SSR4-CDG, an ultra-rare X-linked congenital disorder of glycosylation affecting the TRAP complex: Review of 22 affected individuals including the first adult patient.

Congenital disorders of glycosylation (CDG) are a group of rare, often multi-systemic genetic disorders that result from disturbed protein and lipid glycosylation. SSR4-CDG is an ultra-rare, comparably mild subtype of CDG, presenting mostly in males. It is caused by pathogenic variants in the SSR4 gene, which is located on the X chromosome. SSR4 (signal sequence receptor protein 4) is a subunit of the translocon-associated protein (TRAP) complex, a structure that is needed for the translocation of proteins across the ER membrane. A deficiency of SSR4 leads to disturbed N-linked glycosylation of proteins in the endoplasmic reticulum. Here, we review the most common clinical, biochemical and genetic features of 18 previously published individuals and report four new cases diagnosed with SSR4-CDG, including the first adult affected by this disorder. Based on our review, developmental delay, speech delay, intellectual disability, muscular hypotonia, microcephaly and distinct facial features are key symptoms of SSR4-CDG that are present in all affected individuals. Although these symptoms overlap with many other neurodevelopmental disorders, their combination with additional clinical features, and a quite distinguishable facial appearance of affected individuals make this disorder a potentially recognizable type of CDG. Additional signs and symptoms include failure to thrive, feeding difficulties, connective tissue involvement, gastrointestinal problems, skeletal abnormalities, seizures and, in some cases, significant behavioral abnormalities. Due to lack of awareness of this rare disorder, and since biochemical testing can be normal in affected individuals, most are diagnosed through genetic studies, such as whole exome sequencing. With this article, we expand the phenotype of SSR4-CDG to include cardiac symptoms, laryngeal abnormalities, and teleangiectasia. We also provide insights into the prognosis into early adulthood and offer recommendations for adequate management and care. We emphasize the great need for causal therapies, as well as effective symptomatic therapies addressing the multitude of symptoms in this disease. In particular, behavioral problems can severely affect quality of life in individuals diagnosed with SSR4-CDG and need special attention. Finally, we aim to improve guidance and education for affected families and treating physicians and create a basis for future research in this disorder.

Neurological manifestations in PMM2-congenital disorders of glycosylation (PMM2-CDG): Insights into clinico-radiological characteristics, recommendations for follow-up, and future directions.

PURPOSE: In the absence of prospective data on neurological symptoms, disease outcome, or guidelines for system specific management in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG), we aimed to collect and review natural history data. METHODS: Fifty-one molecularly confirmed individuals with PMM2-CDG enrolled in the Frontiers of Congenital Disorders of Glycosylation natural history study were reviewed. In addition, we prospectively reviewed a smaller cohort of these individuals with PMM2-CDG on off-label acetazolamide treatment. RESULTS: Mean age at diagnosis was 28.04 months. Developmental delay is a constant phenotype. Neurological manifestation included ataxia (90.2%), myopathy (82.4%), seizures (56.9%), neuropathy (52.9%), microcephaly (19.1%), extrapyramidal symptoms (27.5%), stroke-like episodes (SLE) (15.7%), and spasticity (13.7%). Progressive cerebellar atrophy is the characteristic neuroimaging finding. Additionally, supratentorial white matter changes were noted in adult age. No correlation was observed between the seizure severity and SLE risk, although all patients with SLE have had seizures in the past. "Off-label" acetazolamide therapy in a smaller sub-cohort resulted in improvement in speech fluency but did not show statistically significant improvement in objective ataxia scores. CONCLUSION: Clinical and radiological findings suggest both neurodevelopmental and neurodegenerative pathophysiology. Seizures may manifest at any age and are responsive to levetiracetam monotherapy in most cases. Febrile seizure is the most common trigger for SLEs. Acetazolamide is well tolerated.

Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series.

Phosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) (OMIM: 614921) is a rare autosomal recessive inherited metabolic disease caused by the deficiency of the PGM1 enzyme. Like other CDGs, PGM1-CDG has a multisystemic presentation. The most common clinical findings include liver involvement, rhabdomyolysis, hypoglycemia, and cardiac involvement. Phenotypic severity can vary, though cardiac presentation is usually part of the most severe phenotype, often resulting in early death. Unlike the majority of CDGs, PGM1-CDG has a treatment: oral D-galactose (D-gal) supplementation, which significantly improves many aspects of the disorder. Here, we describe five PGM1-CDG patients treated with D-gal and report both on novel clinical symptoms in PGM1-CDG as well as the effects of the D-gal treatment. D-gal resulted in notable clinical improvement in four patients, though the efficacy of treatment varied between the patients. Furthermore, there was a significant improvement or normalization in transferrin glycosylation, liver transaminases and coagulation factors in three patients, creatine kinase (CK) levels in two, while hypoglycemia resolved in two patients. One patient discontinued the treatment due to urinary frequency and lack of clinical improvement. Furthermore, one patient experienced recurrent episodes of rhabdomyolysis and tachycardia even on higher doses of therapy. D-gal also failed to improve the cardiac function, which was initially abnormal in three patients, and remains the biggest challenge in treating PGM1-CDG. Together, our findings expand the phenotype of PGM1-CDG and underline the importance of developing novel therapies that would specifically treat the cardiac phenotype in PGM1-CDG.

An update on benefits and challenges of treating PGM1-CDG with galactose PGM1-CDG is a rare genetic disorder that affects glycosylation, an important biochemical process happening in every cell of the body. Because glycosylation is essential for correct functioning of the cells and happens in every tissue and organ, patients with PGM1-CDG can have a variety of symptoms affecting many different organs. Main symptoms include low blood glucose levels, hyperinsulinism, bleeding disorder, liver, muscle, heart problems, and so on. This disorder is usually diagnosed based on the genetic testing, patient's symptoms, and transferrin glycosylation test, which detects abnormalities in glycosylation in blood. So far, more than 60 patients have been reported. Unlike many genetic disorders, PGM1-CDG has a treatment in the form of a sugar called galactose, which naturally occurs in milk, and can treat many symptoms of the disorder. The patients are advised to take it every day by mouth in the form of powder. Here, we describe five more patients with PGM1-CDG, who were treated with galactose. Each of the patients had novel symptoms and they responded to the treatment differently, which helps us to better understand the disorder and the effects of therapy better. We found that many symptoms improved or normalized; however, some patients experienced persistent symptoms and even adverse events that made them stop treatment. Unfortunately, we did not observe any improvement of heart-related issues. Given that heart issues are the most severe aspect of PGM1-CDG and can result in early death, therapies that target heart issues in PGM1-CDG are still necessary. In conclusion, we describe novel aspects of PGM1-CDG, which will help understand and diagnose the disorder better, and highlight the importance of developing new therapies for this disorder that would specifically treat the heart.

Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation.

