Relation between QT interval variability and cardiac sympathetic innervation in patients with diabetes mellitus

Computing in Cardiology 2011, 18-21 September 2011, Zhejiang University, Hangzhou, ChinaElevated QT interval variability (QTV) has been asso- ciated with increased cardiac mortality, but the underlying mechanisms are incompletely understood. Sympathetic ac- tivity is thought to be a main contributor to QTV. The aim of this study was to investigate the relation between car- diac sympathetic integrity and QTV in 15 patients with type 2 diabetes mellitus and varying degrees of cardiac autonomic neuropathy. Cardiac sympathetic innervation was assessed by 123I-mIBG scintigraphy based on heart- to-mediastinum ratio of 123I-mIBG uptake 4 hours after infusion. To assess QTV high resolution ECGs (1000 Hz) were recorded during standing. Beat-to-beat QT inter- vals were calculated over a period of 5 minutes, using a template-stretching algorithm. QTV was quantified using time and frequency domain measures as well as non-linear approaches (symbolic dynamics, fractal dimension). The group mean and standard deviation of HMR values were 1.07 ± 0.48. Time and frequency domain QTV parame- ters were significantly increased in subjects with sympa- thetic dysinnervation and inversely correlated with HMR (r = −0.7, p < 0.001). In conclusion, there is a clear link between sympathetic dysinnervation and elevated QTV in patients with type 2 diabetes mellitus during sympathetic activation. Sympathetic dysinnervation is associated with increased ventricular repolarization lability.Mathias Baumert, Julian Sacre and Bennett Franjichttp://www.cinc.org/archives/2011

NONINVASIVE ASSESSMENT AND MODELING OF DIABETIC CARDIOVASCULAR AUTONOMIC NEUROPATHY

Noninvasive assessment of diabetic cardiovascular autonomic neuropathy (AN): Cardiac and vascular dysfunctions resulting from AN are complications of diabetes, often undiagnosed. Our objectives were to: 1) determine sympathetic and parasympathetic components of compromised blood pressure regulation in patients with polyneuropathy, and 2) rank noninvasive indexes for their sensitivity in diagnosing AN. Continuous 12-lead electrocardiography (ECG), blood pressure (BP), respiration, regional blood flow and bio-impedance were recorded from 12 able-bodied subjects (AB), 7 diabetics without (D0), 7 with possible (D1) and 8 with definite polyneuropathy (D2), during 10 minutes supine control, 30 minutes 70-degree head-up tilt and 5 minutes supine recovery. During the first 3 minutes of tilt, systolic BP decreased in D2 while increased in AB. Parasympathetic control of heart rate, baroreflex sensitivity, and baroreflex effectiveness and sympathetic control of heart rate and vasomotion were reduced in D2, compared with AB. Baroreflex effectiveness index was identified as the most sensitive index to discriminate diabetic AN. Four-dimensional multiscale modeling of ECG indexes of diabetic autonomic neuropathy: QT interval prolongation which predicts long-term mortality in diabetics with AN, is well known. The mechanism of QT interval prolongation is still unknown, but correlation of regional sympathetic denervation of the heart (revealed by cardiac imaging) with QT interval in 12-lead ECG has been proposed. The goal of this study is to 1) reproduce QT interval prolongation seen in diabetics, and 2) develop a computer model to link QT interval prolongation to regional cardiac sympathetic denervation at the cellular level. From the 12-lead ECG acquired in the study above, heart rate-corrected QT interval (QTc) was computed and a reduced ionic whole heart mathematical model was constructed. Twelve-lead ECG was produced as a forward solution from an equivalent cardiac source. Different patterns of regional denervation in cardiac images of diabetic patients guided the simulation of pathological changes. Minimum QTc interval of lateral leads tended to be longer in D2 than in AB. Prolonging action potential duration in the basal septal region in the model produced ECG and QT interval similar to that of D2 subjects, suggesting sympathetic denervation in this region in patients with definite neuropathy

Diabetes mellitus and sudden cardiac death: What are the data?

Diabetes mellitus has long been linked to an increased risk of sudden cardiac death. However, the magnitude of this association, and the mechanism accounting for this phenomenon, have not been precisely defined. In this review, we evaluate the epidemiological data pertaining to the association between diabetes mellitus and sudden cardiac death and discuss various proposed mechanisms that may account for this relationship. Potential factors contributing to the increased risk of sudden cardiac death observed in patients with diabetes mellitus include silent myocardial ischemia, autonomic nervous system dysfunction, abnormal cardiac repolarization, hypoglycemia, a hypercoaguable state secondary to diabetes mellitus, diabetic cardiomyopathy, and impaired respiratory response to hypoxia and hypercapnea. We conclude that diabetes mellitus does appear to be associated with an increased risk of sudden cardiac death. Although this increased risk is relatively modest, given the large number of diabetic patients worldwide, the absolute number of sudden cardiac deaths attributable to diabetes mellitus remains significant. Little evidence exists to support any specific mechanism(s) accounting for this association. Further investigation into the pathophysiology of sudden cardiac death in diabetes mellitus may yield improved risk stratification tools as well as identify novel therapeutic targets. (Cardiol J 2010; 17, 2: 117-129

