Mahesh Kappanayil

Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis

BackgroundVascular elasticity is crucial for maintaining hemodynamics. Molecular mechanisms involved in human elastogenesis are incompletely understood. We describe a syndrome of lethal arteriopathy associated with a novel,identical mutation in the fibulin 4 gene (FBLN4) in a unique cohort of infants from South India.MethodsClinical characteristics, cardiovascular findings, outcomes and molecular genetics of twenty-two infants from a distinct population subgroup,presenting with characteristic arterial dilatation and tortuosity during the period August 2004 to June 2011 were studied.ResultsPatients (11 males, 11 females) presented at median age of 1.5 months,belonging to unrelated families from identical ethno-geographical background; eight had a history of consanguinity. Cardiovascular features included aneurysmal dilatation, elongation, tortuosity and narrowing of the aorta, pulmonary artery and their branches. The phenotype included a variable combination of cutis laxa (52%), long philtrum-thin vermillion (90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%),sagging cheeks (43%), long slender digits (48%), and visible arterial pulsations (38%). Genetic studies revealed an identical c.608A > C (p. Asp203Ala) mutation in exon 7 of the FBLN4 gene in all 22 patients, homozygous in 21, and compound heterozygous in one patient with a p. Arg227Cys mutation in the same conserved cbEGF sequence.Homozygosity was lethal (17/21 died, median age 4 months). Isthmic hypoplasia (n = 9) correlated with early death (≤4 months).ConclusionsA lethal, genetic disorder characterized by severe deformation of elastic arteries, was linked to novel mutations in the FBLN4 gene. While describing a hitherto unreported syndrome in this population subgroup, this study emphasizes the critical role of fibulin-4 in human elastogenesis.

Preoperative Determinants of Outcomes of Infant Heart Surgery in a Limited-Resource Setting

We studied the effect of preoperative determinants on early outcomes of 1028 consecutive infant heart operations in a limited-resource setting. Comprehensive data on pediatric heart surgery (January 2010-December 2012) were collected prospectively. Outcome measures included in-hospital mortality, prolonged ventilation (>48 hours), and bloodstream infection (BSI) after surgery. Preoperative variables that showed significant individual association with outcome measures were entered into a logistic regression model. Weight at birth was low in 224 infants (21.8%), and failure to thrive was common (mean-weight Z score at surgery was 2.72 ± 1.7). Preoperatively, 525 infants (51%) needed intensive care, 69 infants (6.7%) were ventilated, and 80 infants (7.8%) had BSI. In-hospital mortality (4.1%) was significantly associated with risk adjustment for congenital heart surgery-1 (RACHS-1) risk category (P < 0.001). Neonatal status, preoperative BSI, and requirement of preoperative intensive care and ventilation had significant individual association with adverse outcomes, whereas low birth weight, prematurity, and severe failure to thrive (weight Z score <-3) were not associated with adverse outcomes. On multivariable logistic regression analysis, preoperative sepsis (odds ratio = 2.86; 95% CI: 1.32-6.21; P = 0.008) was associated with mortality. Preoperative intensive care unit stay, ventilation, BSI, and RACHS-1 category were associated with prolonged postoperative ventilation and postoperative sepsis. Neonatal age group was additionally associated with postoperative sepsis. Although severe failure to thrive was common, it did not adversely affect outcomes. In conclusions, preoperative BSI, preoperative intensive care, and mechanical ventilation are strongly associated with adverse outcomes after infant cardiac surgery in this large single-center experience from a developing country. Failure to thrive and low birth weight do not appear to adversely affect surgical outcomes.