BACKGROUND: Given the lack of reliable data on the prevalence of bleeding abnormalities and thrombotic episodes in PMM2-CDG patients, and whether coagulation abnormalities change over time, we prospectively collected and reviewed natural history data. Patients with PMM2-CDG often have abnormal coagulation studies due to glycosylation abnormalities but the frequency of complications resulting from these has not been prospectively studied. METHODS: We studied fifty individuals enrolled in the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study with molecularly confirmed diagnosis of PMM2-CDG. We collected data on prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), platelets, factor IX activity (FIX), factor XI activity (FXI), protein C activity (PC), protein S activity (PS) and antithrombin activity (AT). RESULTS: Prothrombotic and antithrombotic factor activities were frequently abnormal in PMM2-CDG patients, including AT, PC, PT, INR, and FXI. AT deficiency was the most common abnormality in 83.3% of patients. AT activity was below 50% in 62.5% of all patients (normal range 80-130%). Interestingly, 16% of the cohort experienced symptoms of spontaneous bleeding and 10% had thrombosis. Stroke-like episodes (SLE) were reported in 18% of patients in our cohort. Based on the linear growth models, on average, patients did not show significant change in AT (n = 48; t(23.8) = 1.75, p = 0.09), FIX (n = 36; t(61) = 1.60, p = 0.12), FXI (n = 39; t(22.8) = 1.88, p = 0.07), PS (n = 25; t(28.8) = 1.08, p = 0.29), PC (n = 38; t(68) = 1.61, p = 0.11), INR (n = 44; t(184) = -1.06, p = 0.29), or PT (n = 43; t(192) = -0.69, p = 0.49) over time. AT activity positively correlated with FIX activity. PS activity was significantly lower in males. CONCLUSION: Based on our natural history data and previous literature, we conclude that caution should be exercised when the AT levels are lower than 65%, as most thrombotic events occur in patients with AT below this level. All five, male PMM2-CDG patients in our cohort who developed thrombosis had abnormal AT levels, ranging between 19% and 63%. Thrombosis was associated with infection in all cases. We did not find significant change in AT levels over time. Several PMM2-CDG patients had an increased bleeding tendency. More long-term follow-up is necessary on coagulation abnormalities and the associated clinical symptoms to provide guidelines for therapy, patient management, and appropriate counseling. SYNOPSIS: Most PMM2-CDG patients display chronic coagulation abnormalities without significant improvement, associated with a frequency of 16% clinical bleeding abnormalities, and 10% thrombotic episodes in patients with severe antithrombin deficiency.

Long-term outcomes in ALG13-Congenital Disorder of Glycosylation.

ALG13-CDG is a rare X-linked disorder of N-linked glycosylation. Given the lack of long-term outcome data in ALG13-CDG, we collected natural history data and reviewed individuals surviving to young adulthood with confirmed pathogenic variants in ALG13 in our own cohort and in the literature. From the 14 ALG13-CDG patients enrolled into our Frontiers of Congenital Disorders of Glycosylation Consortium natural history study only two patients were older than 16 years; one of these two females is so far unreported. From the 52 patients described in the medical literature with confirmed pathogenic variants in ALG13 only five patients were older than 16 years (all females), in addition to the new, unreported patient from our natural history study. Two male patients have died due to ALG13-CDG, and there were no surviving males older than 16 years with a confirmed ALG13-CDG diagnosis. Our adolescent and young adult cohort of six patients presented with epilepsy, muscular hypotonia, speech, and developmental delay. Intellectual disability was present in all female patients with ALG13-CDG. Unreported features included ataxia, neuropathy, and severe gastrointestinal symptoms requiring G/J tube placement. In addition, two patients from our natural history study developed unilateral hearing loss. Skeletal abnormalities were found in four patients, including osteopenia and scoliosis. Major health problems included persistent seizures in three patients. Ketogenic diet was efficient for seizures in three out of four patients. Although all patients were mobile, they all had severe communication problems with mostly absent speech and were unable to function without parental support. In summary, long-term outcome in ALG13-CDG includes gastrointestinal and skeletal involvement in addition to a chronic, mostly non-progressive neurologic phenotype.

TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels.

TRIT1 defect is a rare, autosomal-recessive disorder of transcription, initially described as a condition with developmental delay, myoclonic seizures, and abnormal mitochondrial function. Currently, only 13 patients have been reported. We reviewed the genetic, clinical, and metabolic aspects of the disease in all known patients, including two novel, unrelated TRIT1 cases with abnormalities in oxidative phosphorylation complexes I and IV in fibroblasts. Taken together the features of all 15 patients, TRIT1 defect could be identified as a potentially recognizable syndrome including myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and variable microcephaly, with normal lactate levels. Half of the patients had oxidative phosphorylation complex measurements and had multiple complex abnormalities.

