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Biomedical subjects

Carlos A Molina

Publications and source records attributed to Carlos A Molina.

At least 19 recordsLinked to original sources
PubMed2007

Monitoring and imaging the clot during systemic thrombolysis in stroke patients.

Intravenous thrombolysis is the only approved treatment for acute ischemic stroke when administered within the first 3 h of stroke onset. Response to systemic thrombolysis depends on several factors including the location of arterial occlusion, clot characteristics and, ultimately, the embolic source. In the last few years, tremendous progress has been made, resulting in the widespread implementation of noninvasive neurovascular techniques. These imaging modalities are being increasingly performed in the acute stroke setting, without substantial delay, in a large number of centers worldwide. Transcranial Doppler ultrasound provides a unique opportunity to assess several aspects of clot dissolution by means of continuous monitoring of recanalization during and after tissue plasminogen activator administration. This approach allows for the evaluation of patients at the bedside and in real time due to the commencement, timing, speed and degree of artery reopening in addition to allowing the documentation of reocclusion after successful recanalization. Gradient refocused echo susceptibility vessel sign (GRE SVS) magnetic resonance imaging may be particularly useful for the identification of an intravascular thrombus during the acute phase of ischemic stroke; GRE SVS may represent a surrogate of clot composition and differential response to thrombolysis. The increasing availability of advanced neurovascular techniques may, in the near future, improve the design of stroke trials. The capability of these techniques to assess not only tissue viability but also key aspects regarding susceptibility to thrombolysis such as location, amount, composition, and age of the offending clot may improve the safety and efficacy profile of thrombolytic therapy for acute ischemic stroke.

Humans↗
PubMed2006

Clinical deterioration after intravenous recombinant tissue plasminogen activator treatment: a multicenter transcranial Doppler study.

BACKGROUND AND PURPOSE: Patients may experience clinical deterioration (CD) after treatment with intravenous recombinant tissue plasminogen activator (rt-PA). We evaluated the ability of flow findings on transcranial Doppler to predict CD and outcomes on modified Rankin Scale. METHODS: Patients with acute stroke received intravenous rt-PA within 3 hours of symptom onset at four academic centers. CD was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score by 4 points or more within 24 hours. Poor long-term outcome was defined by modified Rankin Scale > or =2 at 3 months. Transcranial Doppler findings were interpreted using the Thrombolysis in Brain Ischemia flow grading system as persistent arterial occlusion, reocclusion, or complete recanalization. Multiple regression analysis was used to identify transcranial Doppler flow as a predictor for CD after controlling for age, sex, baseline NIHSS, hypertension, and glucose. RESULTS: A total of 374 patients received intravenous rt-PA at 142+/-60 minutes (median pretreatment NIHSS score 16 points). At the end of intravenous rt-PA infusion, transcranial Doppler showed persistent arterial occlusion in 219 patients (59%), arterial reocclusion in 54 patients (14%), and complete recanalization in 101 patients (27%). CD occurred in 44 patients: 36 had persistent arterial occlusion or reocclusion (82%), 13 symptomatic intracerebral hemorrhage (29%), and both persistent occlusion/reocclusion and symptomatic intracerebral hemorrhage in 10 patients (23%). After adjustment, patient risk for CD with persistent occlusion was OR 1.7 (95% CI: 0.7 to 4) and with arterial reocclusion 4.9 (95% CI: 1.7 to 13) (P=0.002). Patient risk for poor long-term outcomes with persistent occlusion, partial recanalization, or reocclusion was OR 5.2 (95% CI: 2.7 to 9, P=0.001). CONCLUSIONS: Inability to achieve or sustain vessel patency at the end of rt-PA infusion correlates with the likelihood of clinical deterioration and poor long-term outcome. Early arterial reocclusion on transcranial Doppler is highly predictive of CD and poor outcome.

Adult↗
PubMed2006

Transcranial Doppler monitoring of transcervical carotid stenting with flow reversal protection: a novel carotid revascularization technique.

