Prediction of the effectiveness of long term β blocker treatment for dilated cardiomyopathy by signal averaged electrocardiography

Objective—To determine whether the effectiveness of long term β blocker treatment for idiopathic dilated cardiomyopathy can be predicted by signal averaged electrocardiography (ECG).
Patients—31 patients with dilated cardiomyopathy and without bundle branch block were included in a retrospective study and 16 in a prospective study.
Methods—A signal averaged ECG was recorded before β blocker treatment, and three variables were measured from the vector magnitude: QRS duration, root mean square voltage for the last 40 ms (RMS40), and duration of the terminal low amplitude signals (< 40 µV) (LAS40). In the retrospective study, these variables were compared among good responders (showing  0.10 increase in ejection fraction 12 months after start of β blocker treatment) and poor responders without such improvement. The validity of the signal averaged ECG criteria for prediction of the response to β blocker treatment was examined in the prospective study.
Results—In the retrospective study, good responders (n = 16) had a shorter QRS duration (mean (SD): 122.9 (11) v 138 (14.4) ms, p < 0.005) and LAS40 (33.1 (8.9) v 42.5 (7.8) ms, p < 0.005), and a higher RMS40 (31.6 (16.3) v 19.0 (10.3) µV, p < 0.02) than poor responders (n = 15). Signal averaged ECG criteria for good response were defined as two or more of the following: QRS duration < 130 ms, RMS40 > 20 µV, LAS40 < 40 ms (sensitivity 81%, specificity 73%). In the prospective study, six of seven patients who met these criteria showed a good response to the β blocker treatment, while eight of nine who did not showed a poor response (χ² = 6.1, p < 0.02). The signal averaged ECG criteria gave a sensitivity of 86% and a specificity of 89% for predicting the effectiveness of β blocker treatment.
Conclusions—A signal averaged ECG might be useful in predicting the effectiveness of β blocker treatment for dilated cardiomyopathy.

Keywords: signal averaged ECG;  β blockers;  dilated cardiomyopathy     

Long term survival effect of metoprolol in dilated cardiomyopathy

Objective—To evaluate the additive effect of metoprolol treatment on long term incidence of fatal and non-fatal cardiac events in idiopathic dilated cardiomyopathy.
Design—586 patients with idiopathic dilated cardiomyopathy were prospectively enrolled in a multicentre registry and followed up for a mean (SD) of 52 (32) months. Metoprolol, carefully titrated to the maximum tolerated dose, was added to conventional heart failure treatment in 175 patients.
Results—Survival and transplant-free survival at seven years were significantly higher in the 175 metoprolol treated patients than in the remaining 411 on standard treatment (81% v 60%, p < 0.001, and 69% v 49%, p < 0.001, respectively). By multivariate analysis, metoprolol independently predicted survival and transplant-free survival (relative risk reduction values for all cause mortality and combined mortality or transplantation 51% (95% confidence interval 21% to 69%), p = 0.002, and 34% (5% to 53%), p = 0.01, respectively). New York Heart Association class, left ventricular end diastolic diameter, and pulmonary wedge pressure were also predictive. Seven year survival (80% v 62%, p = 0.004) and transplant-free survival (68% v 51%, p = 0.005) were significantly higher in 127 metoprolol treated cases than in 127 controls selected from the entire control cohort and appropriately matched. Metoprolol was associated with a 30% reduction in all cause mortality (7% to 48%, p = 0.015) and a 26% reduction in mortality or transplantation (7% to 41%, p = 0.009).
Conclusions—The addition of metoprolol to standard heart failure treatment, including angiotensin converting enzyme inhibitors, was effective in the long term, reducing both all cause mortality and transplantation in patients with idiopathic dilated cardiomyopathy.

