Case Report of Novel, Automatic Shocking Vector Adjustment Algorithm: A Life-Saving Feature of a Modern Defibrillator.

BACKGROUND: Failed delivery of appropriate shocks against fatal dysrhythmias can be the result of low impedance on high-voltage leads. This malfunction might be missed on routine interrogation. We describe the case of a 66-year-old man with a high-voltage lead short circuit who was successfully rescued with the use of an overcurrent detection and automatic shocking vector adjustment algorithm. CASE REPORT: A 66-year-old man with severe nonischemic cardiomyopathy was admitted after receiving 2 shocks from his cardiac resynchronization therapy cardioverter-defibrillator. Interrogation of his defibrillator confirmed 2 consecutive episodes of ventricular fibrillation. For each episode, the initial shock therapy was aborted due to low impedance (<10 ohms) detected on the default shocking configuration: right ventricle to superior vena cava/implantable cardioverter generator. As a result, the device algorithm excluded the superior vena cava coil and immediately delivered a shock of 40 joules between the right ventricular coil and the cardiac resynchronization therapy cardioverter-defibrillator implantable cardioverter generator. This successfully terminated the ventricular fibrillation. All other lead measurements were normal. CONCLUSION: High-voltage lead malfunctions can lead to failed therapy of life-threatening dysrhythmias. Malfunctions like a low impedance of high-voltage leads may not be detected on routine interrogation. Fortunately, the overcurrent detection algorithm recognized the low impedance, and another shocking configuration was selected and successfully terminated the ventricular dysrhythmias. With these algorithms, overcurrent detection and automatic shocking vector adjustment, this patient was rescued. We suggest this feature be considered in all modern defibrillators.

Outcomes of Early Versus Delayed Transcatheter Closure of Post-Myocardial Infarction Ventricular Septal Defect.

BACKGROUND: Post myocardial infarction ventricular septal defect (VSD) is a rare, but devastating complication which carries a poor prognosis if left untreated. Optimal therapy remains unclear and surgical repair is associated with high mortality. OBJECTIVE: The aim of our study is to compare 30-day survival in patients with early versus late primary transcatheter repair of post myocardial infarction ventricular septal defect. METHODS: We performed a comprehensive search of published data through SCOPUS and identified published reports of primary transcatheter closure of post myocardial infarction VSD. We included case reports and series that reported timing of VSD closure and 30-day survival and excluded those with prior surgical repair. Early repair was defined as transcatheter closure within 14 days of diagnosis of VSD while late repair was defined as transcatheter closure after 14 days of diagnosis of VSD. RESULTS: A total 27 publications describing 193 patients were identified in the SCOPUS search. We excluded 8 publications with no reported timing of VSD repair or 30-day outcome. Of the 193 patients initially included, a total of 126 patients fulfilled all the criteria and were included in the final analysis. The overall 30-day survival rate was found to be 62.7% (79 patients). In the early repair group, only 36.2% of the patients were still alive at 30 days compared to 85.3% in the delayed repair group, P < .01. No significant difference in age, gender, presence of shock, VSD size, presence of significant residual shunt, location of VSD or infarction was observed. The early repair group was found to have a significantly larger Qp: Qs ratio as well as larger occluder size and lower rate of successful repair. CONCLUSION: Compared to the late repair group, the early transcatheter VSD repair group had a larger pre-procedure Qp:Qs and worse 30-day survival. Further studies are needed to determine the optimal timing of transcatheter repair of a post myocardial infarction VSD.

Outcomes of transcatheter aortic valve replacement in bicuspid aortic valve stenosis.

