with monotherapy except for all cause mortality, which was higher in the cohort without heart failure (P=0.04 v P=0.15), and renal failure was significantly higher in the cohort with heart failure (P<0.001 v P=0.79). Conclusion Although dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia, hypotension, and renal failure compared with monotherapy. The risk to benefit ratio argues against the use of dual therapy.

Noninvasive Electroanatomic Mapping of Human Ventricular Arrhythmias with Electrocardiographic Imaging

Noninvasive imaging of cardiac electrical activity during ventricular arrhythmias enables superior diagnosis and treatment. A New View of the Beating Heart Just as a tree’s shadow is an oversimplification of branches and foliage, the electrocardiogram, a decades-old tool for measuring the electrical activity of the heart, captures only an approximate view of the heartbeat, distorted by the intervening tissues between the heart and the few electrodes on the skin. This poses a problem when trying to treat heart diseases such as dangerous ventricular arrhythmias, which destabilize the heartbeat and can lead to sudden cardiac death. Now, with a technique called electrocardiographic imaging (ECGI), Wang and colleagues have married multiple electrical recordings from the skin of patients who have ventricular tachycardia (VT) with detailed computerized axial tomography (CAT) scans of the anatomy of their torso. From these data, the authors can back calculate what is happening, electrically speaking, on the surface of the misbehaving hearts, yielding an individual portrait of that patient’s beating heart so that treatment can be more effectively deployed. Twenty-five patients with VT were scheduled to undergo electrical mapping of their hearts and then ablation of heart tissue to correct the electrical defect with an invasive catheter. The authors augmented this standard treatment by creating an image of their beating hearts with noninvasive ECGI, before the standard procedure. The ECGI and standard procedure identified the same origination point of the tachycardia in almost all of the patients, and ECGI was able to correctly categorize both focal and reentrant mechanisms of VT. The time resolution of ECGI enabled the authors to follow the response of the heart to different patterns of stimulation (or pacing), revealing presystolic activation near the site of origin. They could see variable beat-to-beat conduction patterns and showed that the abnormal conduction patterns often began in regions of scar tissue, relics of previous heart attacks. ECGI yields information comparable to the current procedure for mapping abnormal heart activity with a catheter-fed electrode, repeatedly placed on the heart surface. But it has significant advantages over the current approach: The spatial resolution of the ventricular arrhythmia on the heart surface is high, and it takes into account patient-to-patient variability in body size and shape. Further, it is noninvasive and can map single heartbeats, allowing unprecedented visualization of the anatomy of the electrical activation and beat-to-beat variability. These advantages should enable more effective diagnosis of VT and more appropriate drug or ablation therapy, which can now be directed to the specific characteristics of the patient’s heart instead of a simplified shadow. The rapid heartbeat of ventricular tachycardia (VT) can lead to sudden cardiac death and is a major health issue worldwide. Efforts to identify patients at risk, determine mechanisms of VT, and effectively prevent and treat VT through a mechanism-based approach would all be facilitated by continuous, noninvasive imaging of the arrhythmia over the entire heart. Here, we present noninvasive real-time images of human ventricular arrhythmias using electrocardiographic imaging (ECGI). Our results reveal diverse activation patterns, mechanisms, and sites of initiation of human VT. The spatial resolution of ECGI is superior to that of the routinely used 12-lead electrocardiogram, which provides only global information, and ECGI has distinct advantages over the currently used method of mapping with invasive catheter-applied electrodes. The spatial resolution of this method and its ability to image electrical activation sequences over the entire ventricular surfaces in a single heartbeat allowed us to determine VT initiation sites and continuation pathways, as well as VT relationships to ventricular substrates, including anatomical scars and abnormal electrophysiological substrate. Thus, ECGI can map the VT activation sequence and identify the location and depth of VT origin in individual patients, allowing personalized treatment of patients with ventricular arrhythmias.