     

Potential impact of antiarrhythmic drugs versus implantable defibrillators on the management of ventricular arrhythmias: the Midlands trial of empirical amiodarone versus electrophysiologically guided intervention and cardioverter implant registry data

Background—Survival was prolonged in selected patients with sustained ventricular arrhythmias who received implantable cardioverter defibrillators (ICDs) in the antiarrhythmics versus implantable defibrillators (AVID) study. The Midlands trial of empirical amiodarone versus electrophysiologically guided intervention and cardioverter implant in ventricular arrhythmias (MAVERIC) registry is a population based trial.
Objective—To determine the number of patients who satisfy the AVID criteria because of the high cost of ICDs.
Design—Observational study, based on a continuing trial.
Setting—All coronary care units in the Midlands region in the United Kingdom (population 9.1 million).
Patients—Patients presenting to a coronary care unit with sustained ventricular arrhythmias not related to an acute myocardial infarction are entered onto the registry. Those who consent to the MAVERIC study are randomised to receive either empirical amiodarone or electrophysiologically guided treatment. Demographic data, details of clinical presentation, and echocardiographic findings are collected. These data have been used to calculate the number of patients who satisfy the AVID criteria and would benefit from ICD implantation. The financial implications have been calculated for the region and nationally.
Results—132 patients were entered onto the registry during the first five months of the MAVERIC study; 69 patients fulfilled the AVID criteria. Extrapolation of these data over a 12 month period suggests implantation of at least 166 new ICDs (compared with 23 implants in 1996). This would increase the UK ICD implant rate from five to at least 18 per million of the population, costing the National Health Service £24.1 million per annum.
Conclusion—Application of the AVID criteria in the UK will cause a great increase in the ICD implant rate, with serious financial implications.

Keywords: AVID study;  MAVERIC trial;  implantable cardioverter defibrillator;  economics;  arrhythmias     

Role of invasive EP testing in the evaluation and management of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an inheritable condition that may cause sudden death in the absence of significant symptoms or adverse morphological features. Therefore, there is a need for identification of those patients at sufficiently high risk to warrant prophylactic treatment.Risk stratification for primary prevention of sudden death has relied upon non-invasively derived markers of risk: syncope; a family history of premature sudden death; nonsustained ventricular tachycardia on Holter; abnormal blood pressure response to exercise; and severe left ventricular hypertrophy. The presence of two or more risk factors is associated with a 6-year sudden death survival rate of 72% (56–88%), justifying the consideration of prophylactic therapy. The 6-year sudden death survival rate in patients with one or no risk factors is 94% (91–98%). In these individuals the context and severity of the risk factor may guide the decision for prophylaxis; for example, a highly malignant family history carries greater justification than a large pedigree with only one sudden death.There is a need, however, for determining risk more accurately in those individuals with only one conventional risk factor. Programmed stimulation has been studied for its predictive value in primary prevention. 'Aggressive' protocols have been used and the most commonly induced arrhythmia is polymorphic ventricular tachycardia. These findings, however, are non-specific and of limited prognostic value. In addition the patients studied have been from selected high-risk populations without a low-risk cohort for comparison. Thus invasive EP studies appear to carry little advantage over non-invasive risk stratification. This is not surprising given that the mechanisms of cardiac arrest in HCM can be varied and may be modified by abnormal vascular responses and ischaemia. The relevance of invasively induced arrhythmias may therefore be limited.Other uses for electrophysiological study include the investigation and treatment of individuals with conduction disease and/or Wolff-Parkinson-White syndrome, atrial flutter and fibrillation and monomorphic ventricular tachycardia. Appropriate management may then involve radiofrequency ablation. A permanent pacemaker will be required if the atrio-ventricular node is ablated.     

Prognostic value of non-sustained ventricular tachycardia and the potential role of amiodarone treatment in hypertrophic cardiomyopathy: assessment in an unselected non-referral based patient population

