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Ventricular Arrhythmias in Heart Failure
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Antonis S. Manolis, Antonis A. Manolis, Theodora A. Manolis
Particularly for patients with NICM, optimal HF therapy should precede the decision for ICD implantation by ≥3 months. The SCD-HeFT trial (n=792) provided clear evidence that favored ICD over amiodarone in prevention of SCD in NICM (hazard ratio 0.77, p=0.007).78 Recently, the DANISH trial (n=1,116, LVEF <35%) raised concerns about the role of ICDs in primary prevention of SCD in patients with NICM. ICDs reduced SCD from 8.4% to 4.3% over a mean of 5.6 years, but with no difference in all-cause mortality.98 However, this trial differed from previous trials as over 50% (58%) of patients in both (ICD and medical) arms received CRT (CRT-D or CRT-P). Subsequent meta-analyses that included the DANISH trial did confirm survival benefit from ICD implantation in NICM patients (22–25% relative risk reduction in mortality).99,100 The majority of data involved patients with NYHA class II–ambulatory IV patients; hence, there is uncertainty about the utility of ICD in NICM patients with class I or class IV HF symptoms. Finally, a special group of familial NICM patients includes patients with laminopathies caused by mutations mainly in the lamin A/C gene, who appear to have a high risk of SCD, especially when they are men and have NSVT on Holter monitor, LVEF <45%, and non-missense mutations.101 However, even lamin A/C patients with preserved (>45%) LVEF are at high risk of malignant ventricular arrhythmias in the presence of significant conduction disorders (hazard ratio 5.20; p=0.03).102
Genetics of heart failure
Published in ILEANA PIÑA, SIDNEY GOLDSTEIN, MARK E DUNLAP, The Year in Heart Failure, 2005
RAY HERSHBERGER, EMILY BURKETT
Taylor MRG, Fain PR, Sinagra G, eta/. JAm Col/ Cardio/2003 ; 41: 771-80 BAcK G R o uNo. Mutations in LMNA have been found in patients with DCM with familial conduction defects and muscular dystrophy, but the clinical spectrum, prognosis and clinical relevance of laminopathies In DCM are largely unknown. The authors examined the prevalence, genotype-phenotype correlation and natural history of LMNA gene mutations In subjects with DCM. A cohort of 49 nuclear families, 40 with familial DCM and nine with sporadic DCM (269 subjects, 105 affected), was screened for mutations in LMNA using denaturing high-performance liquid chromatography and sequence analysis. Bivariate analysis of clinical predictors of LMNA mutation carrier status and Kaplan-Meier survival analysis were performed.
Hepatitis D virus (HDV): investigational therapeutic agents in clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Initially designed as a cancer therapeutic, the use of lonafarnib as an HDV therapeutic is predicated upon the inhibition of prenylation of L-HDAg. Distinct from entry inhibition, prenylation in HDV is necessary for HDV viral assembly. Boosting of lonafarnib with ritonavir has allowed for increase in serum drug levels while minimizing adverse gastrointestinal side effects without evidence of viral resistance. Triple therapy with lonafarnib, ritonavir, and pegylated interferon has resulted in a significant reduction in HDV RNA and is currently in phase 3 investigation. Notably, lonafarnib has received orphan drug designation by the U.S. FDA and EMA along with fast track and breakthrough designation by the U.S. FDA and PRIME designation by the EMA for HDV and has been approved for use by the FDA for the treatment of Hutchinson-Guilford Progeria Syndrome and processing-deficient progeroid laminopathies. Lonafarnib is taken orally, which may facilitate daily administration and patient adherence.
Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment
Published in Expert Opinion on Drug Safety, 2019
Claire Lagathu, Véronique Béréziat, Jennifer Gorwood, Soraya Fellahi, Jean-Philippe Bastard, Corinne Vigouroux, Franck Boccara, Jacqueline Capeau
In vitro studies reported that some PIs altered adipocyte function and induced insulin resistance. One possible mechanism is the ability of these molecules to inhibit the enzyme ZMP-STE24 involved into the maturation of the nuclear matrix protein prelamin-A into lamin-A [35,36]. Accumulation of prelamin A, which keeps a farnesyl anchor inserted in the nuclear membrane, resulted in altered adipocyte function and insulin resistance [36,37]. Such alterations are also observed in patients with genetic forms of lipodystrophy due to mutations in the gene encoding lamin A/C, called laminopathies, with central fat redistribution, neck fat accumulation, peripheral lipoatrophy, and insulin resistance, resembling the HIV-related lipodystrophic phenotype [38]. We have also shown that abnormal lamin network precludes the maturation and intranuclear localization of the transcription factor SREBP-1c required for lipogenesis [36], therefore linking adipose dysfunction and altered lipid metabolism. Different PIs present different efficacy to inhibit the enzyme ZMP-STE24 and induce prelamin-A accumulation. The newer ones, atazanavir and darunavir, have milder effects than indinavir, lopinavir and ritonavir [35,39].
Understanding left ventricular hypertrabeculation/noncompaction: pathomorphologic findings and prognostic impact of neuromuscular comorbidities
Published in Expert Review of Cardiovascular Therapy, 2019
Claudia Stöllberger, Josef Finsterer
The prevalence of different NMDs in LVHT, however, is at present unknown since NMDs are not searched in every LVHT patient systematically, and even when they are searched and found, no definite diagnosis can be established in many cases due to organizational and financial restrictions. Furthermore, the prevalence of LVHT in different NMDs is unknown, since not all patients with NMDs are cardiologically investigated and even when they are, LVHT may be overlooked [149]. Furthermore, LVHT may develop over time or possibly LVHT is present for a certain time and disappears after consolidation of the cardiac function. Only if patients with NMD would undergo serial echocardiographic examinations these questions would be resolved. So far, NMDs most frequently associated with LVHT reported are the Barth syndrome and the mitochondrial disorders. NMDs more rarely associated with LVHT include the zaspopathy, laminopathies and myotonic dystrophies [149].