Sandeep S. Hothi

Acute atrial arrhythmogenicity and altered Ca2+ homeostasis in murine RyR2-P2328S hearts

Aims The experiments explored for atrial arrhythmogenesis and its possible physiological background in recently developed hetero-(RyR2+/S) and homozygotic (RyR2S/S) RyR2-P2328S murine models for catecholaminergic polymorphic ventricular tachycardia (VT) for the first time. They complement previous clinical and experimental reports describing increased ventricular arrhythmic tendencies associated with physical activity, stress, or catecholamine infusion, potentially leading to VT and ventricular fibrillation. Methods and results Atrial arrhythmogenic properties were compared at the whole animal, Langendorff-perfused heart, and single, isolated atrial myocyte levels using electrophysiological and confocal fluorescence microscopy methods. This demonstrated that: (i) electrocardiographic parameters in intact anaesthetized wild-type (WT), RyR2+/S and RyR2S/S mice were statistically indistinguishable both before and after addition of isoproterenol apart from increases in heart rates. (ii) Bipolar electrogram and monophasic action potential recordings showed significantly higher incidences of arrhythmogenesis in isolated perfused RyR2S/S, but not RyR2+/S, relative to WT hearts during either regular pacing or programmed electrical stimulation. The addition of isoproterenol increased such incidences in all three groups. (iii) However, there were no accompanying differences in cardiac anatomy or action potential durations at 90% repolarization and refractory periods. (iv) In contrast, episodes of diastolic Ca2+ release were observed under confocal microscopy in isolated fluo-3-loaded RyR2S/S, but not RyR2+/S or WT, atrial myocytes. The introduction of isoproterenol resulted in significant diastolic Ca2+ release in all three groups. Conclusions These findings establish acute atrial arrhythmogenic properties in RyR2-P2328S hearts and correlate these with altered Ca2+ homeostasis in an absence of repolarization abnormalities for the first time.

p.Y1449C SCN5A Mutation Associated with Overlap Disorder Comprising Conduction Disease, Brugada Syndrome, and Atrial Flutter

Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been associated with cardiac arrhythmia syndromes and conduction disease. Specific SCN5A mutations had initially been considered to cause specific phenotypes. More recently, some SCN5A mutations have been associated with overlap syndromes, characterized by phenotypic heterogeneity within and between mutation carriers. Here we report and associate the presence of the p.Y1449C SCN5A mutation in a single family with a spectrum of cardiac phenotypes including conduction disease, Brugada syndrome and atrial arrhythmias, for the first time to our knowledge.

Is low V ˙ O2max/kg in obese heart failure patients indicative of cardiac dysfunction?

PURPOSE Low peak O2 consumption (VO2max/kg) has been widely used as an indirect indicator of poor cardiac fitness, and often guides management of patients with severe heart failure (HF). We hypothesized that it should be as good an indicator of cardiac dysfunction in obese and non-obese HF patients. METHODS We compared the cardiopulmonary exercise performance and non-invasive hemodynamics of 152 obese (BMI>34 kg.m(-2)) and 173 non-obese (BMI≤32) male HF patients in NYHA classes II and III, with reference to 101 healthy male controls. Their physical and cardiac functional reserves were measured during treadmill exercise testing with standard respiratory gas analyses and CO2 rebreathing to measure cardiac output non-invasively during peak exercise. Data are given as mean ± SD. RESULTS Obese HF patients with BMI 40.9 ± 7.5 kg·m(-2) (age 56.1 ± 14.0 years, NYHA 2.5 ± 0.5) exercised to acceptable cardiopulmonary limits (peak RER=1.07 ± 0.12), and achieved a mean VO2max/kg of 18.6 ± 5.2 ml·kg(-1)·min(-1), significantly lower than in non-obese HF counterparts (19.9 ± 5.6 ml·kg(-1)·min(-1), P=0.02, age 55.8 ± 10.6 years, BMI 26.6 ± 3.1, NYHA 2.4 ± 0.5, peak RER=1.07 ± 0.09), with both lower than controls (38.5 ± 9.7 ml·kg(-1)·min(-1), P<10(-6)). In contrast, the uncorrected VO2max was higher in obese (2.31 ± 0.69 ml·min(-1)) than non-obese HF patients (1.61 ± 0.49 ml·min(-1), P<10(-6)). When cardiac dysfunction was evaluated directly, peak cardiac power was significantly greater in obese than non-obese HF patients (4.11 ± 1.21 W vs 2.73 ± 0.82 W, P<10(-6)), with both lower than controls (5.42 ± 1.04 W, P<10(-6)). CONCLUSION These results demonstrate that VO2max/kg is not a generally reliable indicator of cardiac fitness in all patients. Instead, we found that despite having lower VO2max/kg, obese HF patients had stronger hearts capable of generating greater cardiac power than non-obese HF patients of equivalent clinical HF status.

