Update on Myocarditis Kindermann, Ingrid, MD; Barth, Christine; Mahfoud, Felix, MD ...
Journal of the American College of Cardiology,
02/2012, Volume:
59, Issue:
9
Journal Article
Peer reviewed
Open access
Myocarditis is an inflammatory disease of the heart frequently resulting from viral infections and/or post-viral immune-mediated responses. It is one of the important causes of dilated cardiomyopathy ...worldwide. The diagnosis is presumed on clinical presentation and noninvasive diagnostic methods such as cardiovascular magnetic resonance imaging. Endomyocardial biopsy remains the gold standard for in vivo diagnosis of myocarditis. The therapeutic and prognostic benefits of endomyocardial biopsy results have recently been demonstrated in several clinical trials. Although remarkable advances in diagnosis, understanding of pathophysiological mechanisms, and treatment of acute myocarditis were gained during the last years, no standard treatment strategies could be defined as yet, apart from standard heart failure therapy and physical rest. In severe cases, mechanical support or heart transplantation may become necessary. There is some evidence that immunosuppressive and immunomodulating therapy are effective for chronic, virus-negative inflammatory cardiomyopathy. Further investigations by controlled, randomized studies are needed to definitively determine their role in the treatment of myocarditis.
Objectives This study investigated the effect of catheter-based renal sympathetic denervation (RD) on left ventricular hypertrophy (LVH) and systolic and diastolic function in patients with resistant ...hypertension. Background LVH and diastolic dysfunction are associated with elevated sympathetic activity and increased morbidity and mortality. The effect of RD on LVH and LV function is unclear. Methods Forty-six patients underwent bilateral RD, and 18 patients served as controls. Transthoracic echocardiography was performed at baseline, and after 1 month and 6 months. Results Besides reduction of systolic and diastolic blood pressure (−22.5/−7.2 mm Hg at 1 month and −27.8/−8.8 mm Hg at 6 months, p < 0.001 at each time point), RD significantly reduced mean interventricular septum thickness from 14.1 ± 1.9 mm to 13.4 ± 2.1 mm and 12.5 ± 1.4 mm (p = 0.007), and LV mass index from 53.9 ± 15.6 g/m2.7 (112.4 ± 33.9 g/m2 ) to 47.0 ± 14.2 g/m2.7 (103.6 ± 30.5 g/m2 ) and 44.7 ± 14.9 g/m2.7 (94.9 ± 29.8 g/m2 ) (p < 0.001) at 1 month and 6 months, respectively. The mitral valve lateral E/E′ decreased after RD from 9.9 ± 4.0 to 7.9 ± 2.2 at 1 month and 7.4 ± 2.7 at 6 months (p < 0.001), indicating reduction of LV filling pressures. Isovolumic relaxation time shortened (baseline 109.1 ± 21.7 ms vs. 85.6 ± 24.4 ms at 6 months, p = 0.006), whereas ejection fraction significantly increased after RD (baseline: 63.1 ± 8.1% vs. 70.1 ± 11.5% at 6 months, p < 0.001). No significant changes were obtained in control patients. Conclusions Besides the known effect on blood pressure, our study showed for the first time that RD significantly reduces LV mass and improves diastolic function, which might have important prognostic implications in patients with resistant hypertension at high cardiovascular risk.
Abstract Background Insufficient procedural efficacy has been proposed to explain nonresponse to renal denervation (RDN). Objectives The aim of this study was to examine the impact of different ...patterns of lesion placements on the efficacy and consistency of catheter-based radiofrequency RDN in pigs. Methods The impact of increasing number of lesions versus location of RDN was investigated in a porcine model (Group 1; n = 51). The effect of treating the main artery, the branches, and the 2 combined was compared in Group 2 (n = 48). The durability of response and safety of combined treatment of the main artery plus branches was examined in Group 3 (n = 16). Renal norepinephrine (NE) tissue content and renal cortical axon density were assessed. Results Increasing the number of RF lesions (4, 8, and 12) in the main renal artery was not sufficient to yield a clear dose-response relationship on NE content and axon density. In contrast, targeted treatment of the renal artery branches or distal segment of the main renal artery resulted in markedly less variability of response and significantly greater reduction of both NE and axon density than conventional treatment of only the main renal artery. Combination treatment (main artery plus branches) produced the greatest change in renal NE and axon density with the least heterogeneity. The changes were durable through 28 days post-treatment. Conclusions These data provide the rationale for investigation of an optimized approach for RDN in future clinical studies. This may have profound implications for the clinical application of RDN, as this approach may not only achieve greater reductions in sympathetic activity but also reduce treatment effect variability.
