Cardiac medication during pregnancy, data from the ROPAC

BACKGROUND Data on pharmacological management during pregnancy are scarce. The aim of this study was to describe the type and frequency of cardiac medication used in pregnancy in patients with cardiovascular disease and to assess the relationship between medication use and fetal outcome. METHODS AND RESULTS Between 2007 and 2011 sixty hospitals in 28 countries enrolled 1321 pregnant women. All patients had structural heart disease (congenital 66%, valvular 25% or cardiomyopathy 7% or ischemic 2%). Medication was used by 424 patients (32%) at some time during pregnancy: 22% used beta-blockers, 8% antiplatelet agents, 7% diuretics, 2.8% ACE inhibitors and 0.5% statins. Compared to those who did not take medication, patients taking medication were older, more likely to be parous, have valvular heart disease and were less often in sinus rhythm. The odds ratio of fetal adverse events in users versus non-users of medication was 2.6 (95% CI 2.0-3.4) and after adjustment for cardiac and obstetric parameter was 2.0 (95% CI 1.4-2.7). Babies of patients treated with beta-blockers had a significantly lower adjusted birth weight (3140 versus 3240 g, p = 0.002). The highest rate of fetal malformation was found in patients taking ACE inhibitors (8%). CONCLUSION One third of pregnant women with heart disease used cardiac medication during their pregnancy, which was associated with an increased rate of adverse fetal events. Birth weight was significantly lower in children of patients taking beta-blockers. A randomized trial is needed to distinguish the effects of the medication from the effects of the underlying maternal cardiac condition.

Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.

OBJECTIVE Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency. METHODS Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay. RESULTS Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation. INTERPRETATION In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.

Analytical, physiologic, and clinical validation of a radioimmunoassay for measurement of procollagen type III amino terminal propeptide in serum and bronchoalveolar lavage fluid obtained from dogs.

OBJECTIVE To validate a radioimmunoassay for measurement of procollagen type III amino terminal propeptide (PIIINP) concentrations in canine serum and bronchoalveolar lavage fluid (BALF) and investigate the effects of physiologic and pathologic conditions on PIIINP concentrations. SAMPLE POPULATION Sera from healthy adult (n = 70) and growing dogs (20) and dogs with chronic renal failure (CRF; 10), cardiomyopathy (CMP; 12), or degenerative valve disease (DVD; 26); and sera and BALF from dogs with chronic bronchopneumopathy (CBP; 15) and healthy control dogs (10 growing and 9 adult dogs). PROCEDURE A radioimmunoassay was validated, and a reference range for serum PIIINP (S-PIIINP) concentration was established. Effects of growth, age, sex, weight, CRF, and heart failure on S-PIIINP concentration were analyzed. In CBP-affected dogs, S-PIIINP and BALF-PIIINP concentrations were evaluated. RESULTS The radioimmunoassay had good sensitivity, linearity, precision, and reproducibility and reasonable accuracy for measurement of S-PIIINP and BALF-PIIINP concentrations. The S-PIIINP concentration reference range in adult dogs was 8.86 to 11.48 mug/L. Serum PIIINP concentration correlated with weight and age. Growing dogs had significantly higher S-PIIINP concentrations than adults, but concentrations in CRF-, CMP-, DVD-, or CBP-affected dogs were not significantly different from control values. Mean BALF-PIIINP concentration was significantly higher in CBP-affected dogs than in healthy adults. CONCLUSIONS AND CLINICAL RELEVANCE In dogs, renal or cardiac disease or CBP did not significantly affect S-PIIINP concentration; dogs with CBP had high BALF-PIIINP concentrations. Data suggest that the use of PIIINP as a marker of pathologic fibrosis might be limited in growing dogs.

Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero

Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family. We previously showed that disruption of the Speg gene locus in mice leads to a dilated cardiomyopathy with immature-appearing cardiomyocytes. Here we show that cardiomyopathy of Speg(-/-) mice arises as a consequence of defects in cardiac progenitor cell (CPC) function, and that neonatal cardiac dysfunction can be rescued by in utero injections of wild-type CPCs into Speg(-/-) foetal hearts. CPCs harvested from Speg(-/-) mice display defects in clone formation, growth and differentiation into cardiomyocytes in vitro, which are associated with cardiac dysfunction in vivo. In utero administration of wild-type CPCs into the hearts of Speg(-/-) mice results in CPC engraftment, differentiation and myocardial maturation, which rescues Speg(-/-) mice from neonatal heart failure and increases the number of live births by fivefold. We propose that in utero administration of CPCs may have future implications for treatment of neonatal heart diseases.

Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels.

Voltage-gated sodium channels (Nav) are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the Nav. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the Nav by shifting the voltage-dependence of steady state activation toward more negative potentials.

Surgical cryoablation for ventricular tachyarrhythmia arising from the left ventricular outflow tract region.

BACKGROUND Ventricular arrhythmias (VAs) from the left ventricular outflow tract (LVOT) region can be inaccessible for ablation because of epicardial fat or overlying coronary arteries. OBJECTIVE We describe surgical cryoablation of this type of VA. METHODS From March 2009 to 2014, 190 consecutive patients with VAs originating from the LVOT underwent ablation at our institution. Four patients (2%) underwent surgical cryoablation for highly symptomatic VAs after failing catheter ablation. RESULTS In all patients, endocardial or percutaneous epicardial mapping was consistent with origin in the LVOT. In 2 patients, the points of earliest activation during VAs were marked with a bipolar pacing lead in the overlying cardiac vein for guidance during surgery. Surgical cryoablation was successful in 3 of the 4 patients. The fourth patient subsequently had successful endocardial catheter ablation. During a mean follow-up of 22 ± 16 months (range 4-42 months), all patients showed abolition of or marked reduction in symptomatic VA. However, 1 patient subsequently required percutaneous intervention to the left anterior descending coronary artery; another developed progressive left ventricular systolic dysfunction caused by nonischemic cardiomyopathy; and a third patient underwent permanent pacemaker implantation because of complete atrioventricular block after concomitant aortic valve replacement. CONCLUSION Surgical cryoablation is an option for highly symptomatic drug-resistant VAs emanating from the LVOT region. Despite extensive preoperative mapping, the procedure is not effective for all patients, and coronary injury is a risk.

Ablation of ischemic ventricular tachycardia: evidence, techniques, results, and future directions

PURPOSE OF REVIEW This article summarizes current understanding of the arrhythmia substrate and effect of catheter ablation for infarct-related ventricular tachycardia, focusing on recent findings. RECENT FINDINGS Clinical studies support the use of catheter ablation earlier in the course of ischemic disease with moderate success in reducing arrhythmia recurrence and shocks from implantable defibrillators, although mortality remains unchanged. Ablation can be lifesaving for patients presenting with electrical storm. Advanced mapping systems with image integration facilitate identification of potential substrate, and several different approaches to manage hemodynamically unstable ventricular tachycardia have emerged. Novel ablation techniques that allow deeper lesion formation are in development. SUMMARY Catheter ablation is an important therapeutic option for preventing or reducing episodes of ventricular tachycardia in patients with ischemic cardiomyopathy. Present technologies allow successful ablation in the majority of patients, even when the arrhythmia is hemodynamically unstable. Failure of the procedure is often because of anatomic challenges that will hopefully be addressed with technological progress.

Long Term Outcomes Following Catheter Ablation of Ventricular Tachycardia in Patients with and without Structural Heart Disease.

BACKGROUND Long-term outcomes following ventricular tachycardia (VT) ablation are sparsely described. OBJECTIVES To describe long term prognosis following VT ablation in patients with no structural heart disease (no SHD), ischemic (ICM) and non-ischemic cardiomyopathy (NICM). METHODS Consecutive patients (n=695; no SHD 98, ICM 358, NICM 239 patients) ablated for sustained VT were followed for a median of 6 years. Acute procedural parameters (complete success [non-inducibility of any VT]) and outcomes after multiple procedures were reported. RESULTS Compared with patients with no SHD or NICM, ICM patients were the oldest, had more males, lowest left ventricular ejection fraction (LVEF), highest drug failures, VT storms and number of inducible VTs. Complete procedure success was highest in no SHD, compared ICM and NICM patients (79%, 56%, 60% respectively, P<0.001). At 6 years, ventricular arrhythmia (VA)-free survival was highest in no SHD (77%) than ICM (54%) and NICM (38%, P<0.001) and overall survival was lowest in ICM (48%), followed by NICM (74%) and no SHD patients (100%, P<0.001). Age, LVEF, presence of SHD, acute procedural success (non-inducibility of any VT), major complications, need for non-radiofrequency ablation modalities, and VA recurrence were independently associated with all cause mortality. CONCLUSIONS Long term follow up following VT ablation shows excellent prognosis in the absence of SHD, highest VA recurrence and transplantation in NICM and highest mortality in patients with ICM. The extremely low mortality for those without SHD suggests that VT in this population is very rarely an initial presentation of a myopathic process.