C-C Motif Chemokine 5 Attenuates Angiotensin II-Dependent Kidney Injury by Limiting Renal Macrophage Infiltration.

Inappropriate activation of the renin angiotensin system (RAS) is a key contributor to the pathogenesis of essential hypertension. During RAS activation, infiltration of immune cells into the kidney exacerbates hypertension and renal injury. However, the mechanisms underpinning the accumulation of mononuclear cells in the kidney after RAS stimulation remain unclear. C-C motif chemokine 5 (CCL5) drives recruitment of macrophages and T lymphocytes into injured tissues, and we have found that RAS activation induces CCL5 expression in the kidney during the pathogenesis of hypertension and renal fibrosis. We therefore evaluated the contribution of CCL5 to renal damage and fibrosis in hypertensive and normotensive models of RAS stimulation. Surprisingly, during angiotensin II-induced hypertension, CCL5-deficient (knockout, KO) mice exhibited markedly augmented kidney damage, macrophage infiltration, and expression of proinflammatory macrophage cytokines compared with wild-type controls. When subjected to the normotensive unilateral ureteral obstruction model of endogenous RAS activation, CCL5 KO mice similarly developed more severe renal fibrosis and greater accumulation of macrophages in the kidney, congruent with enhanced renal expression of the macrophage chemokine CCL2. In turn, pharmacologic inhibition of CCL2 abrogated the differences between CCL5 KO and wild-type mice in kidney fibrosis and macrophage infiltration after unilateral ureteral obstruction. These data indicate that CCL5 paradoxically limits macrophage accumulation in the injured kidney during RAS activation by constraining the proinflammatory actions of CCL2.

Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI.

Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT1) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-α is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-α is suppressed or enhanced by AT1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-α levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-α production induced by cisplatin. Finally, disrupting TNF-α production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-α levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.

Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.

Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/ß-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of ß-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/ß-catenin signaling pathway.

A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension.

RATIONALE: Human clinical trials using type 1 angiotensin (AT(1)) receptor antagonists indicate that angiotensin II is a critical mediator of cardiovascular and renal disease. However, recent studies have suggested that individual tissue pools of AT(1) receptors may have divergent effects on target organ damage in hypertension. OBJECTIVE: We examined the role of AT(1) receptors on T lymphocytes in the pathogenesis of hypertension and its complications. METHODS AND RESULTS: Deficiency of AT(1) receptors on T cells potentiated kidney injury during hypertension with exaggerated renal expression of chemokines and enhanced accumulation of T cells in the kidney. Kidneys and purified CD4(+) T cells from "T cell knockout" mice lacking AT(1) receptors on T lymphocytes had augmented expression of Th1-associated cytokines including interferon-γ and tumor necrosis factor-α. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT(1) receptor-deficient CD4(+) T cells had enhanced T-bet/GATA-3 expression ratios favoring induction of the Th1 response. Inversely, mice that were unable to mount a Th1 response due to T-bet deficiency were protected from kidney injury in our hypertension model. CONCLUSIONS: The current studies identify an unexpected role for AT(1) receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4(+) T helper cell differentiation.

Assessment of adequate safety margin using single coupling interval-upper limit of vulnerability test.

PURPOSE: Upper limit of vulnerability (ULV) testing using T-wave scanning shocks at multiple coupling intervals correlates well with defibrillation threshold (DFT), but remains underutilized in clinical practice. We measured DFT and ULV at a single coupling interval (SCI), with the aim to identify adequate safety margin at a coupling interval that correlates best with DFT. METHODS: Consecutive patients undergoing implantable cardioverter defibrillator implantation underwent simultaneous SCI-ULV and DFT assessment. Following a drive train of 400 ms, a T-wave-coupled shock was delivered. To minimize shocks, patients were randomized to programmed shock at 20 ms before peak (Group I), at peak (Group II), or 20 ms after peak (Group III) of T wave. An initial T-wave test shock at 9 J was followed by ±2 J shocks, until SCI-ULV was ascertained. Device rescue shocks were programmed at test shock +2 J and +4 J shocks followed by external rescue shock. RESULTS: There were 200 patients: 66 patients in Group I, 67 patients each in Groups II and III; mean age was 68.9 ± 12.4 years; 75% of patients men, 66% with ischemic heart disease and mean ejection fraction of 27.1 ± 7.1%. Overall, the mean number of ventricular fibrillation induction was 1.39 ± 0.8, mean SCI-ULV energy was 7.97 ± 3.39 J, and mean DFT was 8.68 ± 3.19 J. The correlation between SCI-ULV and DFT improved from Group I to Group III and was best in Group III (r(2) = 0.689). There were no major adverse events. CONCLUSIONS: SCI-ULV measured 20 ms after the peak of the T wave correlates well with DFT for assessment of adequate safety margin.