Impact of the International Quality Improvement Collaborative on outcomes after congenital heart surgery: A single center experience in a developing economy

Background: The International Quality Improvement Collaborative (IQIC) for Congenital Heart Surgery in Developing Countries was initiated to decrease mortality and major complications after congenital heart surgery in the developing world. Objective: We sought to assess the impact of IQIC on postoperative outcomes after congenital heart surgery at our institution. Methods: The key components of the IQIC program included creation of a robust worldwide database on key outcome measures and nurse education on quality driven best practices using telemedicine platforms. We evaluated 1702 consecutive patients ≤18 years undergoing congenital heart surgery in our institute from January 2010-December 2012 using the IQIC database. Preoperative variables included age, gender, weight at surgery and surgical complexity as per the RACHS-1 model. The outcome variables included, in- hospital mortality, duration of ventilation, intensive care unit (ICU) stay, bacterial sepsis and surgical site infection. Results: The 1702 patients included 771(45.3%) females. The median age was 8 months (0.03-216) and the median weight was 6.1Kg (1-100). The overall in-hospital mortality was 3.1%, Over the three years there was a significant decline in bacterial sepsis (from 15.1%, to 9.6%, P < 0.001), surgical site infection (11.1% to 2.4%, P < 0.001) and duration of ICU stay from 114(8-999) hours to 72 (18-999) hours (P < 0.001) The decline in mortality from (4.3% to 2.2%) did not reach statistical significance. Conclusions: The inclusion of our institution in the IQIC program was associated with improvement in key outcome measures following congenital heart surgery over a three year period.

Three-dimensional-printed cardiac prototypes aid surgical decision-making and preoperative planning in selected cases of complex congenital heart diseases: Early experience and proof of concept in a resource-limited environment

Introduction: Three-dimensional. (3D) printing is an innovative manufacturing process that allows computer.assisted conversion of 3D imaging data into physical “printouts” Healthcare applications are currently in evolution. Objective: The objective of this study was to explore the feasibility and impact of using patient-specific 3D-printed cardiac prototypes derived from high.resolution medical imaging data. (cardiac magnetic resonance imaging/computed tomography. [MRI/CT]) on surgical decision-making and preoperative planning in selected cases of complex congenital heart diseases. (CHDs). Materials and Methods: Five patients with complex CHD with previously unresolved management decisions were chosen. These included two patients with complex double.outlet right ventricle, two patients with criss-cross atrioventricular connections, and one patient with congenitally corrected transposition of great arteries with pulmonary atresia. Cardiac MRI was done for all patients, cardiac CT for one; specific surgical challenges were identified. Volumetric data were used to generate patient-specific 3D models. All cases were reviewed along with their 3D models, and the impact on surgical decision-making and preoperative planning was assessed. Results: Accurate life-sized 3D cardiac prototypes were successfully created for all patients. The models enabled radically improved 3D understanding of anatomy, identification of specific technical challenges, and precise surgical planning. Augmentation of existing clinical and imaging data by 3D prototypes allowed successful execution of complex surgeries for all five patients, in accordance with the preoperative planning. Conclusions: 3D-printed cardiac prototypes can radically assist decision-making, planning, and safe execution of complex congenital heart surgery by improving understanding of 3D anatomy and allowing anticipation of technical challenges.

Two-ventricle repair for complex congenital heart defects palliated towards single-ventricle repair

OBJECTIVES Complex congenital heart defects that present earlier in life are sometimes channelled towards single-ventricle repair, because of anatomical or logistic challenges involved in two-ventricle correction. Given the long-term functional and survival advantage, we have been consciously exploring the feasibility of a biventricular repair in these patients when they present later for Fontan completion. METHODS Since June 2009, 71 patients were referred for staged completion of the Fontan procedure. Following detailed evaluation that included three-dimensional echocardiography and magnetic resonance imaging, 10 patients (Group 1-median age 6 years) were identified and later underwent complex biventricular repair with takedown of Glenn shunt, while completion of extracardiac Fontan repair was done in 61 patients (Group 2-median age 7 years). RESULTS Two-ventricle repair was accomplished in all the 10 Group 1 patients. One patient developed complete heart block requiring permanent pacemaker insertion. Late patch dehiscence occurred in another (awaiting repair). At a median follow-up of 15 months, there was no mortality among the Group 1 patients and all except for 1 patient were symptom free. There were 2 early deaths (3.3%) in the Group 2 patients. CONCLUSIONS Two-ventricular repair, although surgically challenging, should be considered in all patients with two functional ventricles who come for Fontan completion. Comprehensive preoperative imaging and meticulous planning helps in identifying suitable candidates.

