Coeli Lopes - Academia.edu (original) (raw)

Papers by Coeli Lopes

Biophysical Journal, 2010

may modify the voltage activation threshold of this channel towards more physiological conditions... more may modify the voltage activation threshold of this channel towards more physiological conditions. Flavonoid Naringenin (Nar) is present in all plant species where it plays a central role in the flavonoid biosynthetic pathway. Nar is stored in the vacuoles in glycosylated form. To confirm the presence of non-glycosylated Nar in the cytoplasm we isolated the gene encoding for Arabidopsis glycosyltransferase (AtGT) which glycosilates Nar. AtGT gene was cloned in fusion with yellow fluorescent protein (YFP) and was used for localization studies. When Naringenin was added to cytosolic bath solution, we recorded a dose-dependent reversible decrease in SV channel activity described by a half block concentration of 0.44 mM. Investigating Nar effects on the voltage dependence of the channel, we observed that the activation threshold of the SV channel is shifted towards more positive voltages and that Nar does not affect the single channel conductance. Investigating the effects of Nar at varying pH, we observed an increase in current inhibition with the decrease of the pH. When Naringin, the glycosylated form of Nar, was applied at the cytosolic or at the vacuolar side it did not modify the channel activity. We are currently investigating the role of the phospholipid composition of the membrane in this modulation.

PLoS ONE, 2020

The slow cardiac delayed rectifier current (IKs) is formed by KCNQ1 and KCNE1 subunits and is one... more The slow cardiac delayed rectifier current (IKs) is formed by KCNQ1 and KCNE1 subunits and is one of the major repolarizing currents in the heart. Decrease of IKs currents either due to inherited mutations or pathological remodeling is associated with increased risk for cardiac arrhythmias and sudden death. Ca2+-dependent PKC isoforms (cPKC) are chronically activated in heart disease and diabetes. Recently, we found that sustained stimulation of the calcium-dependent PKCβII isoform leads to decrease in KCNQ1 subunit membrane localization and KCNQ1/KCNE1 channel activity, although the role of KCNE1 in this regulation was not explored. Here, we show that the auxiliary KCNE1 subunit expression is necessary for channel internalization. A mutation in a KCNE1 phosphorylation site (KCNE1(S102A)) abolished channel internalization in both heterologous expression systems and cardiomyocytes. Altogether, our results suggest that KCNE1(S102) phosphorylation by PKCβII leads to KCNQ1/KCNE1 channel...

Biochemical and Biophysical Research Communications, 2015

Protein kinase C (PKC) plays key roles in the regulation of signal transduction and cellular func... more Protein kinase C (PKC) plays key roles in the regulation of signal transduction and cellular function in various cell types. At least ten PKC isoforms have been identified and intracellular localization and trafficking of these individual isoforms are important for regulation of enzyme activity and substrate specificity. PKC can be activated at downstream of G q-protein coupled receptor (G q PCR) signaling and translocated to the various cellular compartments including plasma membrane (PM). Recent reports suggested that a different type of G q PCRs would activate different PKC isoforms (classic, novel and atypical PKCs) with different trafficking patterns. However, the knowledge of isoform-specific activation of PKC by each G q PCR is limited. α 1-Adrenoceptor (α 1-AR) is the one of the G q PCR highly expressed in the cardiovascular system. In this study, we examined the isoform-specific dynamic translocation of PKC in living HEK293T cells by α 1-AR stimulation (α 1-ARS). Rat PKCα, βI, βII, δ, ε and ζ fused with GFP at C-term were co-transfected with human α 1A-AR into HEK293T cells. The isoform-specific dynamic translocation of PKC in living HEK293T cells by α 1-ARS using phenylephrine was measured by confocal microscopy. Before stimulation, GFP-PKCs were localized at cytosolic region. α 1-ARS strongly and rapidly translocated a classical PKC (cPKC), PKCα, (< 30s) to PM, with PKCα returning diffusively into the cytosol within 5 min. α 1-ARS rapidly translocated other cPKCs, PKCβI and PKCβII, to the PM (<30s), with sustained membrane localization. One of novel PKCs (nPKCs), PKCε, but not another nPKC, PKCδ, was translocated by α 1-AR stimulation to the PM (<30s) and its membrane localization was also sustained. Finally, α 1-AR stimulation did not cause a diacylglycerol-insensitive atypical PKC, PKCζ translocation. Our data suggest that PKCα, β and ε activation may underlie physiological and pathophysiological responses of α 1-AR signaling for

Heart Rhythm, 2013

Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQ... more Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events. The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation. The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry. Patients with multiple mutations (n=57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; P=0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p=0.031). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (P=0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (P=0.010) whereas the risk associated with multiple mutation status involving &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, P=0.26). LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.

