Influence of cardiac autonomic neuropathy on cardiac repolarisation during incremental adrenaline infusion in type 1 diabetes.

AIMS/HYPOTHESIS: We examined the effect of a standardised sympathetic stimulus, incremental adrenaline (epinephrine) infusion on cardiac repolarisation in individuals with type 1 diabetes with normal autonomic function, subclinical autonomic neuropathy and established autonomic neuropathy. METHODS: Ten individuals with normal autonomic function and baroreceptor sensitivity tests (NAF), seven with subclinical autonomic neuropathy (SAN; normal standard autonomic function tests and abnormal baroreceptor sensitivity tests); and five with established cardiac autonomic neuropathy (CAN; abnormal standard autonomic function and baroreceptor tests) underwent an incremental adrenaline infusion. Saline (0.9% NaCl) was infused for the first hour followed by 0.01 µg kg-1 min-1 and 0.03 µg kg-1 min-1 adrenaline for the second and third hours, respectively, and 0.06 µg kg-1 min-1 for the final 30 min. High resolution ECG monitoring for QTc duration, ventricular repolarisation parameters (T wave amplitude, T wave area symmetry ratio) and blood sampling for potassium and catecholamines was performed every 30 min. RESULTS: Baseline heart rate was 68 (95% CI 60, 76) bpm for the NAF group, 73 (59, 87) bpm for the SAN group and 84 (78, 91) bpm for the CAN group. During adrenaline infusion the heart rate increased differently across the groups (p = 0.01). The maximum increase from baseline (95% CI) in the CAN group was 22 (13, 32) bpm compared with 11 (7, 15) bpm in the NAF and 10 (3, 18) bpm in the SAN groups. Baseline QTc was 382 (95% CI 374, 390) ms in the NAF, 378 (363, 393) ms in the SAN and 392 (367, 417) ms in the CAN groups (p = 0.31). QTc in all groups lengthened comparably with adrenaline infusion. The longest QTc was 444 (422, 463) ms (NAF), 422 (402, 437) ms (SAN) and 470 (402, 519) ms (CAN) (p = 0.09). T wave amplitude and T wave symmetry ratio decreased and the maximum decrease occurred earlier, at lower infused adrenaline concentrations in the CAN group compared with NAF and SAN groups. AUC for the symmetry ratio was different across the groups and was lowest in the CAN group (p = 0.04). Plasma adrenaline rose and potassium fell comparably in all groups. CONCLUSIONS/INTERPRETATION: Participants with CAN showed abnormal repolarisation in some measures at lower adrenaline concentrations. This may be due to denervation adrenergic hypersensitivity. Such individuals may be at greater risk of cardiac arrhythmias in response to physiological sympathoadrenal challenges such as stress or hypoglycaemia.

End-stage heart failure non-pharmacological therapy: recent advances in pacemakers, pressure monitors, pumps and other devices.

Heart failure is a common, expensive and fatal condition and yet, until recently, there was a paucity of treatment options for patients with end-stage heart failure (ESHF), other than pharmacotherapy or heart transplant. Recent advances mean there is now an array of non-pharmacological therapies available for such patients; two such examples are cardiac resynchronisation therapy (CRT) and implantable cardioverter defibrillators (ICDs), which improve pump function, symptoms, exercise capacity or reduce the risk of arrhythmic death, respectively. Furthermore, prior to transplant or if they are deemed unsuitable, patients now have the option of a left ventricular assist device (LVAD) or total artificial heart (TAH), where available, before heart transplant needs to be considered. The concept of remote monitoring is increasingly popular, and while recording parameters such as blood pressure and weight are not new, what is new is how implantable remote monitoring devices are now able to detect clinical decompensation before even the patient is symptomatic and relay this information onto the clinician. Other more novel therapies for ESHF include nerve stimulators to reduce sympathetic tone, the risk of arrhythmia and augment reverse cardiac remodelling and, perhaps the most novel of all, cardiac contractility modulation, stimulating the heart paradoxically during the absolute refractory period that serves to improve cardiac contractility.

Rate-dependent measures of repolarization predict inducibility of ventricular arrhythmias.