Nutrition interventions in congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDG) are a group of more than 160 inborn errors of metabolism affecting multiple pathways of protein and lipid glycosylation. Patients present with a wide range of symptoms and therapies are only available for very few subtypes. Specific nutritional treatment options for certain CDG types include oral supplementation of monosaccharide sugars, manganese, uridine, or pyridoxine. Additional management includes specific diets (i.e., complex carbohydrate or ketogenic diet), iron supplementation, and albumin infusions. We review the dietary management in CDG with a focus on two subgroups: N-linked glycosylation defects and GPI-anchor disorders.

Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications.

OBJECTIVE: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. METHODS: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. RESULTS: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. INTERPRETATION: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a.

Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study.

A recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study's conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients' lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.

Canines (Canis lupus familiaris) as biodetectors for conservation work: Can they discriminate the rock ptarmigan (Lagopus muta) from the willow grouse (L. lagopus) in a yes/no task?

Alpine and arctic bird populations have shown an unmistakable decrease over the last three decades, and the need for conservation is highly necessary. We investigated the use of five privately-owned dogs (Canis lupus familiaris) as a non-invasive tool to determine the presence of rock ptarmigan (Lagopus muta), through sniffing out faecal pellets, using a yes/no training regime. We carried out 36 double-blind experimental trials per dog and hypothesised that dogs could discriminate the rock ptarmigan from similar species, such as black grouse (Tetrao tetrix), western capercaillie (T. urogallus) and willow grouse (L. lagopus). Our dogs detected differences between the avian species with an average accuracy of 65.9%, sensitivity of 66.7% and specificity of 65.3%. We showed that privately-owned dogs have the potential to be used as biodetectors for conservational work within controlled laboratory conditions for declining species, but overall, only one dog was considered proficient enough. We concluded that dogs could be used as a non-invasive tool to detect the rock ptarmigan, and with further field training and testing, operate in the field for detection surveys.

Scent-sniffing dogs can discriminate between native Eurasian and invasive North American beavers.

The invasion of a species can cause population reduction or extinction of a similar native species due to replacement competition. There is a potential risk that the native Eurasian beaver (Castor fiber) may eventually be competitively excluded by the invasive North American beaver (C. canadensis) from areas where they overlap in Eurasia. Yet currently available methods of census and population estimates are costly and time-consuming. In a laboratory environment, we investigated the potential of using dogs (Canis lupus familiaris) as a conservation tool to determine whether the Eurasian or the North American beaver is present in a specific beaver colony. We hypothesized that dogs can discriminate between the two beaver species, via the odorant signal of castoreum from males and females, in two floor platform experiments. We show that dogs detect scent differences between the two species, both from dead beaver samples and from scent marks collected in the field. Our results suggest that dogs can be used as an "animal biosensor" to discriminate olfactory signals of beaver species, however more tests are needed. Next step should be to test if dogs discern between beaver species in the field under a range of weather conditions and habitat types and use beaver samples collected from areas where the two species share the same habitat. So far, our results show that dogs can be used as a promising tool in the future to promote conservation of the native beaver species and eradication of the invasive one. We therefore conclude that dogs may be an efficient non-invasive tool to help conservationist to manage invasive species in Europe, and advocate for European wildlife agencies to invest in this new tool.

Anatomical variations of the right coronary artery may be a source of difficult block and conduction recurrence in catheter ablation of common-type atrial flutter.