BACKGROUND: Due to abnormal valve geometry, patients with bicuspid aortic valve (BAV) have been excluded in many transcatheter aortic valve replacement (TAVR) trials resulting in very limited data with regards to its safety and efficacy. METHODS: We searched electronic databases including Cochrane Database of Systematic Reviews, MEDLINE and EMBASE for all studies including case series, and original reports published before December 2018 that assessed outcomes following TAVR in BAV stenosis. We also included studies that had patients with TAV for comparison. Pooled effect size was calculated with a random-effect model and weighted for the inverse of variance, to compare outcomes post-TAVR between BAV and TAV. The heterogeneity of effect estimates across the studies was assessed using I2. Publication bias was assessed with funnel plots. Statistical analysis was performed using SPSS version 24 (IBM Corp., SPSS Statistics for Windows, Version 24.0. Armonk, NY.). RESULTS: A total of 19 studies describing 1,332 patients with BAV and 3,610 with TAV. There was no significant difference in the30-day mortality between patients with BAV and TAV [odds ratio (OR): 1.18, 95% confidence interval (CI): 0.7-1.7, P=0.41, I2=0]. One-year mortality rate in the BAV population was 13.1% compared to 15.4% in the TAV patients (P=0.75). Patients with BAV had significantly more moderate to severe paravalvular leak (PVL) post TAVR (PVL ≥3) 8.8% vs. 4.2% in TAV patients (OR: 1.478, 95% CI: 1.000-2.184, P=0.050, I2=0. Device success was significantly higher in TAV patients compared to BAV patients 93.5% vs. 87% (OR: 0.63, 95% CI: 0.49-0.86, P=0.003). CONCLUSIONS: TAVR in patients with BAV is associated with a high incidence of paravalvular regurgitation with a comparable 30-day mortality rate to TAV patients. The use of newer generation valve prosthesis improved outcomes.

Cocaine Positivity in ST-Elevation Myocardial Infarction: A True or False Association.

INTRODUCTION: Every year, more than 500,000 US Emergency Department visits are associated with cocaine use. People who use cocaine tend to have a lower incidence of true ST-elevation myocardial infarction (STEMI). OBJECTIVE: To identify the factors associated with true STEMI in patients with cocaine-positive (CPos) findings. METHODS: We retrospectively analyzed 1144 consecutive patients with STEMI between 2008 and 2013. True STEMI was defined as having a culprit lesion on coronary angiogram. Multivariate and univariate analyses were used to identify risk factors and create a predictive model. RESULTS: A total of 64 patients with suspected STEMI were CPos (mean age 53.1 ± 11.2 years; male = 80%). True STEMI was diagnosed in 34 patients. Patients with CPos true STEMI were more likely to be uninsured than those with false STEMI (61.8% vs 34.5%, p = 0.03) and have higher peak troponin levels (21.1 ng/mL vs 2.12 ng/mL, p = < 0.01) with no difference in mean age between the 2 groups (p = 0.24). In multivariate analyses, independent predictors of true STEMI in patients with CPos findings included age older than 65 years (odds ratio [OR] = 19.3, 95% confidence iterval [CI] = 1.2-318.3), lack of health insurance (OR = 4.9, 95% CI = 1.2-19.6), and troponin level higher than 0.05 (OR = 24.0, 95% CI = 2.6-216.8) (all p < 0.05). A multivariate risk score created with a C-statistic of 82% (95% CI = 71-93) significantly improved the identification of patients with true STEMI. CONCLUSION: Among those with suspected STEMI, patients with CPos findings had a higher incidence of false STEMI. Older age, lack of health insurance, and troponin levels outside of defined limits were associated with true STEMI in this group.

A comprehensive meta-analysis of randomized controlled trials comparing drug-eluting stents with bare-metal stents in saphenous vein graft interventions.

BACKGROUND: Several large randomized controlled trials (RCTs) have proven the superiority of drug-eluting stents (DESs) over bare-metal stents (BMSs) for native coronary stenosis. However, RCTs comparing DESs with BMSs for SVG lesions have predominantly been small in size and have yielded conflicting results. Therefore, we conducted an updated comprehensive meta-analysis of RCTs comparing DESs versus BMSs for SVG interventions using the largest sample size to date. METHODS: Scientific databases and websites were searched to find RCTs. Data from six RCTs involving 1,582 patients were included. Pooled risk ratios (RRs) were calculated using random-effects models. The primary outcome of this meta-analysis was target vessel revascularization (TVR). The secondary outcomes were major adverse cardiac events (MACEs), myocardial infarction (MI), stent thrombosis, all-cause mortality, and cardiac mortality. RESULTS: Data from six RCTs involving 1,582 patients were included. Saphenous vein graft interventions with DESs reduced TVR (RR, 0.52; 95% CI, 0.30-0.88; P = 0.017) and MACE rate (RR, 0.60; 95% CI, 0.42-0.87; P = 0.007) compared to BMSs. No difference between the stents were found in rates of MI (RR, 0.69; 95% CI, 0.43-1.10; P = 0.123), stent thrombosis (RR, 0.61; 95% CI, 0.27-1.41; P = 0.255), all-cause mortality (RR, 1.13; 95% CI, 0.74-1.71; P = 0.554), or cardiac mortality. CONCLUSION: For SVG intervention, the MACE rate was lower for DESs compared to BMSs, driven primarily by decreased non-MI-related TVR. Rates of MI, all-cause mortality, cardiac mortality, and stent thrombosis were not different between the stents.