Left Ventricular Assist Device as a Bridge to Recovery for Patients With Advanced Heart Failure

Background Left ventricular assist devices (LVADs) have been used as an effective therapeutic option in patients with advanced heart failure, either as a bridge to transplantation, as destination therapy, or in some patients, as a bridge to recovery. Objectives This study evaluated whether patients undergoing an LVAD bridge-to-recovery protocol can achieve cardiac and physical functional capacities equivalent to those of healthy controls. Methods Fifty-eight male patients—18 implanted with a continuous-flow LVAD, 16 patients with LVAD explanted (recovered patients), and 24 heart transplant candidates (HTx)—and 97 healthy controls performed a maximal graded cardiopulmonary exercise test with continuous measurements of respiratory gas exchange and noninvasive (rebreathing) hemodynamic data. Cardiac function was represented by peak exercise cardiac power output (mean arterial blood pressure × cardiac output) and functional capacity by peak exercise O2 consumption. Results All patients demonstrated a significant exertional effort as demonstrated with the mean peak exercise respiratory exchange ratio >1.10. Peak exercise cardiac power output was significantly higher in healthy controls and explanted LVAD patients compared with other patients (healthy 5.35 ± 0.95 W; explanted 3.45 ± 0.72 W; LVAD implanted 2.37 ± 0.68 W; and HTx 1.31 ± 0.31 W; p < 0.05), as was peak O2 consumption (healthy 36.4 ± 10.3 ml/kg/min; explanted 29.8 ± 5.9 ml/kg/min; implanted 20.5 ± 4.3 ml/kg/min; and HTx 12.0 ± 2.2 ml/kg/min; p < 0.05). In the LVAD explanted group, 38% of the patients achieved peak cardiac power output and 69% achieved peak O2 consumption within the ranges of healthy controls. Conclusions The authors have shown that a substantial number of patients who recovered sufficiently to allow explantation of their LVAD can even achieve cardiac and physical functional capacities nearly equivalent to those of healthy controls.

Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome.

The gain-of-function Scn5a+/DeltaKPQ mutation in the cardiac Na(+) channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The K(ATP) channel-opener nicorandil (20muM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Delta hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD(90)) that (2) restored transmural repolarization gradients, DeltaAPD(90). Scn5a+/Delta hearts showed longer epicardial but not endocardial APD(90)s, giving shorter DeltaAPD(90)s than WT hearts. Nicorandil reduced epicardial APD(90) in both Scn5a+/Delta and WT hearts thereby increasing DeltaAPD(90). (3) Reduced epicardial critical intervals for re-excitation; Scn5a+/Delta hearts showed greater differences between APD(90) and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD(90) alternans. Scn5a+/Delta hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Delta hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Delta hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Delta and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Delta and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil.

Point-of-care cardiac ultrasound in acute medicine – the quick scan

The optimum management of acute medical patients requires prompt and accurate diagnosis, monitoring and treatment. The clinical history and physical examination remain central to diagnosis, but often need supplementation by laboratory testing or imaging. Echocardiographic assessment of cardiac structure and function provides valuable information that can aid diagnosis and assess clinical progress. It has many advantages as an imaging modality, and recent technological advances have resulted in hand-held, battery-powered ultrasound devices that provide high-quality images. Three broad applications of cardiac ultrasound now exist: conventional echocardiography, focussed echocardiography and the quick-scan. A quick-scan using a hand-held ultrasound device is readily integrated into the bedside clinical assessment, providing information that can be used immediately in diagnostic reasoning; it can also guide pericardiocentesis. Hand-held ultrasound devices can also be used in acute situations, as well as geographically remote areas or special situations (eg disaster zones) where other imaging is not available. However, the diagnostic yield of echocardiography is user dependent, and training is required for its benefits to be realised, adding to the hardware costs. More data are needed on the incremental value of hand-held ultrasonography and a quick-scan over conventional methods of assessment, their impact on clinical outcomes, and cost effectiveness.