OBJECTIVE: The aim of this study was to compare the rate-dependent measures of repolarization in patients with and without inducible ventricular arrhythmias, and so to assess the potential arrhythmogenic role of rate-dependent heterogeneities in cardiac repolarization. METHODS: Two groups of patients were studied during invasive electrophysiological procedures for standard clinical indications. A normal group (n = 17) with supraventricular tachycardia, structurally normal hearts and no inducible ventricular arrhythmias (PES-) and an inducible group (n = 13) with inducible ventricular arrhythmias (PES+). In each patient, we delivered a series of S1-S2 pacing sequences with a baseline S2 of 500 ms, which was progressively reduced. At the same time, a 12-lead electrocardiogram (ECG) was recorded. T-waves were extracted from each ECG recording, and 12 different T-wave measures were obtained from each patient across a range of coupling intervals. These included conventional measures, and those obtained from principal component analysis (PCA) of repolarization waveforms. RESULTS: At baseline S2, there was no significant difference between the PES- and PES+ using conventional T-wave measures. There were significant differences at baseline S2 between groups using PCA-derived measures. These differences showed rate dependence and were larger at shorter coupling intervals. Two dynamic ECG measurements identified subjects who were inducible during PES; maximum relative T-wave residuum >0.10 (odds ratio: 38.5, 95% CI: 4.7-318.5; P < 0.001) and maximum T-wave shape index <0.007 (odds ratio: 180.0, 95% CI: 10.2-3167.0; P < 0.001). CONCLUSION: T-wave shape index is rate dependent and discriminates between PES- and PES+ patients. We propose that patients with inducible arrhythmias have rate-dependent heterogeneity of repolarization which could be a useful tool for risk stratification.

Cardiac Autonomic Regulation and Repolarization During Acute Experimental Hypoglycemia in Type 2 Diabetes.

Hypoglycemia is associated with increased cardiovascular mortality in trials of intensive therapy in type 2 diabetes mellitus (T2DM). We previously observed an increase in arrhythmias during spontaneous prolonged hypoglycemia in patients with T2DM. We examined changes in cardiac autonomic function and repolarization during sustained experimental hypoglycemia. Twelve adults with T2DM and 11 age- and BMI-matched control participants without diabetes underwent paired hyperinsulinemic clamps separated by 4 weeks. Glucose was maintained at euglycemia (6.0 mmol/L) or hypoglycemia (2.5 mmol/L) for 1 h. Heart rate, blood pressure, and heart rate variability were assessed every 30 min and corrected QT intervals and T-wave morphology every 60 min. Heart rate initially increased in participants with T2DM but then fell toward baseline despite maintained hypoglycemia at 1 h accompanied by reactivation of vagal tone. In control participants, vagal tone remained depressed during sustained hypoglycemia. Participants with T2DM exhibited greater heterogeneity of repolarization during hypoglycemia as demonstrated by T-wave symmetry and principal component analysis ratio compared with control participants. Epinephrine levels during hypoglycemia were similar between groups. Cardiac autonomic regulation during hypoglycemia appears to be time dependent. Individuals with T2DM demonstrate greater repolarization abnormalities for a given hypoglycemic stimulus despite comparable sympathoadrenal responses. These mechanisms could contribute to arrhythmias during clinical hypoglycemic episodes.

Diurnal Differences in Risk of Cardiac Arrhythmias During Spontaneous Hypoglycemia in Young People With Type 1 Diabetes.

OBJECTIVE: Hypoglycemia may exert proarrhythmogenic effects on the heart via sympathoadrenal stimulation and hypokalemia. Hypoglycemia-induced cardiac dysrhythmias are linked to the "dead-in-bed syndrome," a rare but devastating condition. We examined the effect of nocturnal and daytime clinical hypoglycemia on electrocardiogram (ECG) in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS: Thirty-seven individuals with type 1 diabetes underwent 96 h of simultaneous ambulatory ECG and blinded continuous interstitial glucose monitoring (CGM) while symptomatic hypoglycemia was recorded. Frequency of arrhythmias, heart rate variability, and cardiac repolarization were measured during hypoglycemia and compared with time-matched euglycemia during night and day. RESULTS: A total of 2,395 h of simultaneous ECG and CGM recordings were obtained; 159 h were designated hypoglycemia and 1,355 h euglycemia. A median duration of nocturnal hypoglycemia of 60 min (interquartile range 40-135) was longer than daytime hypoglycemia of 44 min (30-70) (P = 0.020). Only 24.1% of nocturnal and 51.0% of daytime episodes were symptomatic. Bradycardia was more frequent during nocturnal hypoglycemia compared with matched euglycemia (incident rate ratio [IRR] 6.44 [95% CI 6.26, 6.63], P < 0.001). During daytime hypoglycemia, bradycardia was less frequent (IRR 0.023 [95% CI 0.002, 0.26], P = 0.002) and atrial ectopics more frequent (IRR 2.29 [95% CI 1.19, 4.39], P = 0.013). Prolonged QTc, T-peak to T-end interval duration, and decreased T-wave symmetry were detected during nocturnal and daytime hypoglycemia. CONCLUSIONS: Asymptomatic hypoglycemia was common. We identified differences in arrhythmic risk and cardiac repolarization during nocturnal versus daytime hypoglycemia in young adults with type 1 diabetes. Our data provide further evidence that hypoglycemia is proarrhythmogenic.

Cardiac Resynchronization Therapy Leads to Improvements in Handgrip Strength.