Accurate Prediction of False ST-Segment Elevation Myocardial Infarction: Ready for Prime Time?

The incidence of inappropriate cardiac catheterization lab activation for treatment of a false ST-segment elevation myocardial infarction (STEMI) has been reported to be 2.6%-36%. Excessive inappropriate catheterization lab activation may be associated with risks to patients, provider fatigue and improper resource usage. HYPOTHESIS: To derive and validate a prediction score to more accurately classify patients with STEMI. METHODS AND RESULTS: We conducted a retrospective cohort analysis of 1144 consecutive patients initially diagnosed with STEMI between September 2008 and January 2013. The incidence of catheterization laboratory activation for false STEMI was 21.4%. Multiple logistic regression identified 8 factors as important for prediction of false STEMI. Using a prediction rule derived from these factors, the area under the curve for differentiating false from true STEMI patients was 0.80 (95% CI: 0.75-0.84). Using objective standards, criteria were defined that had 95% specificity for detecting patients with an incorrect diagnosis of STEMI. IN CONCLUSION: A prediction rule has been derived and validated in a large, racially diverse group to identify false STEMI patients with an incorrect classification rate of 5%, which is an improvement over current clinical practice. Prediction rules may be particularly useful in patients with atypical presentations in which emergent catheterization cannot be achieved rapidly or carries significant patient risk.

Stress-induced thrombus: prevalence of thromboembolic events and the role of anticoagulation in Takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy (TCM), also known as stress-induced cardiomyopathy has a favorable prognosis with expected recovery in weeks. Left ventricular (LV) thrombus is a known complication of TCM, which can lead to embolization and potentially a stroke. The prevalence of LV thrombus and the role of anticoagulation have yet to be fully defined in this condition. METHODS: We performed a search of published literature through PubMed and Scopus, which identified 282 patients with TCM in whom the incidence of LV thrombus and/or thromboembolic event was reported. In order to contrast this to the current anticoagulation strategy of atrial fibrillation, the occurrence of LV thrombus was compared to the adjusted stroke rate using the CHADS2 score. RESULTS: Of the 282 patients identified through a literature search, 26 (9.2%) were noted to have a thromboembolic event in the setting of TCM. The incidence of thromboembolic event ranged from 5.3% to as high as 14.3%. When compared to the CH2sDS2-VASc score, the average incidence of LV thrombus in our study equated to a score between 4 and 5. CONCLUSIONS: While the occurrence of LV thrombus in TCM is variable among studies, the average incidence remains relatively high. Thus, making LV thrombus a significant complication of stress-induced cardiomyopathy. Prophylactic anticoagulation until recovery may have a role in reducing the rate of LV thrombus. Further studies will be needed to determine the rate of embolization and utility of anticoagulation in TCM.

Simultaneous acute cardio-cerebral infarction: is there a consensus for management?

Acute ischemic stroke (AIS) and acute myocardial infarction (AMI) are both life-threatening medical conditions with narrow therapeutic time-window that carry grave prognosis if not addressed promptly. The acute management of both condition is well documented in the literature, however the management of a simultaneous presentation of both AIS and AMI is unclear. A delayed intervention of one infarcted territory for the other may result in permanent irreversible morbidity or disability, and even death. In addition, the use of antiplatelet and anticoagulants that are inherently part of an AMI management may increase the risk for hemorrhagic conversion associated with intravenous thrombolysis used in AIS, and the use of a thrombolytic in AIS increases the risk of cardiac wall rupture in the setting of an AMI. Despite this ambiguity, there is no clear evidence-based guideline or clinical studies that have addressed the optimal management of this rare co-occurrence. This review paper examines the existing literature on the management of simultaneous acute cardio-cerebral infarction (CCI) and highlights the existing challenge to management.

Outcomes following transcatheter aortic valve replacement in patients with native aortic valve regurgitation.