BACKGROUND AND PURPOSE: Transfemoral carotid stenting, despite becoming very frequent, has some limitations such as difficult groin access in few patients, lack of distal protection during filter placement, or embolization despite protection. Transcervical stenting (TCS) is a novel technique during which a common carotid to jugular vein shunt is placed creating a protective reversal flow in the internal carotid artery after proximal common carotid artery (CCA) clamping. We aim to study, with transcranial Doppler (TCD), cerebral flow changes and microemboli detection during transcervical stenting. METHODS: From September 2005 to March 2006, of 65 consecutive patients eligible for carotid revascularization, 23 were considered high risk (sapphire criteria) and underwent TCS. Neurologic examination was performed before and after the procedure by a neurologist and a preprocedure vascular reactivity TCD examination was done in all patients. RESULTS: After CCA clamping, flow inversion was observed in the anterior cerebral artery, supplying blood to the middle cerebral artery (MCA) and internal carotid artery (reversal). TCD did not detect any air/solid emboli during stent deployment and angioplasty confirming the reversal flow protection hypothesis. Mean reversal flow time was 15.4 minutes; in all cases, substantial MCA flow was present during CCA clamping (initial mean velocity 30 cm/s), and a slow gradual increase was observed traducing collateral flow recruitment (mean velocity after 5 minutes 36 cm/s, P<0.001). Flow increase was observed in all patients except in those with preprocedural exhausted ipsilateral vascular reactivity (16% versus 2%, P=0.036). The only in-procedure complication was one transient ischemic attack. After CCA unclamping, normal antegrade flow was restored in anterior cerebral artery and mean final MCA velocity increased 16% according to preprocedure flow. CONCLUSIONS: TCS with protective internal carotid artery flow reversal can eliminate showers of micoremboli during stent deployment making it a promising carotid revascularization technique in high-risk patients with carotid stenosis.

Aged↗
PubMed2006

Plasma S100B level after acute spontaneous intracerebral hemorrhage.

BACKGROUND AND PURPOSE: We sought to determine plasma S100B level after acute (<24 hours) spontaneous intracerebral hemorrhage (ICH) and to study its relation with neurological outcome. METHODS: We determined S100B concentration on plasma samples from 78 ICH patients on admission. Clinical (Glasgow Coma Scale and National Institutes of Health Stroke Scale [NIHSS] scores) and radiological information (ICH and perihematomal edema volumes) were collected at baseline and follow-up visits. Early neurological deterioration, defined as the increase of >or=4 points in the NIHSS score at 48 hours, and unfavorable outcome (modified Rankin Scale >2) at 3 months were also recorded. RESULTS: The median S100B level was higher than our laboratory reference values for healthy controls (103.6 versus 48.5 pg/mL; P<0.001) and a positive correlation was observed between S100B level and baseline ICH volume (r=0.45; P<0.0001). The median S100B level was higher in patients who deteriorated early (256.8 versus 89.7 pg/mL; P=0.001) and also in patients with an unfavorable outcome (136 versus 75.9 pg/mL; P=0.003). Multivariate analysis showed baseline ICH volume as the best predictor for both early neurological deterioration (odds ratio 15; 95% CI, 2.9 to 76.3) and unfavorable outcome at 3 months (odds ratio 17; 95% CI, 2.0 to 142). CONCLUSIONS: Increased S100B level is found after acute spontaneous ICH, in association with a worse early and late evolution, and closely related to initial hematoma volume.

Acute Disease↗
PubMed2006

Does clinical-CT 'mismatch' predict early response to treatment with recombinant tissue plasminogen activator?

BACKGROUND: We hypothesized that patients with clinically severe strokes but less severe early ischemic changes on brain CT (i.e., clinical-CT mismatch) may respond better to intravenous recombinant tissue plasminogen activator (i.v. rt-PA) within 3 h of symptom onset. METHODS: In this secondary analysis of the CLOTBUST data, patients with middle cerebral artery occlusions on transcranial Doppler (TCD) were treated with i.v. rt-PA. Alberta Stroke Program Early CT Scores were obtained with raters blinded to the NIH Stroke Scale and TCD results. Two mismatch criteria and three criteria of response to therapy were explored. RESULTS: Of 126 patients, 67% had a mismatch type 1 and 74% had a mismatch type 2. The presence of clinical-CT mismatch by either definition did not correlate with any of the three criteria of response to rt-PA. Recanalization was a strong determinant of response, whether or not mismatch was present. CONCLUSIONS: Mismatch between severity of neurological deficit and CT findings is common but does not predict response to rt-PA therapy given within 3 h.