Summary Background Renal denervation (RDN) with radiofrequency ablation substantially reduces blood pressure in patients with treatment-resistant hypertension. We assessed the long-term ...antihypertensive effects and safety. Methods Symplicity HTN-1 is an open-label study that enrolled 153 patients, of whom 111 consented to follow-up for 36 months. Eligible patients had a systolic blood pressure of at least 160 mm Hg and were taking at least three antihypertensive drugs, including a diuretic, at the optimum doses. Changes in office systolic blood pressure and safety were assessed every 6 months and reported every 12 months. This study is registered with ClinicalTrials.gov , numbers NCT00483808 , NCT00664638 , and NCT00753285. Findings 88 patients had complete data at 36 months. At baseline the mean age was 57 (SD 11) years, 37 (42%) patients were women, 25 (28%) had type 2 diabetes mellitus, the mean estimated glomerular filtration rate was 85 (SD 19) mL/min per 1·73 m2 , and mean blood pressure was 175/98 (SD 16/14) mm Hg. At 36 months significant changes were seen in systolic (−32·0 mm Hg, 95% CI −35·7 to −28·2) and diastolic blood pressure (−14·4 mm Hg, −16·9 to −11·9). Drops of 10 mm Hg or more in systolic blood pressure were seen in 69% of patients at 1 month, 81% at 6 months, 85% at 12 months, 83% at 24 months, and 93% at 36 months. One new renal artery stenosis requiring stenting and three deaths unrelated to RDN occurred during follow-up. Interpretation Changes in blood pressure after RDN persist long term in patients with treatment-resistant hypertension, with good safety. Funding Ardian LLC/Medtronic Inc.
Renal sympathetic activation plays a key role in the pathogenesis of hypertension, as demonstrated by high renal norepinephrine spillover into plasma of patients with essential hypertension. Renal ...denervation has demonstrated a significant reduction in blood pressure in unblinded studies of hypertensive patients. The SYMPLICITY HTN-3 trial, the first prospective, masked, randomized study of renal denervation versus sham control, failed its primary efficacy end point and raised important questions around potentially confounding factors, such as drug changes and adherence, study population, and procedural methods. The SPYRAL HTN Global Clinical Trial Program is designed to address limitations associated with predicate studies and provide insight into the impact of pharmacotherapy on renal denervation efficacy. The 2 initial trials of the program focus on the effect of renal denervation using the Symplicity Spyral multielectrode renal denervation catheter in hypertensive patients in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. The SPYRAL HTN ON-MED study requires patients to be treated with a consistent triple therapy antihypertensive regimen, whereas the SPYRAL HTN OFF-MED study includes a 3- to 4-week drug washout period followed by a 3-month efficacy and safety end point in the absence of antihypertensive medications. The studies will randomize patients with combined systolic-diastolic hypertension to renal denervation or sham procedure. Both studies allow renal denervation treatments in renal artery branches and accessories. These studies will inform the design of the second pivotal phase of the program, which will more definitively analyze the antihypertensive effect of renal denervation.