Due to the absence of annular calcification for device anchoring, it is presumed that transcatheter aortic valve replacement (TAVR) is not suitable for the treatment of native aortic valve regurgitation (NAVR) resulting in very limited data and experience concerning its safety and efficacy. We sought to review published data on the safety and efficacy of TAVR in high-risk patients with NAVR. Studies including case reports, case series and original articles published between 2002 and 2016 on TAVR in patients with NAVR were identified with a systematic electronic search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Only studies reporting data on demographic and procedural characteristics, management and follow up outcomes were analyzed. A total of 30 publications describing 182 patients were identified. Most patients (54%) were men, with a mean age of 70.1±2.6 years, mean logistic European System for Cardiac Operative Risk Evaluation score (EuroSCORE) of 21.8%±4.5% and mean Society of Thoracic Surgeons (STS) score of 8%±1.8% for mortality. The majority (87%) of patients had severe NAVR with no valvular calcification. TAVR was mostly performed through the femoral (58.8%) and apical (33.1%) approach. Device success, defined by VARC-2, was achieved in 86.3% of our study population. A second valve was required in 17 patients (9.3%) during the index procedure for residual aortic regurgitation or malposition. Post-procedure aortic regurgitation of grade 1 or less was present in 80 patients (81%). Pacemaker implantation was required post procedure in 17 patients (9.3%). The 30-day and 1-year mortality was 11.9% and 16.2%, respectively. TAVR is associated with favorable pacemaker implantation and 1-year mortality rates with a high 30-day mortality among selected patients with NAVR.

Cannabinoids and Symptomatic Bradycardia.

Cannabinoids, the bioactive components of marijuana, have adverse cardiovascular consequences, including symptomatic sinus bradycardia, sinus arrest and ventricular asystole. Physicians should be aware of these deleterious consequences which can appear in otherwise healthy persons who are chronic marijuana users.

Impact of Pre-existing Kidney Dysfunction on Outcomes Following Transcatheter Aortic Valve Replacement.

BACKGROUND: Pre-existing chronic kidney disease (CKD) portends adverse outcomes following heart valve surgery. However, only limited and conflicting evidence is available on the impact of CKD on outcomes following transcatheter aortic valve replacement (TAVR). The objective of this review was to evaluate the effect of pre-existing CKD on TAVR outcomes. METHODS: We performed a systematic electronic search using the PRISMA statement to identify all randomized controlled trials and observational studies investigating the effect of pre-existing CKD on outcomes following TAVR. 30-day and long-term outcomes were measured comparing patients with Glomerular filtration rate (GFR) ≥60 to those with GFR <60. RESULTS: Ten studies were analyzed comprising of 8688 patients. Compared to patients with GFR ≥60, those with GFR < 60 had worse 30-day all cause mortality (OR 1.40, 95% CI: 1.13-1.73), cardiovascular mortality (OR 1.66, 95% CI: 1.04-2.67), strokes (OR 1.39, 95% CI: 1.05-1.85), acute kidney injury (OR 1.42, 95% CI: 1.21-1.66) and the risk for dialysis (OR 2.13, 95% CI: 1.07-4.22). There was no difference in device success (p=0.873), major or life threatening bleeds (p = 0.302), major vascular complications (p=0.525), need for pacemaker implantation (p = 0.393) or paravalvular leaks (p = 0.630). All-cause mortality at 1 year was also significantly higher in patients with GFR <60 (OR 1.80, 95% CI: 1.26-2.56). CONCLUSION: Pre-existing CKD defined as GFR <60 is a strong predictor of worse short and longterm outcomes following TAVR. Active measures should be taken to mitigate the postprocedure risk in these group of patients.

Racial Difference in Symptom Onset to Door Time in ST Elevation Myocardial Infarction.