QT interval variability in body surface ECG: measurement, physiological basis, and clinical value: position statement and consensus guidance endorsed by the European Heart Rhythm Association jointly with the ESCWorking Group on Cardiac Cellular Electrophysiology

This consensus guideline discusses the electrocardiographic phenomenon of beat-to-beat QT interval variability (QTV) on surface electrocardiograms. The text covers measurement principles, physiological basis, and clinical value of QTV. Technical considerations include QT interval measurement and the relation between QTV and heart rate variability. Research frontiers of QTV include understanding of QTV physiology, systematic evaluation of the link between QTV and direct measures of neural activity, modelling of the QTV dependence on the variability of other physiological variables, distinction between QTV and general T wave shape variability, and assessing of the QTV utility for guiding therapy. Increased QTV appears to be a risk marker of arrhythmic and cardiovascular death. It remains to be established whether it can guide therapy alone or in combination with other risk factors. QT interval variability has a possible role in non-invasive assessment of tonic sympathetic activity

Myocardial ischemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: therapeutic options

During the last decades, mortality of acute myocardial infarction has been dramatically improved, however, the incidence of post-infarction heart failure is still increasing. Cardioprotection by ischemic conditioning have been discovered more than 3 decades ago, however, its clinical translation is still an unmet need, mainly due to the disrupted cardioprotective signalling pathways in the presence of different cardiovascular risk factors and comorbidities and their medications. Sensory neuropathy is one of the comorbidities that has been shown to interfere with cardioprotection. In the present review we summarize the diverse aetiology of sensory neuropathies and the mechanisms by which neuropathies may interfere with ischemic heart disease and cardioprotective signalling. Moreover, we suggest future therapeutic options targeting ischemic heart and sensory neuropathy simultaneously

Cardiac dysfunction in the ZDF rat: Possible mechanisms and benefits of exercise

Cardiovascular disease has resulted in an increased risk of premature deaths for the 104 million Americans with prediabetes or diabetes and has accounted for approximately 65% of total diabetic deaths annually. Clinical manifestations of diabetic heart disease include left ventricular hypertrophy, diastolic and systolic dysfunction, and diabetic cardiac autonomic neuropathy, which are regularly observed at varying severities in persons with type 2 diabetes. The Zucker diabetic fatty (ZDF) rat has shown promise as a model of diabetic heart disease since it resembles the blending of cardiac diseases seen in humans and as such can be utilized to investigate diabetic heart disease and therapeutic interventions. We chose to investigate the impact of exercise on diabetic heart disease in the ZDF rat, and to explore a novel mechanism. The objectives of the dissertation were to investigate the cardiac dysfunction in the ZDF model, determine whether aerobic exercise training can reverse electrocardiographic (ECG) and hemodynamic changes induced by diabetes, and identify whether cardiac edema may be one of the factors contributing to diabetic heart disease and a possible target of exercise. Myocardial edema is an imbalance between vascular permeability, lymphatic vessels, lymph flow, and cardiac function. It is unknown if diabetes causes myocardial edema. Little is known about the impact of diabetes on the lymphatic system and its receptors, vascular endothelial growth factor receptor 3 (VEGFR-3) and lymphatic endothelial receptor 1(LYVE-1). These receptors are responsible for the uptake of their respective ligands, VEGF-C and hyaluronan. Each receptor's expression is regulated by prospero homeobox protein 1(PROX-1), which is the master switch for the lymphangiogenesis. Myocardial fluid imbalances have been implicated in the fibrosis and hypertrophy associated with common cardiovascular diseases, which makes edema a suitable target for possible interventions. Diabetes in the ZDF rat caused crucial changes in R wave amplitudes (p<0.001), heart rate variability (p<0.01), QT intervals (p<0.001) and QTc intervals (p<0.001). R wave amplitude augmentation in sedentary diabetic rats from baseline to termination was ameliorated by exercise, resulting in R wave amplitude changes in exercised diabetic rats similar to control rats. Of these changes, aerobic exercise training was only able to correct R wave amplitude changes. In addition, exercise had beneficial effects in this diabetic rat model with regards to ECG correlates of left ventricular mass. Of the 24 hemodynamic parameters tested, 15 were negatively affected by diabetes. The debility of diabetic heart disease was evident in the diastolic filling, isovolumic contraction, ejection, and isovolumic relaxation phases. Importantly, exercise training restored 13 of the 15 hemodynamic parameters affected by diabetes. However, we did not observe differences in left ventricular weights, a direct measure of myocardial edema, or alterations in the levels of VEGF-C, VEGFR-3, LYVE-1, or hyaluronan. We were able to observe systemic differences in plasma interleukin (IL)-2 levels, reductions in dP/dtmax, and differences in PROX-1 protein levels and DNA binding activity that were suggestive of the presence of myocardial edema in the ZDF rat. However, these alterations are indirect measures of myocardial edema, therefore we were unable to conclude in the 19 week old ZDF rat if myocardial edema exists and plays a role in diabetic heart disease