AIMS: Although Eustachian valves and recesses have been related to resistance to block, the effect of convective cooling by the right coronary artery (RCA) has not been evaluated in the clinical setting. METHODS AND RESULTS: The distance and course of the RCA in relation to the cavotricuspid isthmus (CTI) in addition to variants of CTI anatomy and the presence of Eustachian valves were analysed from computed tomography scans of 54 patients. Ablation power was titrated using a step-up protocol. Invasive follow-up was available for 34 patients. The RCA came closest to the CTI inferiorly separated by a mean of 5.3 ± 2.5 mm compared with 7.3 ± 3.3 mm septally and 5.7 ± 2.3 mm anteriorly (P < 0.01). The maximum power required for CTI block correlated inversely with the distance of the RCA to the CTI, whereas the cumulative energy was highest in the presence of recesses. Neither failure of acute block nor a higher rate of conduction recurrence could be attributed to variants of CTI anatomy or the presence of a Eustachian valve. Using multivariate analysis, a position of the RCA underneath the central part of the CTI was the only significant predictor for late conduction recurrence. These patients showed a 2.7 mm larger distance of the RCA to the tricuspid valve plane (P = 0.05). CONCLUSION: The RCA affects CTI ablation as higher power settings are required at closer distances to the ablation site. Late conduction recurrences were observed in patients with a variation of the RCA, leaving the atrioventricular groove towards the atrial aspect.

Introduction of an expert system for the discrimination of local pulmonary vein and atrial far field signals.

BACKGROUND: Discrimination of local and far field potentials during sinus rhythm and atrial fibrillation (AF) is essential for successful pulmonary vein (PV) isolation. We sought to introduce an expert system for the classification of electrophysiologic PV signals. METHODS: For the expert system database, we analyzed ablation procedures of 50 patients with paroxysmal and persistent AF. Standard circumferential catheters and bipolar recordings were required. In a prospective trial, the expert system was compared with the performing electrophysiologists' classifications of potentials during 15 procedures. A total of 1,343 recordings of local PV and far field signals were validated by the sudden disappearance of local potentials during ablation, the presence of dissociated PV activity, and pacing maneuvers. A fast Fourier transform was applied to the individual potentials. Analysis continued in the amplitude and phase representation. RESULTS: Four parameters significant (p < 0.001) for classification were identified and entered a logistic regression model. Overall sensitivity and specificity of the model was 87% with minor, nonsignificant variations for individual PVs and different underlying rhythms. Concordance with ad hoc electrophysiologists' classification of local potentials was 70%, which increased during post hoc analysis to 86% since classification of 14% of the potentials had to be revised. For these potentials, the expert system correctly predicted their local origin in 86%. CONCLUSION: An expert system for the evaluation of electrophysiologic signals based on morphology analysis using the Fourier transform is feasible. The ease of use and online availability facilitate a widespread use for AF ablation procedures.

Slow wall motion rather than electrical conduction delay underlies mechanical dyssynchrony in postinfarction patients with narrow QRS complex.

INTRODUCTION: The mechanism of mechanical dyssynchrony in postinfarction patients with a narrow QRS complex is not defined but essential for cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Left ventricular electrical activation and subsequent wall motion were recorded for 16 patients with ischemic cardiomyopathy during intrinsic rhythm using a modified NOGA electromechanical mapping system. Ten patients presented mechanical dyssynchrony on tissue Doppler imaging, while 6 patients served as control subjects. The local activation time (LAT) was set by the maximum downslope of the unipolar electrogram. Local wall motion time (LMT) was defined as the time needed for the catheter tip to traverse half of its maximum inward deflection during systole. LAT and LMT were measured relative to the onset of the QRS complex. Electrical activation showed a septal-to-lateral pattern in all patients with a mean endocardial activation time of 65 +/- 13 ms. Control subjects exhibited 97.5% of all LMTs <290 +/- 17 ms. Delayed motion areas (cut-off LMT > 300 ms) showed no slowing of conduction. Wall motion time corrected for differences in electrical activation (LMT-LAT) was significantly longer in delayed (289 +/- 34 ms) than in regular (204 +/- 24 ms) motion areas (P = 0.002). Delayed motion segments were hypokinetic on echocardiography and presented a lower maximum inward motion (9.9 +/- 1.1 mm) compared to regular segments (10.9 +/- 1.2 mm) on electromechanical maps (P = 0.004). Viability, however, was preserved with unipolar and bipolar voltage amplitude >7 mV and >1.5 mV for 79% of all delayed motion areas. CONCLUSION: Dyssynchronous segments of an ischemic myocardium show unimpaired local activation but slow wall motion, thereby limiting the benefit of ventricular preexcitation via CRT.