BACKGROUND: There are poorer outcomes following ST elevation myocardial infarction in blacks compared to white patients despite comparable door-to-reperfusion time. We hypothesized that delays to hospital presentation may be contributory. METHODS AND RESULTS: We conducted a retrospective analysis of the 1144 patients admitted for STEMI in our institution from 2008 to 2013. The door-to-balloon time (D2BT) and symptom-onset-to-door time (SODT) were compared by race. Bivariate analysis was done comparing the median D2BT and SODT. Stratified analyses were done to evaluate the effect of race on D2BT and SODT, accounting for insurance status, age, sex and comorbidities. The mean age was 59±13 years; 56% of this population was black and 41% was white. Males accounted for 66% of this population. The median D2BT was 60 minutes (interquartile range [IQR] 42-82), and median SODT was 120 minutes (IQR 60-720). There was no significant difference in D2BT by race (P=0.86). Black patients presented to the emergency room (ER) later than whites (SODT=180 [IQR 60-1400] vs 120 [IQR 60-560] minutes, P<0.01) and were more likely to be uninsured (P<0.01). After controlling for comorbidities, insurance, and socioeconomic status, blacks were 60% more likely to present late after a STEMI (OR 1.6, P<0.01). A subset analysis excluding transferred patients showed similar results. CONCLUSIONS: Black patients present later to the ER after STEMI with no difference in D2BT compared to whites. This difference in time to presentation may be one of the factors accounting for poor outcomes in this population.

A Case of Isolated Coronary Artery Ectasia in the Setting of Chronic Inflamation From human Immunodeficiency Virus Infection.

Coronary artery ectasia also known as dilated coronopathy is a relatively rare finding that is most commonly associated with atherosclerosis. Several alternative reasons including congenital malformations and chronic inflammation have been identified as a cause of CAE. In this case, we discuss a 61-year-old male with postoperative chest pain who was found to have localized CAE in the absence of significant atherosclerosis. We also elucidate the recently proposed markers of chronic inflammation that might be associated with coronary artery ectasia.

Atrophied cardiomyocytes and their potential for rescue and recovery of ventricular function.

Cardiomyocytes must be responsive to demands placed on the heart's contractile work as a muscular pump. In turn, myocyte size is largely dependent on the workload they perform. Both hypertrophied and atrophic myocytes are found in the normal and diseased ventricle. Individual myocytes become atrophic when encumbered by fibrillar collagen, such as occurs at sites of fibrosis. The mechanisms include: (a) being immobilized and subject to disuse with ensuing protein degradation mediated by redox-sensitive, proteolytic ligases of the ubiquitin-proteasome system and (b) dedifferentiated re-expressing fetal genes induced by low intracellular triiodothyronine (T3) via thyroid hormone receptor ß1. This myocyte-selective, low T3 state is a consequence of heterocellular signaling emanating from juxtaposed scar tissue myofibroblasts and their secretome with its de novo generation of angiotensin II. In a paracrine manner, angiotensin II promotes myocyte Ca(2+) entry and subsequent Ca(2+) overload with ensuing oxidative stress that overwhelms antioxidant defenses to activate deiodinase-3 and its enzymatic degradation of T3. In the failing heart, atrophic myocytes represent an endogenous population of viable myocytes which could be rescued to augment contractile mass, reduce systolic wall stress (afterload) and recover ventricular function. Experimental studies have shown the potential for the rescue and recovery of atrophic myocytes in rebuilding the myocardium--a method complementary to today's quest in regenerating myocardium using progenitor cells.

Myofibroblast secretome and its auto-/paracrine signaling.

Myofibroblasts (myoFb) are phenotypically transformed, contractile fibroblast-like cells expressing α-smooth muscle actin microfilaments. They are integral to collagen fibrillogenesis with scar tissue formation at sites of repair irrespective of the etiologic origins of injury or tissue involved. MyoFb can persist long after healing is complete, where their ongoing turnover of collagen accounts for a progressive structural remodeling of an organ (a.k.a. fibrosis, sclerosis or cirrhosis). Such persistent metabolic activity is derived from a secretome consisting of requisite components in the de novo generation of angiotensin (Ang) II. Autocrine and paracrine signaling induced by tissue AngII is expressed via AT1 receptor ligand binding to respectively promote: i) regulation of myoFb collagen synthesis via the fibrogenic cytokine TGF-ß1-Smad pathway; and ii) dedifferentiation and protein degradation of atrophic myocytes immobilized and ensnared by fibrillar collagen at sites of scarring. Several cardioprotective strategies in the prevention of fibrosis and involving myofibroblasts are considered. They include: inducing myoFb apoptosis through inactivation of antiapoptotic proteins; AT1 receptor antagonist to interfere with auto-/paracrine myoFb signaling or to induce counterregulatory expression of ACE2; and attacking the AngII-AT1R-TGF-ß1-Smad pathway by antibody or the use of triplex-forming oligonucleotides.