BACKGROUND: A reduction in skeletal muscle performance measured by handgrip strength is common in heart failure. No trial has investigated the role of cardiac resynchronization therapy, which leads to improvements in cardiac performance, on the function of skeletal muscle in patients with heart failure. METHODS: Nineteen patients were recruited, 18 male, age 69 ± 8 years, New York Heart Association class II-IV, QRS duration 173 ± 21 ms and left ventricular ejection fraction 26±8%. Handgrip strength was measured at baseline before, and 6 and 12 months, following cardiac resynchronization therapy. Response was assessed using quality of life questionnaire, 6-minute walk distance, left ventricular end-diastolic volume, and cardiopulmonary exercise testing at the same time points. RESULTS: Fourteen patients were identified as responders, demonstrating significant improvements in all four markers of response. There was no significant difference at baseline in left or right handgrip strength between responders and non-responders. Compared to baseline, handgrip strength significantly increased in responders during follow-up, left (34.4 ± 11.4 to 40.3 ± 11.3 kgf, P < 0.001) and right (35.7 ± 12.5 to 42.2 ± 11.5 kgf, P < 0.001) at 12 months. No such improvement was seen in non-responders. CONCLUSIONS: This study demonstrates that positive response to cardiac resynchronization therapy is associated with significant gains in handgrip strength, suggesting that cardiac resynchronization therapy may indirectly lead to secondary gains in skeletal muscle function.

Measures of endothelial dysfunction predict response to cardiac resynchronisation therapy.

OBJECTIVES: Cardiac resynchronisation therapy (CRT) improves morbidity and mortality in heart failure (HF). Impaired endothelial function, as measured by flow-mediated dilation (FMD) is associated with increased morbidity and mortality in HF and may help to differentiate responders from non-responders. METHODS: 19 patients were recruited, comprising 94% men, mean age 69±8 years, New York Heart Association functional classes II-IV, QRSd 161±21 ms and mean left ventricular ejection fraction 26±8%. Markers of response and FMD were measured at baseline, 6 and 12 months following CRT. RESULTS: 14 patients were responders to CRT. Responders had significant improvements in VO2 (12.6±1.7 to 14.7±1.5 mL/kg/min, p<0.05), quality of life score (44.4±22.9-24.1±21.3, p<0.01), left ventricular end diastolic volume (201.5±72.5 mL-121.3±72.0 mL, p<0.01) and 6-min walk distance (374.0±112.8 m at baseline to 418.1±105.3 m, p<0.05). Baseline FMD in responders was 2.9±1.9% and 7.4±3.73% in non-responders (p<0.05). CONCLUSIONS: Response to CRT at 6 and 12 months is predicted by baseline FMD. This study confirms that FMD identifies responders to CRT, due to endothelium-dependent mechanisms alone.

Nonviral gene delivery: techniques and implications for molecular medicine.

Medical research continues to illuminate the origins of many human diseases. Gene therapy has been widely proposed as a novel strategy by which this knowledge can be used to deliver new and improved therapies. Viral gene transfer is relatively efficient but there are concerns relating to the use of viral vectors in humans. Conversely, nonviral vectors appear safe but inefficient. Therefore, the development of an efficient nonviral vector remains a highly desirable goal. This review focuses on the numerous challenges preventing efficient nonviral gene transfer in vivo and discusses the many technologies that have been adopted to overcome these problems.

Preventing saphenous vein graft failure: does gene therapy have a role?

Gene therapy potentially allows local delivery and expression of cytokines, growth factors, and other mediators. In spite of increasing knowledge of the human genome, applications in clinical practice are only just beginning. The main limitations of effective clinical gene therapy are safety and low transfection efficiency. Saphenous vein grafts permit the transfection of the conduit ex vivo. This allows a variety of transfection techniques to be used, enhancing the transfection efficiency while limiting the risk of systemic complications. This review examines the potential mechanisms of gene delivery and genetic targets that may be applied to saphenous vein graft failure.

Closing the loop: modelling of heart failure progression from health to end-stage using a meta-analysis of left ventricular pressure-volume loops.

INTRODUCTION: The American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for the classification of heart failure (HF) are descriptive but lack precise and objective measures which would assist in categorising such patients. Our aim was two fold, firstly to demonstrate quantitatively the progression of HF through each stage using a meta-analysis of existing left ventricular (LV) pressure-volume (PV) loop data and secondly use the LV PV loop data to create stage specific HF models. METHODS AND RESULTS: A literature search yielded 31 papers with PV data, representing over 200 patients in different stages of HF. The raw pressure and volume data were extracted from the papers using a digitising software package and the means were calculated. The data demonstrated that, as HF progressed, stroke volume (SV), ejection fraction (EF%) decreased while LV volumes increased. A 2-element lumped parameter model was employed to model the mean loops and the error was calculated between the loops, demonstrating close fit between the loops. The only parameter that was consistently and statistically different across all the stages was the elastance (Emax). CONCLUSIONS: For the first time, the authors have created a visual and quantitative representation of the AHA/ACC stages of LVSD-HF, from normal to end-stage. The study demonstrates that robust, load-independent and reproducible parameters, such as elastance, can be used to categorise and model HF, complementing the existing classification. The modelled PV loops establish previously unknown physiological parameters for each AHA/ACC stage of LVSD-HF, such as LV elastance and highlight that it this parameter alone, in lumped parameter models, that determines the severity of HF. Such information will enable cardiovascular modellers with an interest in HF, to create more accurate models of the heart as it fails.

Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk.

Recent trials of intensive glycemic control suggest a possible link between hypoglycemia and excess cardiovascular mortality in patients with type 2 diabetes. Hypoglycemia might cause arrhythmias through effects on cardiac repolarization and changes in cardiac autonomic activity. Our aim was to study the risk of arrhythmias during spontaneous hypoglycemia in type 2 diabetic patients with cardiovascular risk. Twenty-five insulin-treated patients with type 2 diabetes and a history of cardiovascular disease or two or more risk factors underwent simultaneous continuous interstitial glucose and ambulatory electrocardiogram monitoring. Frequency of arrhythmias, heart rate variability, and markers of cardiac repolarization were compared between hypoglycemia and euglycemia and between hyperglycemia and euglycemia matched for time of day. There were 134 h of recording at hypoglycemia, 65 h at hyperglycemia, and 1,258 h at euglycemia. Bradycardia and atrial and ventricular ectopic counts were significantly higher during nocturnal hypoglycemia compared with euglycemia. Arrhythmias were more frequent during nocturnal versus daytime hypoglycemia. Excessive compensatory vagal activation after the counterregulatory phase may account for bradycardia and associated arrhythmias. QT intervals, corrected for heart rate, >500 ms and abnormal T-wave morphology were observed during hypoglycemia in some participants. Hypoglycemia, frequently asymptomatic and prolonged, may increase the risk of arrhythmias in patients with type 2 diabetes and high cardiovascular risk. This is a plausible mechanism that could contribute to increased cardiovascular mortality during intensive glycemic therapy.

Treatment planning for multiunit restorations--the use of diagnostic planning to predict implant and esthetic results in patients with congenitally missing teeth.

Patients afflicted with congenitally missing teeth are a unique patient population for consideration of treatment with osseointegrated implants. Frequently, these patients have limited development of the alveolar process and differences in spatial position relative to the opposing arch, which places emphasis on ancillary treatment with orthodontics and oral surgery. A thorough diagnostic workup should include an interdisciplinary approach to ensure optimal treatment and timing of treatment in those who are developing. This article outlines considerations for treating these types of patients and scenarios of treatment paths frequently taken to restore the partially dentate and edentulous to esthetics and function.

VP22-mediated intercellular transport correlates with enhanced biological activity of MybEngrailed but not (HSV-I) thymidine kinase fusion proteins in primary vascular cells following non-viral transfection.

BACKGROUND: The intercellular transport properties of the herpes simplex virus (HSV) protein VP22 have been harnessed to enhance the effectiveness of viral gene transfer. We investigated the intercellular transport and biological effects of VP22 fused with the dominant negative c-Myb chimera, MybEngrailed (MybEn) and HSV-I thymidine kinase (TK), in primary vascular smooth muscle cells (VSMC) following non-viral transfection. MATERIALS AND METHODS: Porcine VSMC transfected with plasmids encoding MybEn, TK and their respective N- and C-terminal VP22 fusion proteins were assayed for the extent and distribution of transgene expression (by immunohistochemistry), culture growth and apoptosis. RESULTS: The N-terminal MybEn fusion with VP22 (MybEnVP22) and both TK fusions, but not VP22MybEn, exhibited intercellular spread from primary transfected to up to 200 surrounding cells. pMybEnVP22-transfected cultures exhibited growth inhibition and apoptosis rates that were 10.6 +/- 3.6 and 3.2 +/- 1.0 fold higher than in pMybEn-transfected cultures; pVP22MybEn-transfected cultures showed no difference in these parameters. pTK-transfected cultures underwent 60-70% cell death in the presence of ganciclovir despite <2% primary transfection, which was not increased in cultures transfected with plasmids encoding VP22-TK fusions. CONCLUSIONS: The close correlation between immunocytochemical and biological assays suggests that intercellular transport is crucial to the enhanced biological activity of the MybEnVP22 fusion. The "intrinsic" bystander activity of TK was 4-fold greater than was "engineered" by VP22 fusion, probably reflecting the abundance of gap junctions between VSMC. VP22 fusion may enhance the efficiency of non-viral gene delivery when combined with the appropriate therapeutic transgene, target tissue and transfection method.