Brain Ischemia↗
PubMed2006

Tandem internal carotid artery/middle cerebral artery occlusion: an independent predictor of poor outcome after systemic thrombolysis.

BACKGROUND AND PURPOSE: Although tandem internal carotid artery/middle cerebral artery (MCA; TIM) occlusion has been associated with low recanalization rate after IV tissue plasminogen activator (tPA), its independent contribution on stroke outcome remains unknown. Moreover, whether the relative resistance to thrombolysis in tandem lesions varies depending on the location of MCA clot remains uncertain. METHODS: Two hundred and twenty-one consecutive stroke patients with an acute MCA occlusion treated with IV tPA were studied. Emergent carotid artery ultrasound and transcranial Doppler (TCD) examinations were performed in all patients before treatment. Recanalization was assessed on TCD at 2 hours of tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and after 24 hours. Modifed Rankin Scale score was used to assess outcome at 3 months. RESULTS: Median prebolus NIHSS score was 16 points. On TCD, 156 (71.6%) patients had a proximal and 65 (29.4%) a distal MCA occlusion. TIM occlusion was identified in 44 (19.9%) patients. Eighteen (41.9%) patients with and 123 (69.5%) without TIM lesions achieved an MCA recanalization (P=0.01). In a logistic regression model, hyperglycemia >140 mg/dL (odds ratio [OR] 3.3, 95% CI, 1.6 to 6.8) and the presence of TIM occlusion (OR 2.8, 95% CI, 1.1 to 6.9) emerged as independent predictors of absence of recanalization. However, the independent contribution of TIM lesions on poor response to thrombolysis varied depending on the location of MCA occlusion. TIM occlusion independently predicted resistance to thrombolysis in patients with proximal (OR 4.63, 95% CI, 1.79 to 11.96), but not in those with distal MCA occlusion. Patients with TIM occlusion had worse short- (P<0.0001) and long-term (P<0.0001) clinical outcome. CONCLUSIONS: TIM occlusion independently predicts poor outcome after IV thrombolysis. However, its impact varies depending on the location of MCA clot. Therefore, emergent carotid ultrasound plus TCD examinations may improve the selection of patients for more aggressive reperfusion strategies.

Adult↗
PubMed2006

Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke.

BACKGROUND AND PURPOSE: Abnormal expression of some matrix metalloproteinases (MMP) has shown to play a deleterious role in brain injury in experimental models of cerebral ischemia. We aimed to investigate MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in brain parenchyma in both ischemic and hemorrhagic strokes. METHODS: Postmortem fresh brain tissue from 6 ischemic and 8 hemorrhagic stroke patients was obtained within the first 6 hours after death. Finally, 78 brain tissue samples from different areas (infarct, peri-infarct, perihematoma and contralateral hemisphere) were studied. To quantify gelatinase content we performed gelatin zymograms that were confirmed by Western Blot Analysis, immunohistochemistry to localize MMP source, and in situ zymography to detect gelatinase activity. RESULTS: Among ischemic cases, gelatin zymography showed increased MMP-9 content in infarct core although peri-infarct tissue presented also higher levels than contralateral hemisphere (P<0.0001 and P=0.042, respectively). Within infarct core, MMP-9 was mainly located around blood vessels, associated to neutrophil infiltration and activated microglial cells. In peri-infarct areas the major source of MMP-9 were microglial cells. Tissue around intracranial hemorrhage also displayed higher MMP-9 levels than contralateral hemisphere (P=0.008) in close relationship with glial cells. MMP-2 was constitutively expressed and remained invariable in different brain areas. CONCLUSIONS: Our results demonstrate in situ higher levels of MMP-9 in human brain tissue after ischemic and hemorrhagic stroke, suggesting a contribution of MMP-9 to ischemic brain injury and perihematoma edema.