Background—Amiodarone has been reported to reduce the likelihood of sudden death in patients with hypertrophic cardiomyopathy (HCM). However, data regarding the clinical course in HCM have traditionally come from selected referral populations biased toward assessment of high risk patients.
Aims—To evaluate antiarrhythmic treatment for sudden death in an HCM population not subject to tertiary referral bias, closely resembling the true disease state present in the community.
Methods—Cardiovascular mortality was assessed in relation to the occurrence of non-sustained ventricular tachycardia (NSVT) on 24 or 48 hour ambulatory Holter recording, a finding previously regarded as a marker for sudden death, particularly when the arrhythmia was frequent, repetitive or prolonged. 167 consecutive patients were analysed by multiple Holter ECG recordings (mean (SD) 157 (129) hours) and followed for a mean of 10 (5) years. Only patients with multiple repetitive NSVT were treated with amiodarone, and in relatively low doses (220 (44) mg/day).
Results—Nine HCM related deaths occurred: 8 were the consequence of congestive heart failure, but only 1 was sudden and unexpected. Three groups of patients were segregated based on their NSVT profile: group 1 (n = 39), multiple ( 2 runs) and repetitive bursts (on 2 Holters) of NSVT, or prolonged runs of ventricular tachycardia, included 4 deaths due to heart failure; group 2 (n = 38), isolated infrequent bursts of NSVT, included 1 sudden death; group 3 (n = 90), without NSVT, included 4 heart failure deaths. Kaplan-Meier survival analysis showed no significant differences in survival between the three groups throughout follow up.
Conclusions—In an unselected patient population with HCM, isolated, non-repetitive bursts of NSVT were not associated with adverse prognosis and so this arrhythmia does not appear to justify chronic antiarrhythmic treatment. Amiodarone, administered in relatively low doses, did not carry an independent and additive risk for cardiac mortality. Amiodarone may have contributed to the absence of sudden cardiac death in patients believed to be at higher risk because of multiple repetitive NSVT.

Keywords: hypertrophic cardiomyopathy; ventricular tachycardia; amiodarone     

Relation between the insulin lowering rate and changes in bone mineral density: Analysis among subtypes of type 1 diabetes mellitus

Aims/IntroductionThe bone mineral density in patients with type 1 diabetes mellitus is reduced due to impaired insulin secretion. However, it is unclear whether the rate of bone mineral density reduction is affected by the type 1 diabetes mellitus subtype. This study aimed to clarify the difference in bone mineral density across type 1 diabetes mellitus subtypes: slowly progressive (SP), acute‐onset (AO), and fulminant (F).MethodsThis was a retrospective, single‐center, cross‐sectional study conducted on 98 adult type 1 diabetes mellitus patients. The main outcome included the bone mineral density Z‐score (BMD‐Z) measured at the lumbar spine and femoral neck.ResultsThe lumbar spine BMD‐Z was lower in the acute‐onset than in the slowly progressive subtype (P = 0.03). No differences were observed when compared with the fulminant subtype. The femoral neck BMD‐Z tended to be higher in the slowly progressive than in the acute‐onset and fulminant subtypes. Multiple regression analyses showed that the lumbar spine BMD‐Z was associated with subtypes (AO vs SP) (P = 0.01), but not subtypes (F vs SP), adjusted for sex, duration, retinopathy, and C‐peptide immunoreactivity (CPR). When the patients were divided into disease duration tertiles, in the first and second tertiles, the CPR levels were lower in the acute‐onset or fulminant than in the slowly progressive subtype. In contrast, the lumbar spine and femoral neck BMD‐Z differed between the acute‐onset and slowly progressive only in the second tertiles (both P < 0.01), with a similar tendency between the fulminant and slowly progressive subtypes.ConclusionsAmong the type 1 diabetes mellitus subtypes, bone mineral density undergoes time‐dependent changes, which reveals that the bone mineral density decline follows the impaired insulin secretion. These results provide novel insights into the association between the low insulin exposure duration and bone mineral density.     

The distal C terminus of the dihydropyridine receptor β1a subunit is essential for tetrad formation in skeletal muscle