Is uremic cardiomyopathy a direct consequence of chronic kidney disease

Heart failure is a major cause of morbidity and mortality in chronic kidney disease (CKD). Rather than merely secondary to traditional vascular factors, CKD is also an independent risk factor for heart failure, termed uremic cardiomyopathy (UCM). Echocardiography commonly reveals structural left ventricular hypertrophy in CKD, without clarifying whether it is adaptive or maladaptive. Corresponding functional assessments have been mostly conducted at rest. To unravel the extents and mechanisms UCM, a next step involves the adoption of direct measurements of CKD-induced cardiac pumping incapacity at peak exercise. This could potentially lead to future novel interventions to ameliorate or reverse UCM.

Impacts of valve intervention on the Functional REServe of the Heart: The FRESH-valve pilot study

PURPOSE Severe valve lesions require corrective interventions to avoid progression to heart failure (HF) and premature demise. We tested the hypothesis that despite operative risks, corrective valvular interventions will lead to significant improvements in overall cardiac pump function, especially before the onset of cardiac decompensation. METHODS We compared the cardiopulmonary exercise performance and non-invasive haemodynamics of 46 consecutive patients with severe valvular disease before and after valvular intervention with reference to 101 healthy male and 139 female controls without cardiovascular disease. Cardiac and physical functional reserves were measured with standard respiratory gas analyses and CO2 rebreathing to measure cardiac output non-invasively during peak treadmill exercise. Data are given as mean ± SD and statistical significance accepted at P<0.05. RESULTS The entire patient cohort showed no significant improvement in peak O2 consumption (V˙O2max, P=0.74) or in peak cardiac power (CPOmax, P=0.34) after valvular intervention, but we found instead a dichotomous outcome depending on preoperative cardiac function: (i) the pre-operative cardiac decompensatory subgroup (LoW, n=26) showed increased CPOmax (2.63 ± 0.67 to 3.42 ± 0.98 W, P<0.0001) and V˙O2max (1.38 ± 0.55 to 1.56 ± 0.59 L·min(-1), P<0.01); and (ii) the pre-operative non-decompensatory subgroup (HiW) showed reduced CPOmax (4.58 ± 0.96 to 3.84 ± 0.92 W, P<0.001) and V˙O2max (2.29 ± 0.72 to 1.97 ± 0.75 L·min(-1), P<0.01). Changes in NYHA class were found to be discrepant with these objective measurements. CONCLUSION This investigation found an unexpected finding that valvular interventions performed in routine clinical practice do not consistently improve cardiac function, especially in those without pre-operative cardiac decompensation. Assessing cardiac functional gains would open up new avenues for future trials of valvular interventions.