The Electrophysiological Cardiac Ventricular Substrate in Patients After Myocardial Infarction: Noninvasive Characterization With Electrocardiographic Imaging

OBJECTIVES The aim of this study was to noninvasively image the electrophysiological (EP) substrate of human ventricles after myocardial infarction and define its characteristics. BACKGROUND Ventricular infarct border zone is characterized by abnormal cellular electrophysiology and altered structural architecture and is a key contributor to arrhythmogenesis. The ability to noninvasively image its electrical characteristics could contribute to understanding of mechanisms and to risk-stratification for ventricular arrhythmia. METHODS Electrocardiographic imaging, a noninvasive functional EP imaging modality, was performed during sinus rhythm (SR) in 24 subjects with infarct-related myocardial scar. The abnormal EP substrate on the epicardial aspect of the scar was identified, and its location, size, and morphology were compared with the anatomic scar imaged by other noninvasive modalities. RESULTS Electrocardiographic imaging constructs epicardial electrograms that have characteristics of reduced amplitude (low voltage) and fractionation. Electrocardiographic imaging colocalizes the epicardial electrical scar to the anatomic scar with a high degree of accuracy (sensitivity 89%, specificity 85%). In nearly all subjects, SR activation patterns were affected by the presence of myocardial scar. Late potentials could be identified and were almost always within ventricular scar. CONCLUSIONS Electrocardiographic imaging accurately identifies areas of anatomic scar and complements standard anatomic imaging by providing scar-related EP characteristics of low voltages, altered SR activation, electrogram fragmentation, and presence of late potentials.

Electrophysiologic Substrate in Congenital Long QT Syndrome Noninvasive Mapping With Electrocardiographic Imaging (ECGI)

Background— Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. Methods and Results— Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation–recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation–recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients; P <0.05). Conclusions— LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification. # CLINICAL PERSPECTIVE {#article-title-34}Background— Congenital Long QT syndrome (LQTS) is an arrhythmogenic disorder that causes syncope and sudden death. Although its genetic basis has become well-understood, the mechanisms whereby mutations translate to arrhythmia susceptibility in the in situ human heart have not been fully defined. We used noninvasive ECG imaging to map the cardiac electrophysiological substrate and examine whether LQTS patients display regional heterogeneities in repolarization, a substrate that promotes arrhythmogenesis. Methods and Results— Twenty-five subjects (9 LQT1, 9 LQT2, 5 LQT3, and 2 LQT5) with genotype and phenotype positive LQTS underwent ECG imaging. Seven normal subjects provided control. Epicardial maps of activation, recovery times, activation-recovery intervals, and repolarization dispersion were constructed. Activation was normal in all patients. However, recovery times and activation–recovery intervals were prolonged relative to control, indicating delayed repolarization and abnormally long action potential duration (312±30 ms versus 235±21 ms in control). Activation–recovery interval prolongation was spatially heterogeneous, with repolarization gradients much steeper than control (119±19 ms/cm versus 2.0±2.0 ms/cm). There was variability in steepness and distribution of repolarization gradients between and within LQTS types. Repolarization gradients were steeper in symptomatic patients (130±27 ms/cm in 12 symptomatic patients versus 98±19 ms/cm in 13 asymptomatic patients; P<0.05). Conclusions— LQTS patients display regions with steep repolarization dispersion caused by localized action potential duration prolongation. This defines a substrate for reentrant arrhythmias, not detectable by surface ECG. Steeper dispersion in symptomatic patients suggests a possible role for ECG imaging in risk stratification.

Platypnea-Orthodeoxia Syndrome: A Diagnostic Challenge

Platypnea-orthodeoxia (P-O) syndrome is an underdiagnosed condition characterized by dyspnea and deoxygenation accompanying a change from a recumbent to an upright position. It is caused by increased right-to-left shunting of blood on assuming an upright position. The diagnosis of this shunt is often challenging. A case where a diagnosis was missed despite performing a tilt transesophageal echocardiogram with bubble study and a technetium labeled macroaggregated albumin scan is presented. However, a large patent foramen ovale (PFO) was found on autopsy. A brief overview of the diagnostic workup and management of this condition along with methods to increase the sensitivity of diagnostic tests is discussed.

Electrophysiologic Scar Substrate in Relation to VT: Noninvasive High-Resolution Mapping and Risk Assessment with ECGI

Ischemic cardiomyopathy (ICM) can provide the substrate for ventricular tachycardia (VT).