Aged↗
PubMed2006

Transcriptional regulation of cyclin D2 by the PKA pathway and inducible cAMP early repressor in granulosa cells.

Cyclin D2 (Ccnd2) is an essential gene for folliculogenesis, as null mutation in mice impairs granulosa cell proliferation in response to FSH. Ccnd2 mRNA is induced during the estrus cycle by FSH and is rapidly inhibited by LH. Yet, the responsive elements and transcription factors accounting for the gene expression of cyclin D2 in the ovary have not been fully characterized. Using primary cultures of rat granulosa cells and immortalized mouse granulosa cells, we demonstrate a mechanism for the regulation of cyclin D2 at the level of transcription via a PKA-dependent signaling mechanism. The promoter activity of cyclin D2 was shown to be induced by FSH and the catalytic alpha subunit of PKA (PRKACA), and this activity was repressible by inducible cAMP early repressor (ICER), a cAMP response element (CRE) modulator isoform. In silico analysis of the mouse, rat, and human cyclin D2 promoters identified two CRE-binding protein sites, a conserved proximal element and a less conserved distal element relative to the translation start site. The mutation on the proximal element drastically decreases the effects of PRKACA and ICER on the promoter activity, whereas the mutation on the distal element did not contribute to the decrease in the promoter activity. Electrophoretic mobility shift assays and deoxyribonuclease footprint analysis confirmed ICER binding to the proximal element, and chromatin immunoprecipitation analysis demonstrated the occurrence of this binding in vivo. These results showed a CRE within the upstream region of Ccnd2 that is (at least partly) implicated in the stimulation and repression of cyclin D2 transcription. Finally, our data suggest that ICER involvement in the regulation of granulosa cell proliferation as overexpression of ICER results in the inhibition of PRKACA-induced DNA synthesis.

Animals↗
PubMed2006

Poststroke C-reactive protein is a powerful prognostic tool among candidates for thrombolysis.

BACKGROUND AND PURPOSE: After acute stroke, an increased level of C-reactive protein (CRP) measured at discharge predicts unfavorable outcome. We sought to investigate whether CRP measured before tissue plasminogen activator (tPA) treatments may add prognostic information to guide stroke thrombolysis. METHODS: Our target was 151 consecutive patients with an ischemic stroke involving the middle cerebral artery territory who received tPA within 3 hours of symptom onset. High-sensitivity CRP was measured before tPA administration, and CRP gene polymorphisms were determined (G1059C and C1444T). Functional outcome was evaluated by 3-month modified Rankin Scale (mRS). RESULTS: A total of 143 tPA-treated patients were valid for analyses after exclusion of those with inflammatory diseases and those probably infected (CRP >6 mg/dL). Patients with history of previous stroke, hypertension, or atrial fibrillation had higher levels of CRP (P<0.05). CRP was higher in patients who died after thrombolysis (n=19) than in survivors (0.85 versus 0.53 mg/dL; P=0.002). Among the 94 patients with proximal middle cerebral artery occlusions, CRP level was 0.53 for 81 survivors versus 0.81 mg/dL for 13 who died (P=0.001). CRP-survival association was found even among patients who recanalized by the end of tPA infusion (P=0.007). A correlation between CRP and mRS was found (r=0.36, P=0.02), although CRP polymorphisms were not related to neurological outcome. In a logistic regression model, CRP (odds ratio=8.51; 95% CI, 2.16 to 33.5; P=0.002) and age (odds ratio=6.25; 95% CI, 1.44 to 27.19; P=0.015) were the only baseline mortality predictors. CONCLUSIONS: Admission CRP predicts mortality among tPA-treated stroke patients. Very early recanalization does not ameliorate the negative prognostic impact of elevated CRP.