Role of vaptans in the management of hyponatremia.

Hyponatremia, the most commonly encountered electrolyte abnormality, affects as many as 30% of hospitalized patients. It is a powerful predictor of poor outcomes, especially in patients with congestive heart failure or cirrhosis. The failure to excrete electrolyte-free water that results from persistent secretion of antidiuretic hormone despite low serum osmolality usually underlies the development of hyponatremia. Treatment depends on several factors, including the cause, overall volume status of the patient, severity of hyponatremic symptoms, and duration of hyponatremia at presentation. This review focuses on the role of the vasopressin receptor antagonists, or vaptans, in the treatment of hyponatremia. These recently introduced agents have the unique ability to induce an aquaresis, the excretion of electrolyte-free water without accompanying solutes. After a brief historical perspective and discussion of pharmacologic characteristics of vaptans, we review the accumulated experience with vaptans for the treatment of hyponatremia. Vaptans have been shown to increase serum sodium concentrations in patients with euvolemic or hypervolemic hyponatremia in a reproducible manner, but their safe use requires full understanding of their indications and contraindications.

Characteristics of telemetry interference with pacemakers caused by digital media players.

BACKGROUND: Contemporary implantable heart rhythm devices communicate multiple complex data simultaneously using radiofrequency telemetry. Interference in communication can expose them to the risk of potential corruption, leading to adverse clinical consequences. METHODS & RESULTS: We studied the characteristics of interference with uplink (real time intracardiac electrograms, marker channel, and stored histograms) and downlink (attempt to program a change in the lower rate limit, the pacing mode, and the ventricular lead configuration) data transmission between the wand and the pacemaker caused by digital media players (iPods--Photo and 3G) in 50 patients. We also measured and characterized worst-case magnetic field emissions (MFE) from the wand (

High defibrillation threshold: the science, signs and solutions.

Defibrillation threshold (DFT) testing has traditionally been an integral part of implantable cardioverter defibrillator (ICD) implantation. With the increasing number of patients receiving ICDs, physicians are encountering high DFT more often than before. Tackling the problem of high DFT, warrants an in-depth understanding of the science of defibrillation including the key electrophysiological concepts and the underlying molecular mechanisms. Numerous factors have been implicated in the causation of high DFT. Due consideration to the past medical history, pharmacotherapy, laboratory data and cardiac imaging, help in assessing the pre-procedural risk for occurrence of high DFT. Drugs, procedural changes, type and location of ICD lead system are some of the key players in predicting DFT during implantation. In the event of encountering an unacceptably high DFT, we recommend to follow a step-wise algorithm. Ruling out procedural complications like pneumothorax and tamponade is imperative before embarking on a search for potentially reversible clinical or metabolic derangements. Finally, if these attempts fail, the electrophysiologist must choose from a wide range of options for device adjustment and system modification. Although this review article is meant to be a treatise on the science, signs and solutions for high DFT, it is bound by limitations of space and scope of the article.

Electromagnetic interference in an implantable loop recorder caused by a portable digital media player.

The implantable loop recorder has been shown to be a cost-effective tool for diagnosis of intermittent cardiovascular symptoms such as syncope and palpitations. Electromagnetic interference in these recorders may be caused by commonly encountered electronic devices such as antitheft electronic surveillance systems and magnetic resonance imaging cameras. In this report, we describe interference in two patients with implantable loop recorders from a portable digital media player.

Reel syndrome-not a twiddler variant.

We report three cases of an unusual form of "reel syndrome" characterized by isolated, reeling dislodgement of a single lead in patients with dual-chamber or biventricular devices. One of these patients presented with worsening heart failure due to loss of left ventricular pacing and the others were detected incidentally during scheduled device checks. We suspect that a ratchet mechanism was probably responsible for this and that this type of dislodgement is not a twiddler variant. We propose a simple solution for prevention.

CMR assessment of the left ventricle apical morphology in subjects with unexplainable giant T-wave inversion and without apical wall thickness ≥15 mm.