Heart Rhythm, 2010

Cardiac events in patients with long QT syndrome type 2 (LQT2) are predominately associated with ... more Cardiac events in patients with long QT syndrome type 2 (LQT2) are predominately associated with sudden arousal. However, exercise-induced events also occur in this population. The purpose of this study was to test the hypothesis that risk factors show a trigger-specific association with cardiac events in LQT2 patients. The study population consisted of 634 genetically confirmed LQT2 patients from the U.S. portion of the International LQTS Registry. Multivariate Cox proportional hazards regression analysis was used to determine the independent contribution of clinical and genetic risk factors to the first occurrence of trigger-specific cardiac events, categorized as arousal, exercise-induced, and nonarousal/nonexercise, from birth through age 40 years. Study patients experienced 204 cardiac events during follow-up, of which 44% were associated with arousal triggers, 13% with exercise activity, and 43% with nonexercise/nonarousal triggers. Risk factors for arousal-triggered cardiac events included gender (female:male &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 13 years: hazard ratio [HR] 9.10, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001) and the presence of pore-loop mutations (HR 2.19, P = .009). In contrast, non-pore-loop transmembrane mutations were the predominant risk factor for exercise-triggered events (HR 6.84, P…

Circulation. Arrhythmia and electrophysiology, 2017

Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage... more Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype. Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressor...

Journal of the American Heart Association

Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life‐thre... more Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life‐threatening events in women with either type 1 or type 2 long QT. Methods and Results The prognostic model was derived from the Rochester Long QT Syndrome Registry, comprising 767 women with type 1 long QT (n=404) and type 2 long QT (n=363) from age 15 through 60 years. The risk prediction model included the following variables: genotype/mutation location, QTc‐specific thresholds, history of syncope, and β‐blocker therapy. A model was developed with the end point of CEs (syncope, aborted cardiac arrest, or long QT syndrome–related sudden cardiac death), and was applied with the end point of life‐threatening events (aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shocks). External validation was performed with data from the Mayo Clinic Genetic Heart Rhythm Clinic (N=467; type 1 long QT [n=286] and type 2 long QT [n=181]). The cumulative follow‐up duration among the ...

Annals of Noninvasive Electrocardiology

Biophysical Journal

KCNQ (M-type) K þ channels and TRPC cation channels are regulated via G q/11-protein-mediated sig... more KCNQ (M-type) K þ channels and TRPC cation channels are regulated via G q/11-protein-mediated signals in brain and peripheral ganglia. Stimulation of G q/11-coupled receptors both consumes PIP 2 via PLC hydrolysis and stimulates PIP 2 synthesis via rises in Ca 2þ i and other signals. Using brain-slice electrophysiology and Ca 2þ imaging, we characterized threshold K þ currents in mouse dentate gyrus granule cells (DGGCs) and CA1 pyramidal cells, the effects of M 1 mAChR (M1R) stimulation on M current and on neuronal discharge properties, and elucidated the underlying signaling mechanisms. We found disparate signaling between DGGCs and CA1 neurons. DGGCs displayed M1R-induced enhancement of M current, rather than its suppression, due to profound stimulation of PIP 2 synthesis, which was paralleled by increased PIP 2-regulated GIRK currents provoked by stimulation of endogenous GABA B receptors. Nonetheless, stimulation of M1Rs increased excitability under current-clamp, as previously reported. Using Cre-lox breeding, deficiency of KCNQ2-containing M channels in DGGCs ablated M1Rinduced enhancement of the M-type current. Simultaneously, M1R stimulation in DGGCs induced robust increases in [Ca 2þ ] i , largely via TRPC currents, which increased excitability. With TRPC channels blocked, M1R stimulation induced no increases in excitability, and with blockade of PI(4) P 5-kinase, M1R stimulation suppressed M current. On the other hand, M current in CA1 pyramidal neurons was suppressed by M1R stimulation, similar to widely-described M channel inhibition involving PIP 2 depletion in peripheral ganglia. Use of expressed hM3q DREADD receptors gave similar results. Both types of neurons displayed a much more slowly deactivating Kþ current that was, at most, only weakly affected by M1R agonists. Therefore, there are pleotropic mechanisms of cholinergic signals that direct cell-type specific, precise control of hippocampal function, with strong implications for hyperexcitability and epilepsy.