Aged↗
PubMed2006

Temporal profile of recanalization after intravenous tissue plasminogen activator: selecting patients for rescue reperfusion techniques.

BACKGROUND AND PURPOSE: Intravenous thrombolysis in stroke achieves arterial recanalization in approximately 50% of cases. Determining temporal profile of recanalization may address patient selection and potential benefits of further rescue reperfusion techniques. METHODS: We studied 179 consecutive intravenous tissue plasminogen activator (t-PA)-treated patients with intracranial artery occlusion. Continuous transcranial Doppler assessed recanalization (none-partial-complete) at 60 minutes (early), 120 minutes (delayed) after t-PA bolus, and 6 hours (late) from symptom onset. Outcomes were determined: National Institutes of Health Stroke Scale (NIHSS; 48-hour NIHSS) and 3-month modified Rankin Scale (mRS). RESULTS: On admission, 68% of patients presented proximal middle cerebral artery occlusion, median NIHSS 17. Early recanalization was complete for 30 patients (17%), partial for 50 (28%), and none for 99 (55%). Delayed recanalization was complete for 56 patients (31%), partial for 39 (22%), and none for 84 (47%). Although early flow improvement was observed in up to 45% of patients, only 19% of patients with persistent occlusion (11% of total) presented delayed recanalization (odds ratio [OR] delayed/early recanalization, 0.16; 95% CI, 0.085 to 0.304; P<0.001). Among patients with persistent occlusion at 2 hours, only 13 (7% of total) presented late flow improvement (OR late/early recanalization, 0.09; 95% CI, 0.043 to 0.196; P<0.001). The few patients with late recanalization presented comparable median 48-hour NIHSS to those with early/delayed recanalization (3 versus 4.5; P=0.9) and much lower than those with persistent occlusion after 6 hours (3 versus 15; P=0.005). At 3 months, the rate of mRS < or =2 was not statistically different between patients with early/delayed versus late recanalization (55% versus 86%; P=0.12) but was lower if occlusion persisted 6 hours after onset (22%; P<0.001). CONCLUSIONS: The majority of t-PA-induced recanalizations occur during the first hour after treatment. Recanalizations during the following hours are rare but still related to clinical improvement if achieved within 6 hours from onset. Rescue reperfusion techniques should be considered if flow improvement is not observed 60 minutes after t-PA bolus.

Adult↗
PubMed2006

Stroke patients with cardiac atrial septal abnormalities: differential infarct patterns on DWI.

BACKGROUND: Stroke mechanism in patent foramen ovale (PFO) and/or atrioseptal aneurysm (ASA) remains unclear. We aimed to study the stroke pattern on diffusion weighted imaging (DWI), in cryptogenetic stroke according to septal abnormalities. METHODS: We prospectively evaluated 314 cryptogenetic strokes. Patients were categorized according to transesophageal echocardiography (TEE) findings: PFO with ASA, PFO alone, and no abnormalities. The study group consisted of 126 patients with acute DWI lesions within the first 7 days after the stroke onset. We considered the presence of scattered lesions or a cortico-subcortical territorial lesion as highly suggestive of an embolic pattern. RESULTS: PFO was identified in 77 patients (61%) and no alterations in 49 patients (39%). TEE revealed ASA in 42 patients (54.5% of PFO patients). An "embolic" pattern was depicted in 84 (66.7%) and subcortical in 42 (33.3%). An "embolic" pattern was significantly (P= .01) more frequently seen in PFO with ASA patients (n= 37;44%) as compared to PFO without ASA (n= 22; 26.2%) or no abnormalities (n= 25; 29.8%) on TEE. Univariate analysis revealed that age (P= .06), hyperlipidemia (P= .04), degree of shunt on TEE (P= .002), and the presence of an ASA (P= .008) were associated with an embolic pattern. After adjusting for sex, age, and vascular risk factors, only the presence of PFO, with ASA (OR 7.27; 95% CI 1.5-35.22 P= .014) was independently associated with an embolic pattern. CONCLUSION: In patients with cryptogenetic stroke, the presence of PFO with ASA, but not isolated PFO, is associated with an embolic pattern on DWI. These findings provide insights into the patho-mechanism of stroke in patients with PFO.