The role of IKs in atrial arrhythmogenesis

Atrial fibrillation (AF) is the most common arrhythmia reported in clinical practice, affecting 10% of individuals over 80 years of age. Whilst short periods of AF may result in palpitations, light-headedness and shortness of breath, long durations of AF can lead to heart failure. Furthermore, due to stasis of blood, thromboembolic complications including strokes are serious consequences of this arrhythmia. Recently studies have attempted to identify a genetic basis for AF and thus far up to six genetic loci have been implicated. In particular, the gene encoding KCNQ1, which co-assembles with KCNE1 to form functional repolarizing IKs, has been mapped to the 11p15.5 locus and a gain of function point mutation in KCNQ1 has been associated with persistent AF in a large Chinese family (Chen et al. 2003). Current strategies in the medical management of AF include rate control versus pharmacological cardioversion and subsequent maintenance of sinus rhythm, in addition to the prevention of thromboembolic events through the use of anti-coagulants. However, such treatments have poor efficacy with potentially serious side-effects including ventricular proarrhythmia and an increased risk of bleeding. The challenge to develop successful treatments for AF is compounded by an incomplete understanding of the underlying arrhythmogenic mechanisms. Since the late 1800s there has been a range of competing mechanisms of AF, including hyperectopia, single-circuit re-entry and multiple circuit re-entry (Nattel, 2002). A study by Moe et al. in (1964) proposed that AF consisted of multiple wavelets of functional re-entry in the atria which collided with one another to spawn daughter wavelets thereby maintaining fibrillatory conduction. The maintenance of re-entrant excitation has been deemed to be dependent upon a wavelength given by the product of the conduction velocity of the excitatory wavefront and the refractory period. This concept has been studied by Allessie and colleagues who, using experimental manoeuvres that altered these two critical parameters, had demonstrated that AF induction is dependent on the wavelength. They further formalized concepts of functional re-entrant pathways in AF with their ‘leading circle’ hypothesis (Allessie et al. 1977). In such a scheme, AF inducibility is dependent on the size of available tissue relative to the wavelength, and the cycle length of the arrhythmia is then governed by the smallest re-entrant circuit. A recent addition to the many mechanisms proposed to underlie AF is that of spiral-wave activity. The size of the mouse heart was once deemed too small for the generation of cardiac arrhythmias; however, recently numerous studies have shown that the mouse heart can support both atrial and ventricular arrhythmias thereby lending itself towards the study of such arrhythmias. Approaches using genetically modified mice could thus prove to be a powerful tool for the study of arrhythmogenic mechanisms. A recent article in The Journal of Physiology by Sampson et al. (2008) used a genetically modified mouse model over-expressing KCNQ1 alongside KCNE1 (IKs+/+ mouse) to study the relationship between adrenergically mediated increases in IKs and AF.

36 Direct Measurement of Cardiac Compensation in Valvular Heart Disease

Purpose The natural history of valvular heart disease (VHD) suggests that the heart initially adapts to compensate for valve lesions and thereby maintain physiological function. When these compensatory mechanisms become exhausted, cardiac decompensation commences. We tested the hypothesis that all VHD patients with normal exercise capacity are in the compensatory phase with no symptoms and normal cardiac reserve. Methods Unselected consecutive male patients with VHD performed cardiopulmonary exercise (CPX) testing with non-invasive central haemodynamic measurements during symptom-limited treadmill exercise. Exercise capacity was represented by peak oxygen consumption (VO2max) and cardiac pumping capability by peak exercise cardiac power output (CPOmax). Data are given as mean±SD. Results Of the entire VHD patient cohort (n = 215), 81.4% (n = 175) had VO2max which were within or above the reference range of healthy male sedentary controls (n = 101). This is shown in Figure 1A where individual patient VO2max is expressed as a percentage of the average VO2max of age- and sex-matched controls. These 175 patients with normal VO2max had a mean age of 63.1 ± 14.0 years, and consisted of 98 (56%) who were asymptomatic (NYHA class I) and 77 (44%) who were discordantly symptomatic in NYHA II+ (.001). As shown in Figure 1B, 117 patients (66.9%) had CPOmax within the normal range, of whom 80 (45.7%) were asymptomatic, but 37 (21.1%) were in NYHA II+ despite having normal VO2max and CPOmax (.001). Conversely, 58 (33.1%) had CPOmax below the normal range, and yet 18 (10.3%) of these were discordantly still in NYHA I (P < 0.001). These patients were classified asymptomatic by their responsible clinicians but our results revealed they had early, objective evidence of cardiac decompensation. Abstract 36 Figure 1 (a) Peak O2 consumption (VO2max) and (b) peak cardiac power output (CPOmax) expressed as a percentage of the average VO2max of age- and sex-matched controls Conclusions This investigation demonstrates that it is now possible to directly and objectively measure whether patients are in the compensated or decompensated phases of VHD. There were discrepancies between subjective symptomatic statuses and objectively measured cardiac and physical functional statuses. The possibility to determine whether patients are in the compensatory phase or not, might help in the management of difficult VHD cases. Abstract 36 Figure 2 Valve disease patients with normal exercise capacity (VO 2max ) and their compositions with respect to NHYA classification and low or normal peak cardiac power output (CPOmax)