Continuous ECGI mapping of spontaneous VT initiation, continuation, and termination with antitachycardia pacing

A 40-year-old woman with nonischemic cardiomyopathy and a left ventricular (LV) ejection fraction of 35% was referred for recurrent ventricular tachycardia (VT). She experienced 248 VT episodes treated by antitachycardia pacing (ATP) over 14 days. In 2005, she received an implantable cardioverter defibrillator for an episode of syncope and nonsustained VT. She later underwent an invasive electrophysiology study (EPS) with inducible VT and an ablation of the AV nodal reentrant tachycardia. Since then, she experienced symptomatic VT, terminated by ATP. Her VT was unresponsive to sotalol and mexiletine. Two EPS in early 2010 failed to induce VT despite intravenous isoproterenol and triple extrastimuli at two right ventricular (RV) sites; therefore, no ablations were performed.

The Electrophysiologic Cardiac Ventricular Substrate in Patients after Myocardial Infarction: Noninvasive Characterization with ECG Imaging (ECGI)

OBJECTIVES The aim of this study was to noninvasively image the electrophysiological (EP) substrate of human ventricles after myocardial infarction and define its characteristics. BACKGROUND Ventricular infarct border zone is characterized by abnormal cellular electrophysiology and altered structural architecture and is a key contributor to arrhythmogenesis. The ability to noninvasively image its electrical characteristics could contribute to understanding of mechanisms and to risk-stratification for ventricular arrhythmia. METHODS Electrocardiographic imaging, a noninvasive functional EP imaging modality, was performed during sinus rhythm (SR) in 24 subjects with infarct-related myocardial scar. The abnormal EP substrate on the epicardial aspect of the scar was identified, and its location, size, and morphology were compared with the anatomic scar imaged by other noninvasive modalities. RESULTS Electrocardiographic imaging constructs epicardial electrograms that have characteristics of reduced amplitude (low voltage) and fractionation. Electrocardiographic imaging colocalizes the epicardial electrical scar to the anatomic scar with a high degree of accuracy (sensitivity 89%, specificity 85%). In nearly all subjects, SR activation patterns were affected by the presence of myocardial scar. Late potentials could be identified and were almost always within ventricular scar. CONCLUSIONS Electrocardiographic imaging accurately identifies areas of anatomic scar and complements standard anatomic imaging by providing scar-related EP characteristics of low voltages, altered SR activation, electrogram fragmentation, and presence of late potentials.

Dual RAS blockade—unresolved controversy?

We read with interest the News & Views commentary by Piero Ruggenenti and Giuseppe Remuzzi (Ruggenenti, P. & Remuzzi, G. Meta-analyses can misdirect decisions on treatment. Nat. Rev. Nephrol. 9, 311–312; 2013),1 which was written in response to our meta-analysis that compared the efficacy and safety outcomes of dual renin–angiotensin system (RAS) blockade with that of monotherapy in 68,405 patients with hypertension, dia betes or proteinuria.2 RAS inhibition using angiotensin-converting enzyme (ACE) inhibitors or angiotensinreceptor blockers (ARBs) versus other antihyper tensive agents has unequivocally been shown to reduce renal outcomes in patients with proteinuria.3,4 Many researchers, including ourselves and Remuzzi’s team, have hypothesized that more intense RAS inhibi tion using more than one RAS blocker versus a single agent would offer more benefit in patients with proteinuric renal disease. However, our meta-analysis showed that dual RAS blockade compared with monotherapy failed to reduce mortality and was associated with an excessive risk of adverse events.2 Ruggenenti and Remuzzi suggest that the lack of benefit of dual versus single RAS blockade in our meta-analysis could be due to the inclusion of the ALTITUDE trial,5 which evaluated an aliskiren-based regimen. However, even after excluding ALTITUDE we found no difference in all-cause mortality (P = 0.35) and cardio vascular mortality (P = 0.15) between the dual RAS blockade and monotherapy groups. Despite a significant fall in blood pressure, aliskiren conferred no benefit in terms of risk of stroke in the ALTITUDE5 trial and no such benefit has been shown with ACE inhibitor plus ARB combinations.6 Thus we disagree with the authors that aliskiren-based combinations are associated with an increased stroke risk. Ruggenenti and Remuzzi also emphasized that a 23% reduction in heart failure hospitalizations and cardiovascular mortality was reported in patients with heart Dual RAS blockade—unresolved controversy?

Non-invasive electrophysiological imaging of acute rejection in a transplanted heart.

We present the first case of non-invasive cardiac electrophysiological mapping using electrocardiographic imaging (ECGI) of a 51-year-old man with acute cellular rejection 9 months after cardiac transplantation. He had moderate right ventricular (RV) systolic dysfunction and global left ventricular (LV) dysfunction (LVEF 40–45%) on …