Brain↗
PubMed2006

Flow diversion in transcranial Doppler ultrasound is associated with better improvement in patients with acute middle cerebral artery occlusion.

BACKGROUND: Flow diversion (FD) can occur with an acute middle cerebral artery (MCA) occlusion. FD is thought to represent the collateral blood flow to the occluded MCA territory, but it is unclear whether or not FD lessens the stroke severity or leads to improved outcome. METHODS: Patients with a proximal MCA occlusion were selected from the CLOTBUST trial data bank. FD to the anterior or posterior cerebral artery was determined using transcranial Doppler ultrasound. Stroke severity and clinical improvement were measured using the National Institutes of Health Stroke Scale (NIHSS) scores. RESULTS: We evaluated 47 patients with an isolated M1 MCA occlusion who received intravenous tissue-type plasminogen activator (t-PA) within 3 h of symptom onset. FD was present in 83% of the patients. Median baseline NIHSS scores were 15.5 in the FD- group and 18 in the FD+ group (n.s.). Complete recanalization rates were 25 and 25.6% (n.s.). In 35 patients with a persistent occlusion, the average NIHSS score reduction was 22% (FD+) and 0.52% (FD-) during 90 min after t-PA bolus (p=0.017), and 29 versus -25% during the first 24 h after the t-PA bolus, respectively (p=0.01). CONCLUSIONS: In patients with persistent MCA occlusions after thrombolytic treatment, arterial blood flow diversion is associated with earlier and better neurological improvement. FD has protective effects on the ischemic brain tissue with persistent MCA occlusion.

Aged↗
PubMed2005

Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator.

BACKGROUND AND PURPOSE: We sought to evaluate the effects of administration of microbubbles (MBs) on the beginning, speed, and degree of middle cerebral artery (MCA) recanalization during systemic thrombolysis and continuous 2-MHz pulsed-wave transcranial Doppler (TCD) monitoring. METHODS: We evaluated 111 patients with acute stroke attributable to MCA occlusion treated with intravenous tissue plasminogen activator (tPA). Thirty-eight patients were treated with tPA plus continuous 2-hour TCD monitoring plus 3 doses of 2.5 g (400 mg/mL) of galactose-based MBs given at 2, 20, and 40 minutes after tPA bolus (MB group). These patients were compared with 73 patients who were allocated to receive tPA plus continuous 2-hour TCD ultrasound (US) monitoring (tPA/US group) or tPA plus placebo monitoring (tPA group), most of whom were enrolled in a previous study of US-enhanced thrombolysis. The beginning, degree, and time to maximum completeness of recanalization during the first 2 hours of tPA bolus were recorded. RESULTS: Median prebolus National Institutes of Health Stroke Scale (NIHSS) score was 18. Eighty patients (72%) had a proximal and 31 (28%) a distal MCA occlusion on TCD. Thirty-seven patients (33%) received tPA/US, 38 (34%) received tPA/US/MB, and 36 (32%) were treated with tPA alone. Stroke severity, time to treatment, location of MCA occlusion, and presence of carotid artery disease were similar among groups. Two-hour recanalization was seen in 14 (39%), 25 (68%), and 27 patients (71%) in the tPA, tPA/US, and tPA/US/MB groups, respectively (P=0.004). Two-hour complete recanalization rate was significantly (P=0.038) higher in the tPA/US/MB group (54.5%) compared with tPA/US (40.8%) and tPA (23.9%) groups. The time to beginning of recanalization after tPA bolus was 26+/-18 minutes in the tPA/US group and 19+/-12 minutes in the tPA/US/MB group (P=0.12). Four patients (3.6%) experienced symptomatic intracranial hemorrhage: 2 (5.5%), 1 (2.7%), and 1 patient (2.6%) who received tPA only, tPA/US, and tPA/US/MB, respectively, experienced symptomatic intracranial hemorrhage. At 24 hours, 31%, 41%, and 55% of tPA, tPA/US, and tPA/US/MB improved >4 points in the NIHSS score. CONCLUSIONS: Administration of MBs induces further acceleration of US-enhanced thrombolysis in acute stroke, leading to a more complete recanalization and to a trend toward better short- and long-term outcome.