Circulation, Jan 26, 2016

Original research article BACKGROUND: Risk stratification in patients with type 3 long-QT syndrom... more Original research article BACKGROUND: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy has not been studied previously in a large LQT3 population. METHODS:The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years. RESULTS: Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome-related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent β-blocker therapy was associated with an 83% reduction in CEs in females (P=0.015) but not in males (who had many fewer events), with a significant sex × β-blocker interaction (P=0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events (P<0.02). CONCLUSIONS: Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, β-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events. clinical aspects of type 3 long-Qt syndrome an international Multicenter study

J Cardiovasc Electrophysiol, 2010

Phenotype-Negative LQTS. Background: Data regarding possible ion channel mechanisms that predispo... more Phenotype-Negative LQTS. Background: Data regarding possible ion channel mechanisms that predispose to ventricular tachyarrhythmias in patients with phenotype-negative long-QT syndrome (LQTS) are limited. Methods and Results: We carried out cellular expression studies for the S349W mutation in the KCNQ1 channel, which was identified in 15 patients from the International LQTS Registry who experienced a high rate of cardiac events despite lack of significant QTc prolongation. The clinical outcome of S349W mutation carriers was compared with that of QTc-matched carriers of haploinsufficient missense (n = 30) and nonsense (n = 45) KCNQ1 mutations. The channels containing the mutant S349W subunit showed a mild reduction in current (<50%), in the haploinsuficient range, with an increase in maximal conductance compared with wild-type channels. In contrast, expression of the S349W mutant subunit produced a pronounced effect on both the voltage dependence of activation and the time constant of activation, while haploinsuficient channels showed no effect on either parameter. The cumulative probability of cardiac events from birth through age 20 years was significantly higher among S349W mutation carriers (58%) as compared with carriers of QTc-matched haploinsufficent missense (21%, P = 0.004) and nonsense (25%, P = 0.01) mutations. Conclusions: The S349W mutation in the KCNQ1 potassium channel exerts a relatively mild effect on the ion channel current, whereas an increase in conductance compensates for impaired voltage activation of the channel. The changes observed in voltage activation of the channel may underlie the mechanisms predisposing to arrhythmic risk among LQTS patients with a normal-range QTc.

Circulation, Nov 22, 2011

Circulation, Nov 23, 2010

Biochimica Et Biophysica Acta Biomembranes, 1991

The effects of ethanol, n-butanol, n-hesanoi and n-octanol on lipid-protein interactions in sarco... more The effects of ethanol, n-butanol, n-hesanoi and n-octanol on lipid-protein interactions in sarcoplasmic reticulum vesicles (SRV) are investigated using the C-14 nitroxide spin-labeled phosphatidylcholine, n-Alkanols, which activate the Ca2+-dependent ATPase of sarcoplasmic reticulum but decrease net Ca z÷ uptake by the vesic|es, are shown to affect the lipids interacting with the protein surface. Spectral analysis revealed that increasing co~centrations of the alcohols progressively displace and mobilize lipids from the |~pid/protein interface. For butanol, hexanol and octanol maximally activated SRV, 23 to 30% of the protein-interacting lipids are displaced. Thus, the displacement of more than 30% of the annular lipids by these alkanols cause inhibition of the enzyme. The motiona| properties of the labels that remain restricted by the protein surface are unaffected by the alcohols. The degree of mobilization attained by the labels displaced from the interface is much greater than that observed in alcohol~reated dispersions of extracted iipids. We propose that the alcohol molecales interfere with the protein-Hpid interactions creating fluid clusters around the proteins. These fluidized regions would affect the enzyme conformation, perturbing its function. Fluidized annular lipids apparently increase the number of ion-co~aducting defecgs around the enzyme, increasing Ca z+ effiux, and thereby reducing net uptake.

Journal of the American College of Cardiology, 2016

Biophysical Journal, 2016

Long QT type 3 (LQT3) is a common form of LQT syndrome caused by mutations in the cardiac sodium ... more Long QT type 3 (LQT3) is a common form of LQT syndrome caused by mutations in the cardiac sodium channel. These mutations lead to an increase in the cardiac sodium current during the late phases of the cardiac action potential (AP), leading to cardiac arrhythmias. We attempted to predict mutation-specific cardiac event risk for LQT3 mutations using a combination of in vitro and in silico risk assessment. For that, we first characterized, using patch clamp, eight common mutations associated with LQT3. Using our data as an input to a cardiomyocyte computer model, we predicted action potential duration (APD) and early after-depolarization (EAD) susceptibility for these mutants, at different heart rates. Our risk predictions correlated well to the cardiac event risk observed in patients with these mutations. Second, we measured the effect of the late sodium blocker ranolazine for each of the mutants tested. We used the model to predict drug treatment efficacy. Interestingly, ranolazine showed mutation-specific effects, with some mutations showing strongly shortened APDs and decreased predicted risk, while little effect was observed in other mutants. Most importantly, for one of the mutations assessed, risk was predicted to be increased, despite shortening of APD. Thus, our results suggest that drug treatment efficacy is mutation-specific. In summary, our results show that mutation-specific in silico models may be an important new tool for clinical risk assessment in LQT3.