Cukrzyca a nagły zgon sercowy - jakie są wyniki badań?

Cukrzycę od dawna wiązano ze zwiększonym ryzykiem nagłego zgonu sercowego (SCD). Jednak nie do końca określono stopień zwiększenia ryzyka oraz mechanizmy przyczyniające się do opisywanego zjawiska. W niniejszej pracy oceniono dane epidemiologiczne dokumentujące związek między występowaniem cukrzycy a SCD oraz przedyskutowano różne proponowane mechanizmy, które mogą się przyczyniać do zaistnienia opisywanej zależności. Do potencjalnych czynników zwiększających ryzyko SCD obserwowane u chorych na cukrzycę należą: nieme niedokrwienie mięśnia sercowego, dysfunkcja autonomicznego układu nerwowego, nieprawidłowa repolaryzacja komórek mięśnia sercowego, hipoglikemia, stan nadkrzepliwości wtórny do cukrzycy, kardiomiopatia cukrzycowa oraz upośledzona odpowiedź na niedotlenienie i hiperkapnię. Według autorów niniejszej pracy, wydaje się, że cukrzyca wiąże się ze zwiększonym ryzykiem SCD. Chociaż w wartościach względnych stopień zwiększenia ryzyka jest umiarkowany, to biorąc pod uwagę olbrzymią liczbę pacjentów chorych na cukrzycę na całym świecie, bezwzględna liczba SCD, które można powiązać z cukrzycą, jest istotna. Wciąż brakuje dowodów, które mogłyby potwierdzać jakikolwiek specyficzny mechanizm(y) przyczyniający się do opisywanego związku. Przyszłe badania dotyczące patofizjologii SCD u chorych na cukrzycę mogą dostarczyć użytecznych narzędzi stratyfikacji ryzyka oraz pomóc w identyfikacji nowych celów terapeutycznych. (Folia Cardiologica Excerpta 2010; 5, 4: 206-219