Adult↗
PubMed2005

A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis.

cAMP plays crucial roles in cardiac remodeling and the progression of heart failure. Recently, we found that expression of cAMP hydrolyzing phosphodiesterase 3A (PDE3A) was significantly reduced in human failing hearts, accompanied by up-regulation of inducible cAMP early repressor (ICER) expression. Angiotensin II (Ang II) and the beta-adrenergic receptor agonist isoproterenol (ISO) also induced persistent PDE3A down-regulation and concomitant ICER up-regulation in vitro, which is important in Ang II- and ISO-induced cardiomyocyte apoptosis. We hypothesized that interactions between PDE3A and ICER may constitute an autoregulatory positive feedback loop (PDE3A-ICER feedback loop), and this loop would cause persistent PDE3A down-regulation and ICER up-regulation. Here, we demonstrate that ICER induction repressed PDE3A gene transcription. PDE3A down-regulation activated cAMP/PKA signaling, leading to ICER up-regulation via PKA-dependent stabilization of ICER. With respect to Ang II, the initiation of the PDE3A-ICER feedback loop depends on activation of Ang II type 1 receptor (AT1R), classical PKC(s), and CREB (cAMP response element binding protein). We further show that the PDE3A-ICER feedback loop is essential for Ang II-induced cardiomyocyte apoptosis. ISO and PDE3 inhibitors also induced the PDE3A-ICER feedback loop and subsequent cardiomyocyte apoptosis, highlighting the importance of this PDE3A-ICER feedback loop and cAMP signaling in cardiomyocyte apoptosis. Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Extending reperfusion therapy for acute ischemic stroke: emerging pharmacological, mechanical, and imaging strategies.

BACKGROUND AND PURPOSE: Reperfusion is the most beneficial of all therapeutic strategies for acute ischemic stroke. However, the standard cerebral reperfusion treatment of the first decade of the reperfusion era, noncontrast computed tomography (CT)-guided, < or =3 hours, intravenous tissue plasminogen activator, has many limitations. This review surveys emerging strategies that have the potential to extend cerebral reperfusion therapy to larger numbers of patients. SUMMARY OF REVIEW: Innovative intravenous pharmacological reperfusion strategies include novel fibrinolytic agents (tenecteplase, reteplase, desmetolplase, plasmin, and microplasmin), glycoprotein (GP) IIb/IIIa antagonists with platelet disaggregating effects (abciximab and tirofiban), combination therapies to improve efficacy of clot lysis (fibrinolytics and GP IIb/IIIa agents, and fibrinolytics and direct thrombin inhibitors), increase the time window for clot lysis (fibrinolytics and neuroprotectants), and reduce the frequency of hemorrhagic complications (fibrinolytics and vasoprotectants), and externally applied ultrasound to enhance enzymatic fibrinolysis. Promising intra-arterial pharmacological reperfusion approaches include novel fibrinolytic agents, combined intravenous and intra-arterial fibrinolysis, and combined fibrinolytics and GP IIb/IIIa agents. Emerging endovascular mechanical reperfusion strategies include intra-arterial thrombectomy (clot retrieval devices and suction thrombectomy devices), mechanical disruption (micro-guidewire passage, laser photoacoustic emulsification, and primary intracranial angioplasty), and augmented fibrinolysis by endovascular ultrasound. Multimodal imaging, with magnetic resonance (MR) or CT, can rapidly assess infarct core, penumbra, site of vessel occlusion, and tissue hemorrhagic propensity, enabling improved selection of patients for reperfusion therapy beyond any arbitrary fixed time window. CONCLUSIONS: Therapeutic reperfusion is emerging as a treatment strategy of remarkable power and scope for rescuing patients experiencing acute brain ischemia, applicable within and beyond the 3-hour time window.

Algorithms↗