The skeletal muscle dihydropyridine receptor (DHPR) β_1a subunit is indispensable for full trafficking of DHPRs into triadic junctions (i.e., the close apposition of transverse tubules and sarcoplasmic reticulum [SR]), facilitation of DHPRα_1S voltage sensing, and arrangement of DHPRs into tetrads as a consequence of their interaction with ryanodine receptor (RyR1) homotetramers. These three features are obligatory for skeletal muscle excitation–contraction (EC) coupling. Previously, we showed that all four vertebrate β isoforms (β₁–β₄) facilitate α_1S triad targeting and, except for β₃, fully enable DHPRα_1S voltage sensing [Dayal et al., Proc. Natl. Acad. Sci. U.S.A. 110, 7488–7493 (2013)]. Consequently, β₃ failed to restore EC coupling despite the fact that both β₃ and β_1a restore tetrads. Thus, all β-subunits are able to restore triad targeting, but only β_1a restores both tetrads and proper DHPR–RyR1 coupling [Dayal et al., Proc. Natl. Acad. Sci. U.S.A. 110, 7488–7493 (2013)]. To investigate the molecular region(s) of β_1a responsible for the tetradic arrangement of DHPRs and thus DHPR–RyR1 coupling, we expressed loss- and gain-of-function chimeras between β_1a and β₄, with systematically swapped domains in zebrafish strain relaxed (β₁-null) for patch clamp, cytoplasmic Ca²⁺ transients, motility, and freeze-fracture electron microscopy. β_1a/β₄ chimeras with either N terminus, SH3, HOOK, or GK domain derived from β₄ showed complete restoration of SR Ca²⁺ release. However, chimera β_1a/β₄(C) with β₄ C terminus produced significantly reduced cytoplasmic Ca²⁺ transients. Conversely, gain-of-function chimera β₄/β_1a(C) with β_1a C terminus completely restored cytoplasmic Ca²⁺ transients, DHPR tetrads, and motility. Furthermore, we found that the nonconserved, distal C terminus of β_1a plays a pivotal role in reconstitution of DHPR tetrads and thus allosteric DHPR–RyR1 interaction, essential for skeletal muscle EC coupling.