Screening for TBX1 Gene in Children With or Without Microdeletion of Chromosome 22q11 and Conotruncal Defect

Objective: In order to understand the role of the TBX1 gene in humans, Indian children with or without a microdeletion of chromosome 22q11 and conotruncal defects were screened by fluorescent in situ hybridization (FISH) using a TBX1 commercial probe. Methods: All patients were tested with commercial FISH probes on chromosome 22q11. Besides these, the deletion of the distal arm of chromosome 10 was analyzed, and phenotypic features were also taken into consideration. Results: A comparable result showing 22q11 deletion was obtained using the 3 probes (TBX1, TUPLE1, and N25) from the chromosome 22q11 region. Conclusion: The study confirms the role of contiguous genes including TBX1 in the pathogenesis of conotruncal defects. It also indicates that in a routine clinical practice either of the FISH probes (ie, TUPLE1, N25 or TBX1) can be used to detect 22q11 deletion. Such genetic testing is important, since patients with 22q11 deletion need early medical intervention based on associated symptoms.

Variation in prevalence of chromosome 22q11 deletion in subtypes of conotruncal defect in 254 children.

Aim:  To determine the frequency of chromosomal aberrations particularly 22q11 deletion in Indian children ≤2 years with different types of conotruncal malformations and their association with abnormal aortic arch. Additionally, extracardiac features were also studied.

Images in cardiovascular medicine. Arterial tortuosity syndrome: phenotypic features and cardiovascular manifestations.

Arterial tortuosity syndrome is a recently defined rare genetic syndrome with autosomal recessive inheritance characterized by elongation, tortuosity, stenosis, and aneurysm formation of major arteries. These images are of a 1-year-old girl with arterial tortuosity syndrome. She was a first-born child of nonconsanguineous parentage and was referred with recurrent respiratory tract infections since 7 months of age. She …Arterial tortuosity syndrome is a recently defined rare genetic syndrome with autosomal recessive inheritance characterized by elongation, tortuosity, stenosis, and aneurysm formation of major arteries. These images are of a 1-year-old girl with arterial tortuosity syndrome. She was a first-born child of nonconsanguineous parentage and was referred with recurrent respiratory tract infections since 7 months of age. She …

Arterial Tortuosity Syndrome Phenotypic Features and Cardiovascular Manifestations

Arterial tortuosity syndrome is a recently defined rare genetic syndrome with autosomal recessive inheritance characterized by elongation, tortuosity, stenosis, and aneurysm formation of major arteries. These images are of a 1-year-old girl with arterial tortuosity syndrome. She was a first-born child of nonconsanguineous parentage and was referred with recurrent respiratory tract infections since 7 months of age. She …Arterial tortuosity syndrome is a recently defined rare genetic syndrome with autosomal recessive inheritance characterized by elongation, tortuosity, stenosis, and aneurysm formation of major arteries. These images are of a 1-year-old girl with arterial tortuosity syndrome. She was a first-born child of nonconsanguineous parentage and was referred with recurrent respiratory tract infections since 7 months of age. She …

Acute rheumatic fever: Subcutaneous nodules and carditis

We present images of an 8-year-old child with a fever for the preceding 45 days, migratory polyarthralgia involving large joints, and progressively worsening dyspnea on exertion. Examination revealed subcutaneous nodules over the bony prominences of the spine, scapulae, forehead, extensor surfaces of bilateral elbow joints and knee joints, ankles, and the rib cage (Figure 1). The nodules were 0.5 to 1.5 cm in size, rounded, firm, nontender, and mobile. A …