Summary Background Studies have challenged the appropriateness of accepted blood pressure targets. We hypothesised that different levels of low blood pressure are associated with benefit for some, ...but harm for other outcomes. Methods In this analysis, we assessed the previously reported outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination, with a median follow-up of 56 months. Detailed descriptions of randomisation and intervention have already been reported. We analysed the associations between mean blood pressure achieved on treatment; prerandomisation baseline blood pressure; or time-updated blood pressure (last on treatment value before an event) on the composite outcome of cardiovascular death, myocardial infarction, stroke, and hospital admission for heart failure; the components of the composite outcome; and all-cause death. Analysis was done by Cox regression analysis, ANOVA, and χ2 . These trials were registered with ClinicalTrials.gov , number NCT00153101. Findings Recruitment for ONTARGET took place between Dec 1, 2001, and July 31, 2008. TRANSCEND took place between Nov 1, 2001, and May 30, 2004. 30 937 patients were recruited from 733 centres in 40 countries and followed up for a median of 56 months. In ONTARGET, 25 127 patients known to be tolerant to angiotensin-converting-enzyme (ACE)-inhibitors were randomly assigned after a run-in period to oral ramipril 10 mg/day (n=8407), telmisartan 80 mg/day (n=8386), or the combination of both (n=8334). In TRANSCEND, 5810 patients who were intolerant to ACE-inhibitors were randomly assigned to oral telmisartan 80 mg/day (n=2903) or placebo (n=2907). Baseline systolic blood pressure (SBP) 140 mm Hg or higher was associated with greater incidence of all outcomes compared with 120 mm Hg to less than 140 mm Hg. By contrast, a baseline diastolic blood pressure (DBP) less than 70 mm Hg was associated with the highest risk for most outcomes compared with all DBP categories 70 mm Hg or more. In 4052 patients with SBP less than 120 mm Hg on treatment, the risk of the composite cardiovascular outcome (adjusted hazard ratio HR 1·14, 95% CI 1·03–1·26), cardiovascular death (1·29, 1·12–1·49), and all deaths (1·28, 1·15–1·42) were increased compared with those in whom SBP was 120–140 mm Hg during treatment (HR 1 for all outcomes, n=16099). No harm or benefit was observed for myocardial infarction, stroke, or hospital admission for heart failure. Mean achieved SBP more accurately predicted outcomes than baseline or time-updated SBP, and was associated with the lowest risk at approximately 130 mm Hg, and at 110–120 mm Hg risk increased for the combined outcome, cardiovascular death, and all-cause death except stroke. A mean DBP less than 70 mm Hg (n=5352) during treatment was associated with greater risk of the composite primary outcome (HR 1·31, 95% CI 1·20–1·42), myocardial infarction (1·55, 1·33–1·80), hospital admission for heart failure (1·59, 1·36–1·86) and all-cause death (1·16, 1·06–1·28) than a DBP 70–80 mm Hg (14 305). A pretreatment and mean on-treatment DBP of about 75 mm Hg was associated with the lowest risk. Interpretation Mean achieved SBP less than 120 mm Hg during treatment was associated with increased risk of cardiovascular outcomes except for myocardial infarction and stroke. Similar patterns were observed for DBP less than 70 mm Hg, plus increased risk for myocardial infarction and hospital admission for heart failure. Very low blood pressure achieved on treatment was associated with increased risks of several cardiovascular disease events. These data suggest that the lowest blood pressure possible is not necessarily the optimal target for high-risk patients, although it is not possible to rule out some effect of reverse causality. Funding Boehringer Ingelheim.
Atrial Autonomic Innervation Linz, Dominik, MD; Ukena, Christian, MD; Mahfoud, Felix, MD ...
Journal of the American College of Cardiology,
01/2014, Volume:
63, Issue:
3
Journal Article
Peer reviewed
Open access
Atrial fibrillation is the most common arrhythmia and is associated with significant morbidity and mortality. The autonomic nervous system contributes to the creation of atrial fibrillation ...substrates. Atrial electrophysiology is influenced differently by sympathetic and parasympathetic activation. Several strategies are available to modulate the complex interaction between the autonomic nervous system and the heart. However, different approaches target the problem differently making the prediction of arrhythmogenic and/or antiarrhythmic effects difficult. We discuss the role of the autonomic nervous system on the development of a substrate for atrial fibrillation and explore the potential antiarrhythmic and/or arrhythmogenic effect of modulation of the autonomic nervous system by renal sympathetic denervation, ganglionated plexi ablation, ganglion stellatum ablation, high thoracic epidural anesthesia, low-level vagal nerve stimulation, and baroreflex stimulation.
Objectives This study investigated the effect of catheter-based renal sympathetic denervation (RD) on central hemodynamics in patients with resistant hypertension. Background High central blood ...pressure (BP) increases cardiovascular events and mortality independently of peripheral BP. The effect of RD on central BP is unclear. Methods A total of 110 patients underwent bilateral RD. Radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressure and hemodynamic indices at baseline and 1, 3, and 6 months after ablation. Ten patients with resistant hypertension not undergoing RD served as controls. Results RD significantly reduced mean central aortic BP from 167/92 mm Hg to 149/88 mm Hg, 147/85 mm Hg, and 141/85 mm Hg at 1, 3, and 6 months (p < 0.001), respectively. Aortic pulse pressure decreased from 76.2 ± 23.3 mm Hg to 61.5 ± 17.5 mm Hg, 62.7 ± 18.1 mm Hg, and 54.5 ± 15.7 mm Hg 1, 3, and 6 months after RD (p < 0.001), respectively. Six months after RD aortic augmentation and augmentation index were significantly reduced by −11 mm Hg (p < 0.001) and −5.3% (p < 0.001), respectively. Carotid to femoral pulse wave velocity showed a significant reduction from 11.6 ± 3.2 m/s to 9.6 ± 3.1 m/s at 6 months (p < 0.001). Consistently, ejection duration and aortic systolic pressure load were significantly diminished, indicating improvement of cardiac work load by RD. No significant changes were obtained in control patients. Conclusions Besides the known effect of RD on brachial blood pressure, the study showed for the first time that this novel approach significantly improves arterial stiffness and central hemodynamics, which might have important prognostic implications in patients with resistant hypertension at high cardiovascular risk.