Excitation–contraction (EC) coupling in skeletal muscle is initiated by depolarization of the muscle cell membrane induced by motor neuron input, which subsequently induces myofibril contractions. This transduction event depends on junctions between the surface membrane and its invaginations (transverse [T] tubules) and the sarcoplasmic reticulum (SR), in structures termed Ca²⁺ release units. The dihydropyridine receptor (DHPR) in the T-tubular membrane of the muscle cell functions as voltage sensor for this excitation signal. EC coupling in vertebrate skeletal muscle is based on Ca²⁺-influx–independent interchannel protein–protein interaction between the DHPR and ryanodine receptor (RyR1) in the SR membrane (1–3). Because of this physical interaction, the depolarization-induced conformational change of the DHPR is transmitted to the RyR1 channel, which opens to release large amounts of Ca²⁺ ions from the SR Ca²⁺ stores—a process that is the final trigger for myofibril contraction (4, 5).The skeletal muscle DHPR complex consists of the central, pore-forming, and voltage-sensing α_1S subunit and the accessory subunits β_1a, α₂δ-1, and γ₁ (6–8). Among them, the α_1S and the β_1a subunits are indispensable for skeletal muscle EC coupling (9–11). Akin to DHPRα_1S-null (dysgenic) (9) and RyR1-null (dyspedic) (12) mice, β₁-null mice (10) and β₁-null zebrafish (strain relaxed) (11) show a lethal phenotype due to complete absence of skeletal muscle contractility that leads to asphyxia. Besides the two canonical DHPR subunits, the junctional proteins Stac3 and junctophilin-2 (JP2) are also crucial for proper DHPR–RyR1 interaction that enables concerted voltage-induced SR Ca²⁺ release in skeletal muscle (13).In DHPRβ₁-null zebrafish strain relaxed, a lack of the β_1a subunit results in 1) reduced DHPRα_1S expression in the T-tubular membrane, 2) elimination of α_1S charge movement, and 3) a lack of the arrangement of DHPRs into groups of four (tetrads) opposite every other RyR1 (11). These three features are prerequisite for the tight protein–protein interaction between the DHPR and RyR1 and thus form the structural–functional basis for skeletal muscle EC coupling. Using zebrafish strain relaxed as a very convenient expression system, we previously showed that all four vertebrate β-isoforms (β₁–β₄), and also the ancestral β-subunit of Musca domestica (β_Μ) (14), are able to fully target α_1S into triads (15). Additionally, except for β₃, all other vertebrate β-isoforms are able to restore full charge movement (16) (SI Appendix, Fig. S1). Consequently, despite the surprising fact that β₃, akin to β_1a, is able to accurately cause the organization of DHPRs into tetrads, it is unable to restore EC coupling (16). Interestingly, only expression of β_1a fulfills all the three structural–functional prerequisites, i.e., proper DHPR triad and tetrad restoration, as well as proper charge movement facilitation and consequently, accurate DHPR–RyR1 interaction (15). As a result, native skeletal muscle β_1a is the only DHPRβ subunit that supports proper skeletal muscle EC coupling (SI Appendix, Fig. S1).To identify a structural domain(s) of β_1a essential for restoration of DHPR voltage sensing, and hence to probe how the DHPRα_1S–β_1a interaction affects this initial step of EC coupling, we previously performed reconstitution studies in the relaxed system using chimeras between β_1a and β₃ (16). Voltage-gated Ca²⁺ channel β-subunits are intracellular proteins with a five-domain organization and two conserved domains, the src homology 3 (SH3) and guanylate kinase (GK) domains that are connected by the variable HOOK region and flanked by variable N and C termini (17–20). The outcome of systematic domain swapping between β_1a and β₃ in the study of Dayal et al. (16) revealed a pivotal role of the β_1a SH3 domain and the C terminus in charge movement restoration. The results indicate that this domain–domain interaction is dependent on a SH3-binding polyproline (PXXP) motif in the proximal C terminus of the β_1a subunit. Consequently, it was concluded that the β_1a subunit, apparently via its SH3–C-terminal PXXP interaction, adopts a discrete conformation required for inducing a proper conformational change in the α_1S subunit crucial for “turning on” its voltage-sensing function (16).Nevertheless, we are just beginning to understand the importance of distinct molecular domains of the β_1a subunit in skeletal muscle EC coupling. In the present study, we characterized the second crucial structural prerequisite, tetrad formation, which contrary to the promiscuous structural property of DHPR triad targeting by all β-subunits, is shared by only β_1a and β₃ (SI Appendix, Fig. S1). To identify β_1a domains responsible for proper DHPR tetrad formation and thus proper DHPR–RyR1 protein–protein interaction as a basis for induction of SR Ca²⁺ release and finally muscle contractility/motility, we expressed putative loss- and gain-of-function chimeras with systematically swapped domains between β_1a and β₄ in zebrafish strain relaxed for patch clamp, cytoplasmic Ca²⁺ transients, motility, and freeze-fracture electron microscopy (EM) analyses.Here we report that our loss- and gain-of-function chimeras indicate the importance and exclusivity of the nonconserved distal C terminus of β_1a in DHPR tetrad formation and thus a DHPR–RyR1 interaction essential for proper skeletal muscle EC coupling. Within the distal C terminus, we found that a hydrophobic surface (L₄₉₆L₅₀₀W₅₀₃), previously postulated to be important for activation of RyR1 (21), does not appear to play a role in EC coupling Ca²⁺ release. Based on these results, we propose a model in which the distal β_1a C terminus enables a conformation of the β-subunit, which in turn causes the intracellular domains of α_1S to assume the positioning required for the interaction with RyR1 and thus the tetradic arrangement of DHPRs (22, 23).     

Emerging trends and the clinical impact of food insecurity in patients with diabetes

Food insecurity is a major public health concern in the United States affecting 15 million households according to data in 2017 from the US Department of Agriculture. Food insecurity, or the inability to consistently obtain nutritious food, disproportionately affects socioeconomically disadvantaged households, as well as those with chronic diseases including diabetes mellitus (DM). This review article explores the literature over the past 10 years pertaining to the complex relationship between food insecurity, social determinants of health, and chronic disease with an emphasis on diabetes and glycemic control. Those with diabetes and food insecurity together have been shown to have worse glycemic control compared to those who are food secure, but it remains unclear exactly how food insecurity affects glycemic control. Prior interventional studies have targeted aspects of food insecurity in patients with diabetes but have reported variable outcomes with respect to improvement in glycemic control despite effectively reducing rates of food insecurity. Additionally, few data exist regarding long‐term outcomes and diabetes‐related complications in this population. It is likely that many factors at both the community and individual levels impact glycemic control outcomes in the setting of food insecurity. Further studies are needed to better understand these factors and to create multifaceted targets for future interventional studies aimed at improving glycemic control in this population.