Catheter motion during atrial ablation due to the beating heart and respiration: impact on accuracy and spatial referencing in three-dimensional mapping.

BACKGROUND: The accuracy of three-dimensional mapping systems is affected by cardiac contraction and respiration. OBJECTIVE: The study sought to determine relative motion of cardiac and thoracic structures to assess positional errors and guide the choice of an optimized spatial reference. METHODS: Motion of catheters placed at the coronary sinus (CS), pulmonary vein (PV) ostia, left atrial (LA) isthmus and roof, cavotricuspid isthmus (CTI), and right atrial appendage (RAA) were recorded for 30 patients using Ensite-NavX. The right subclavian vein, left brachiocephalic vein, azygos vein, pulmonary arteries, and a static reference were included. The displacement from a mean position was calculated for each pair of sites. Respiration effects were assessed by the shift of the motion curve during in- and expiration phases. RESULTS: The PVs showed a mean interpair displacement of 4.1 +/- 0.2 mm and a shift of 5.0 +/- 0.5 mm. Proximal CS references for all LA structures (4.0 +/- 1.1 mm) were superior to the static reference (4.9 +/- 0.7 mm; P = .01). In addition, the shift due to respiration was less pronounced at 3.5 +/- 0.8 mm versus 4.9 +/- 0.5 mm (P = .004), respectively. Motion of extracardiac vessels was influenced by a mean shift of 6.8 +/- 1 mm. The remote subclavian and brachiocephalic veins were more affected (7.6 +/- 0.7 mm) than the pulmonary arteries (5.9 +/- 0.4 mm; P = .002). For the CTI, a minimized mean displacement of less than 4.6 +/- 2.0 mm relative to the proximal CS, RAA, and azygos vein was found. CONCLUSION: Respiration is the major source of relative motion, which increases with distance from the heart. For LA procedures, a proximal CS reference position is superior to a static reference position.

Catheter ablation of multiple ventricular tachycardias after myocardial infarction guided by combined contact and noncontact mapping.

BACKGROUND: Insights gained from noncontact mapping of ventricular tachycardia (VT) have not been systematically applied to contact maps. This study sought to unify both techniques for an individualized approach to the patient with multiple ischemic VTs irrespective of cycle length. METHODS AND RESULTS: For 12 consecutive patients with chronic myocardial infarction and recurrent VT, bipolar contact maps were acquired during sinus or paced rhythm. Additional noncontact maps were obtained during 48 induced VTs (cycle length 192 to 579 ms). Endocardial exit sites were superimposed on contact maps and verified by pace-mapping. Radiofrequency lesions were extended for critical borders defined by multiple neighboring exits and followed the isovoltage contour line of contact maps. Nine critical borders were identified in 8 patients and constituted the substrate for 31 VTs. The voltage at exit sites was 0.8 mV (range 0.1 to 2.3). Noncontact maps revealed 23+/-18% of isthmus conduction. Thirty-seven (77%) of all and 83% of clinically documented VTs were rendered noninducible irrespective of cycle length by application of 27 radiofrequency lesions (range 18 to 56). Spontaneous transitions between distinct VTs along critical borders were demonstrated in 4 patients. Pace-mapping reproduced the QRS morphology of 81% of VTs and was associated with successful ablation (P<0.01). Noninducibility of any sustained VT was reached for 8 (67%) patients. During 15 months (range 5 to 28) of follow-up, 8 patients remained without recurrence, and VT episodes were reduced in the other 4 patients (P<0.01). VT cycle length was not predictive for acute or long-term success. CONCLUSIONS: The combined approach of contact and noncontact mapping effectively defines critical borders as the substrate of multiple VTs without limitation for unstable VTs.