Increased sympathetic activation during acute ventricular ischemia is involved in the occurrence of life-threatening arrhythmias.
To test the effect of sympathetic inhibition by renal denervation ...(RDN) on ventricular ischemia/reperfusion arrhythmias.
Anesthetized pigs, randomized to RDN or SHAM treatment, were subjected to 20 minutes of left anterior descending coronary artery (LAD) occlusion followed by reperfusion. Infarct size, hemodynamics, premature ventricular contractions, and spontaneous ventricular tachyarrhythmias were analyzed. Monophasic action potentials were recorded with an epicardial probe at the ischemic area.
Ventricular ischemia resulted in an acute reduction of blood pressure (-29%) and peak left ventricular pressure rise (-40%), which were not significantly affected by RDN. However, elevation of left ventricular end-diastolic pressure (LVEDP) during LAD ligation was attenuated by RDN (ΔLVEDP: +1.8 ± 0.6 mm Hg vs +9.7 ± 1 mm Hg in the SHAM group; P = .046). Infarct size was not affected by RDN compared to SHAM. RDN significantly reduced spontaneous ventricular extrabeats (160 ± 15/10 min in the RDN group vs 422 ± 36/10 min in the SHAM group; P = .021) without affecting coupling intervals. In 5 of 6 SHAM-treated animals, ventricular fibrillation (VF) occurred during LAD occlusion. By contrast, only 1 of 7 RDN-treated animals experienced VF (P = .029). Beta-receptor blockade by atenolol showed comparable effects. Neither VF nor transient shortening of monophasic action potential duration during reperfusion was inhibited by RDN.
RDN reduced the occurrence of ventricular arrhythmias/fibrillation and attenuated the rise in LVEDP during left ventricular ischemia without affecting infarct size, changes in ventricular contractility, blood pressure, and reperfusion arrhythmias. Therefore, RDN may protect from ventricular arrhythmias during ischemic events.
Objectives This study sought to investigate the effects of interventional renal sympathetic denervation (RD) on cardiorespiratory response to exercise. Background RD reduces blood pressure at rest in ...patients with resistant hypertension. Methods We enrolled 46 patients with therapy-resistant hypertension as extended investigation of the Symplicity HTN-2 (Renal Denervation With Uncontrolled Hypertension) trial. Thirty-seven patients underwent bilateral RD and 9 patients were assigned to the control group. Cardiopulmonary exercise tests were performed at baseline and 3-month follow-up. Results In the RD group, compared with baseline examination, blood pressure at rest and at maximum exercise after 3 months was significantly reduced by 31 ± 13/9 ± 13 mm Hg (p < 0.0001) and by 21 ± 20/5 ± 14 mm Hg (p < 0.0001), respectively. Achieved work rate increased by 5 ± 13 W (p = 0.029) whereas peak oxygen uptake remained unchanged. Blood pressure 2 min after exercise was significantly reduced by 29 ± 17/8 ± 15 mm Hg (p < 0.001 for systolic blood pressure; p = 0.002 for diastolic blood pressure). Heart rate at rest decreased after RD (4 ± 11 beats/min; p = 0.028), whereas maximum heart rate and heart rate increase during exercise were not different. Heart rate recovery improved significantly by 4 ± 7 beats/min after renal denervation (p = 0.009). In the control group, there were no significant changes in blood pressure, heart rate, maximum work rate, or ventilatory parameters after 3 months. Conclusions RD reduces blood pressure during exercise without compromising chronotropic competence in patients with resistant hypertension. Heart rate at rest decreased and heart rate recovery improved after the procedure. (Renal Denervation With Uncontrolled Hypertension; Symplicity HTN-2; NCT00888433 )
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