Novel role for p21-activated kinase 2 in thrombin-induced monocyte migration.

To understand the role of thrombin in inflammation, we tested its effects on migration of THP-1 cells, a human monocytic cell line. Thrombin induced THP-1 cell migration in a dose-dependent manner. Thrombin induced tyrosine phosphorylation of Pyk2, Gab1, and p115 RhoGEF, leading to Rac1- and RhoA-dependent Pak2 activation. Downstream to Pyk2, Gab1 formed a complex with p115 RhoGEF involving their pleckstrin homology domains. Furthermore, inhibition or depletion of Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA, or Pak2 levels substantially attenuated thrombin-induced THP-1 cell F-actin cytoskeletal remodeling and migration. Inhibition or depletion of PAR1 also blocked thrombin-induced activation of Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA, and Pak2, resulting in diminished THP-1 cell F-actin cytoskeletal remodeling and migration. Similarly, depletion of Gα12 negated thrombin-induced Pyk2, Gab1, p115 RhoGEF, Rac1, RhoA, and Pak2 activation, leading to attenuation of THP-1 cell F-actin cytoskeletal remodeling and migration. These novel observations reveal that thrombin induces monocyte/macrophage migration via PAR1-Gα12-dependent Pyk2-mediated Gab1 and p115 RhoGEF interactions, leading to Rac1- and RhoA-targeted Pak2 activation. Thus, these findings provide mechanistic evidence for the role of thrombin and its receptor PAR1 in inflammation.

The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis.

The enzyme 15-lipoxygenase (15-LO) plays a role in atherogenesis (also known as atherosclerosis), but the underlying mechanisms are unclear. We found that 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], the major 15-LO-dependent metabolite of arachidonic acid, stimulated the production of reactive oxygen species (ROS) by monocytes through the xanthine oxidase-mediated activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS production led to the Syk-, Pyk2-, and mitogen-activated protein kinase (MAPK)-dependent production of the proinflammatory cytokine interleukin-17A (IL-17A) in a manner that required the transcription factor CREB (cyclic adenosine monophosphate response element-binding protein). In addition, this pathway was required for the 15(S)-HETE-dependent migration and adhesion of monocytes to endothelial cells. Consistent with these observations, we found that peritoneal macrophages from apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (a mouse model of atherosclerosis) exhibited increased xanthine oxidase and NADPH oxidase activities; ROS production; phosphorylation of Syk, Pyk2, MAPK, and CREB; and IL-17A production compared to those from similarly fed ApoE-/-:12/15-LO-/- mice. These events correlated with increased lipid deposits and numbers of monocytes and macrophages in the aortic arches of ApoE-/- mice, which resulted in atherosclerotic plaque formation. Together, these observations suggest that 15(S)-HETE exacerbates atherogenesis by enhancing CREB-dependent IL-17A production and inflammation.

Protein kinase N1 is a novel substrate of NFATc1-mediated cyclin D1-CDK6 activity and modulates vascular smooth muscle cell division and migration leading to inward blood vessel wall remodeling.

Toward understanding the mechanisms of vascular wall remodeling, here we have studied the role of NFATc1 in MCP-1-induced human aortic smooth muscle cell (HASMC) growth and migration and injury-induced rat aortic wall remodeling. We have identified PKN1 as a novel downstream target of NFATc1-cyclin D1/CDK6 activity in mediating vascular wall remodeling following injury. MCP-1, a potent chemoattractant protein, besides enhancing HASMC motility, also induced its growth, and these effects require NFATc1-dependent cyclin D1 expression and CDK4/6 activity. In addition, MCP-1 induced PKN1 activation in a sustained and NFATc1-cyclin D1/CDK6-dependent manner. Furthermore, PKN1 activation is required for MCP-1-induced HASMC growth and migration. Balloon injury induced PKN1 activation in NFAT-dependent manner and pharmacological or dominant negative mutant-mediated blockade of PKN1 function or siRNA-mediated down-regulation of its levels substantially suppressed balloon injury-induced smooth muscle cell migration and proliferation resulting in reduced neointima formation. These novel findings suggest that PKN1 plays a critical role in vascular wall remodeling, and therefore, it could be a promising new target for the next generation of drugs for vascular diseases, particularly restenosis following angioplasty, stent implantation, or vein grafting.