AIMS: Patients with unexplainable giant T-wave inversion in the precordial leads and apical wall thickness <15 mm have been reported. These patients cannot be diagnosed as apical hypertrophic cardiomyopathy (AHCM) according to the current criteria. The objective of this study was to evaluate the apical morphological features of this type of patients using cardiac magnetic resonance. METHODS AND RESULTS: Institutional ethics approval and written informed consent were obtained. A total of 60 subjects with unexplainable giant T-wave inversion and 76 healthy volunteers were prospectively enrolled in the study. The segmented left ventricular (LV) wall thickness was measured according to the American Heart Association 17-segmented model. The apical angle (apA) as well as the regional variations in LV wall thickness was analysed. Considerable variation in LV wall thickness in normals was observed with progressive thinning from the base to apex (male and female, P < 0.01). The apical thickness of subjects with giant T-wave inversion was 8.10 ± 1.67 mm in male, which is thicker than that of controls (4.14 ± 1.17 mm, P < 0.01). In female, the apical thickness was also significantly different from controls (5.85 ± 2.16 vs. 2.99 ± 0.65 mm, P < 0.01). Compared with normals, the apA decreased significantly in male (87.44 ± 13.86 vs.115.03 ± 9.90°, P < 0.01) and female (90.69 ± 8.84 vs. 110.07 ± 13.58°, P < 0.01) subjects, respectively. CONCLUSION: Although the absolute thickness of apical wall was below the current diagnostic criteria of AHCM, the apical morphological features of subjects with unexplainable giant T-wave inversion were significantly different from normals. Whether these subjects should be included into a preclinical scope of AHCM needs further investigations.

Device-Detected Atrial Fibrillation-Perils and Pitfalls: An Update.

Stroke and thromboembolism are catastrophic complications of atrial fibrillation (AF). Cardiac implantable electronic devices (CIED) with an atrial lead can reliably detect atrial high-rate events (AHRE). However, this correlation may be imperfect because of oversensing and undersensing of atrial signals and spurious arrhythmias. The critical duration, frequency, or overall burden of AHRE that increases stroke risk is still unknown; thus, the threshold level of AHRE (duration and frequency) that warrants anticoagulation in patients with CIED-detected AHRE is still unclear. This article reviews current literature on the risk of stroke with CIED-detected AHRE and raises questions that need further clarification.

Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron.

Hypertension is among the most prevalent and catastrophic chronic diseases worldwide. While the efficacy of renin angiotensin system (RAS) blockade in lowering blood pressure illustrates that the RAS is broadly activated in human hypertension, the frequent failure of RAS inhibition to prevent or reverse hypertensive organ damage highlights the need for novel therapies to combat RAS-dependent hypertension. We previously discovered elevated levels of the macrophage cytokine IL-1 in the kidney in a murine model of RAS-mediated hypertension. Here we report that IL-1 receptor (IL-1R1) deficiency or blockade limits blood pressure elevation in this model by mitigating sodium reabsorption via the NKCC2 co-transporter in the nephron. In this setting, IL-1R1 activation prevents intra-renal myeloid cells from maturing into Ly6C(+)Ly6G(-) macrophages that elaborate nitric oxide, a natriuretic hormone that suppresses NKCC2 activity. By revealing how the innate immune system regulates tubular sodium transport, these experiments should lead to new immunomodulatory anti-hypertensive therapies.

Transcatheter intervention in cor triatriatum sinister.

Cor triatriatum sinister is a rare condition caused by a membrane in the left atrium, resulting in left ventricular inflow obstruction. This developmental anomaly is usually diagnosed in childhood. However, a rare presentation during adulthood is observed when the membrane is incomplete. Surgical excision of the membrane is the first line of treatment. We present a 51-year-old woman who underwent successful transcatheter balloon dilation with complete loss of the membrane waist and hemodynamic and symptomatic improvement.

Implantable atrial flow regulator for severe, irreversible pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe, progressive and fatal disease. The creation of an interatrial right-to-left shunt in patients with PAH may enhance systemic ventricular output at the expense of desaturation. However, creating sustainable restricted interatrial communication is challenging. We describe the successful use of an atrial flow regulator, a novel implantable atrial communication device, in a 54-year-old female with severe irreversible PAH.

Safety and effectiveness of compassionate use of LARIAT® device for epicardial ligation of anatomically complex left atrial appendages.

BACKGROUND: Percutaneous left atrial appendage (LAA) ligation using an epicardial suture system (LARIAT®, SentreHEART, Palo Alto, CA) has been used in patients with nonvalvular atrial fibrillation (AF) and contraindication to oral anticoagulation. However, complex LAA anatomy may preclude its use. We report the safety and effectiveness of compassionate use of first-generation LARIAT® device for epicardial ligation of large, complex left atrial appendages. METHODS: Between January 2010 and March 2013, 93 patients with AF, high CHADS2 score, and contraindication(s) for oral anticoagulation therapy were evaluated for LAA ligation. Complex anatomy detected by 3D cardiac computed tomography CT angiography led to preclusion of 25 patients (27%). Of these, nine patients who opted for epicardial LAA ligation on compassionate grounds were studied. RESULTS: Mean age was 68.1 ± 8.2 years, four females, all with large LAA width (>40 mm, 45-58 mm) and additional anatomic complexities such as bilobed (two), long C-shaped-like (two), goose neck-like (one), multilobed cauliflower-like (two), cactus-like (one), and chicken wing-like (one) LAA. LAA ligation with LARIAT® was successfully performed with surgical standby in all patients. Seven patients (78%) were safely treated percutaneously and only two patients required minimally invasive thoracotomy (one due to inability to release the epicardial snare from long C-shaped LAA and other due to preexisting adhesions precluding pericardial entry). There were no major complications. Repeat trans-esophageal echocardiography at 3 months showed no remnant flow and none had stroke off Coumadin at 19.3 ± 8.2 months of follow-up. CONCLUSIONS: Despite a high preclusion rate, percutaneous LAA ligation may be safely and effectively performed on compassionate grounds using the first-generation LARIAT® device with surgical standby in patients with large and complex LAA.

Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension.

Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease. In this regard, we recently identified a role for proinflammatory Th1 T-lymphocyte responses in hypertensive kidney injury. Because Th1 cells generate interferon-γ and tumor necrosis factor-α (TNF-α), we hypothesized that interferon-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system. Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking interferon-γ or TNF-α to our model of hypertensive chronic kidney disease. Interferon deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (knockout) mice had blunted hypertensive responses and reduced end-organ damage in our model. As angiotensin II-infused TNF knockout mice had exaggerated endothelial nitric oxide synthase expression in the kidney and enhanced nitric oxide bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF knockout kidneys into wild-type recipients before the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to angiotensin II and augmented renal endothelial nitric oxide synthase expression, confirming a role for kidney-derived TNF-α to promote angiotensin II-induced blood pressure elevation by limiting renal nitric oxide generation.

Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor-mediated kidney fibrosis.

In a wide array of kidney diseases, type 1 angiotensin (AT1) receptors are present on the immune cells that infiltrate the renal interstitium. Here, we examined the actions of AT1 receptors on macrophages in progressive renal fibrosis and found that macrophage-specific AT1 receptor deficiency exacerbates kidney fibrosis induced by unilateral ureteral obstruction (UUO). Macrophages isolated from obstructed kidneys of mice lacking AT1 receptors solely on macrophages had heightened expression of proinflammatory M1 cytokines, including IL-1. Evaluation of isolated AT1 receptor-deficient macrophages confirmed the propensity of these cells to produce exaggerated levels of M1 cytokines, which led to more severe renal epithelial cell damage via IL-1 receptor activation in coculture compared with WT macrophages. A murine kidney crosstransplantation concomitant with UUO model revealed that augmentation of renal fibrosis instigated by AT1 receptor-deficient macrophages is mediated by IL-1 receptor stimulation in the kidney. This study indicates that a key role of AT1 receptors on macrophages is to protect the kidney from fibrosis by limiting activation of IL-1 receptors in the kidney.

Snare coupling of the pre-pectoral pacing lead delivery catheter to the femoral transseptal apparatus for endocardial cardiac resynchronization therapy : mid-term results.

AIMS: Limitations imposed by the coronary sinus venous anatomy triggered the transseptal approach for endocardial LV lead placement. The alignment of the interatrial septum (IAS) and its neighborhood anatomy does not favor transseptal puncture from the pre-pectoral area. Locating and advancing a pre-pectoral LV lead delivery catheter (PDC) through an opening created in the IAS via femoral transseptal puncture (FTP) is time consuming and technically difficult. We describe a method where the PDC is snare coupled to the femoral transseptal apparatus (FTA). When the FTA is advanced into the left atrium (LA) the coupled PDC follows. METHODS: The catheter of a 25-mm loop snare kit is replaced with the PDC (SelectSite®). The snare loop is positioned in the right common iliac vein from the pre-pectoral access. The PDC is coupled to the FTA by advancing the transseptal apparatus through the open snare loop. After conventional FTP, the FTA is withdrawn back into the right atrium (RA) over an extra support wire positioned in the LA. The PDC with open snare loop is pulled over the FTA up to the RA. The PDC is advanced to close the snare loop on the extra support wire immediately distal to the tip of the dilator close to the puncture site. The PDC is deflected to align with the FTA. The snare coupled catheters are gently advanced across the IAS into the LA. The PDC is released from the FTA by advancing the snare and opening the loop; the snare is then removed from the PDC. The PDC is deflected and advanced into the left ventricle (LV). After positioning the 4.1 Fr lumen less LV lead, the PDC is sliced and removed. RESULTS: The PDC snare coupled to the FTA was advanced into the LA in all five patients, however, access was lost during catheter manipulation in the one right-sided case. Endocardial LV lead was successfully positioned in all five patients. CONCLUSION: Snare coupling the pre-pectoral SelectSite® catheter to the FTA is technically simple, reliable and a safe method for transseptal endocardial LV lead placement for left pre-pectoral implantation.