Autonomisen hermoston toimintakokeiden vaikutukset sydämen repolarisaatioon

The autonomic nervous system is an important modulator of ventricular repolarization and arrhythmia vulnerability. This study explored the effects of cardiovascular autonomic function tests on repolarization and its heterogeneity, with a special reference to congenital arrhythmogenic disorders typically associated with stress-induced fatal ventricular arrhythmias. The first part explored the effects of standardized autonomic tests on QT intervals in a 12-lead electrocardiogram and in multichannel magnetocardiography in 10 healthy adults. The second part studied the effects of deep breathing, Valsalva manouvre, mental stress, sustained handgrip and mild exercise on QT intervals in asymptomatic patients with LQT1 subtype of the hereditary long QT syndrome (n=9) and in patients with arrhythmogenic right ventricular dysplasia (ARVD, n=9). Even strong sympathetic activation had no effects on spatial QT interval dispersion in healthy subjects, but deep respiratory efforts and Valsalva influenced it in ways that were opposite in electrocardiographic and magnetocardiographic recordings. LQT1 patients showed blunted QT interval and sinus nodal responses to sympathetic challenge, as well as an exaggerated QT prolongation during the recovery phases. LQT1 patients showed a QT interval recovery overshoot in 2.4 ± 1.7 tests compared with 0.8 ± 0.7 in healthy controls (P = 0.02). Valsalva strain prolonged the T wave peak to T wave end interval only in the LQT1 patients, considered to reflect the arrhythmogenic substrate in this syndrome. ARVD patients showed signs of abnormal repolarization in the right ventricle, modulated by abrupt sympathetic activation. An electrocardiographic marker reflecting interventricular dispersion of repolarization was introduced. It showed that LQT1 patients exhibit a repolarization gradient from the left ventricle towards the right ventricle, significantly larger than in controls. In contrast, ARVD patients showed a repolarization gradient from the right ventricle towards the left. Valsalva strain amplified the repolarization gradient in LQT1 patients whereas it transiently reversed it in patients with ARVD. In conclusion, intrathoracic volume and pressure changes influence regional electrocardiographic and magnetocardiographic QT interval measurements differently. Especially recovery phases of standard cardiovascular autonomic functions tests and Valsalva manoeuvre reveal the abnormal repolarization in asymptomatic LQT1 patients. Both LQT1 and ARVD patients have abnormal interventricular repolarization gradients, modulated by abrupt sympathetic activation. Autonomic testing and in particular the Valsalva manoeuvre are potentially useful in unmasking abnormal repolarization in these syndromes.Autonominen, eli tahdosta riippumaton hermosto osallistuu moniin elimistön säätelytoimintoihin, vaikuttaen suoraan myös sydämeen. Autonominen hermosto jaetaan sympaattiseen hermostoon, joka aktivoituu äkillisissä elimistön kriisitilanteissa kuten vihastumisen, stressin ja rasituksen yhteydessä, sekä parasympaattiseen hermostoon, joka puolestaan toimii vilkkaammin elimistön lepotilassa. Äkillisesti lisääntynyt sympaattisen hermoston aktiivisuus lisää vakavien rytmihäiriöiden vaaraa mm. kasvattamalla ohimenevästi sydämen sähköiseen toipumisvaiheen (repolarisaatioon) keston alueellisia eroja. Tämän ilmiön merkitys korostuu tietyissä vakaville rytmihäiriöille altistavissa perinnöllisissä taudeissa, joissa repolarisaatio on valmiiksi poikkeava. Näille taudeille on tunnusomaista henkeä uhkaavan rytmihäiriön ilmaantumisen riski tilanteissa joissa autonomisen hermoston toiminta muuttuu äkillisesti. Väitöskirjatutkimuksessa selvitettiin vakioitujen autonomisen hermoston toimintakokeiden vaikutuksia sydämen repolarisaatioon, mittaamalla monikanavaisesta sydänsähkökäyrästä (EKG) repolarisaatiota kuvaavaa QT-aikaa lyönti lyönniltä. Erityisesti tutkittiin testisarjan (syväänhengityskoe, Valsalvan koe, henkinen stressitesti, isometrinen puristuskoe, kevyt rasitus) vaikutuksia QT-aikaan kahdessa perinnöllisessä rytmihäiriösairaudessa; 1-tyypin pitkä-QT oireyhtymässä (LQT1) ja oikean kammion arytmogeenisessä dysplasiassa (ARVD). LQT1-potilailla syketaajuuden nousu ja QT-ajan lyheneminen olivat normaalia vaimeampia sympaattiseen aktivaation aikana, ja tunnusomaista oli QT-ajan poikkeava piteneminen testien palautumisvaiheissa. Lisäksi Valsalvan kokeen ponnistusvaihe pidensi ohimenevästi T-aallon huipusta T-aallon loppuun mitattua aikaintervallia, mikä katsotaan olevan rytmihäiriöriskiä parhaiten kuvaava EKG-ilmiö tässä oireyhtymässä. ARVD-potilailla havaittiin merkkejä poikkeavasta oikean kammion repolarisaatiosta, ja sen muuttumisesta sympaattisen aktivaation vaikutuksesta. Tutkimuksessa esitettiin lisäksi uusi tapa kuvata repolarisaation epäyhtenäisyyttä, arvioimalla EKG:n avulla sydämen oikean ja vasemman kammion välistä repolarisaatiogradienttia. Gradientti oli normaalia suurempi ja suunnaltaan vasemmalta oikealle LQT1-potilailla, mutta päinvastainen eli oikealta vasemmalle ARVD-potilailla. Valsalvan kokeen ponnistusvaihe korosti entisestään gradienttia LQT1-potilailla ja käänsi ohimenevästi sen suuntaa ARVD-potilailla. Autonomisen hermoston testit ja niistä erityisesti Valsalvan koe osoittautuivat käyttökelpoiseksi poikkeavan repolarisaation paljastamisessa LQT1- ja ARVD-potilailla. Kuvatuista menetelmistä saattaa jatkossa olla apua näiden sairauksien hoitolinjauksissa ja rytmihäiriöriskin arvioimisessa

Multimodality imaging in ischemic heart disease, from prevention to outcome

The diversity in medicine and the scope of both non-invasive and invasive diagnostic instruments and treatments for ischemic heart disease have grown exponentially the last few decades. The objective of this thesis was to establish the value of different imaging techniques and treatments targeting different stages of ischemic heart disease. The results reported have demonstrated that multimodality imaging is of high relevance in patients with ischemic heart disease, facilitating the decision-making process in different groups of patients and allowing medical and (non-)invasive treatments to be better tailored to individual cases from prevention to treatment while potentially improving prognoses.LUMC / Geneeskunde Repositoriu