Murine studies suggest that aortic-root dilation in Marfan's syndrome is due to excessive signaling by transforming growth factor β (TGF-β) and can be mitigated by TGF-β antagonists, such as ...angiotensin II–receptor blockers (ARBs). This study reviewed data on 18 pediatric patients with Marfan's syndrome who had begun ARB therapy and had been followed for at least 12 months. The rate of increase in aortic-root diameter was significantly slowed after the initiation of ARB therapy.
This study reviewed data on pediatric patients with Marfan's syndrome who had begun ARB therapy. The rate of increase in aortic-root diameter was significantly slowed after the initiation of ARB therapy.
Marfan's syndrome, an autosomal dominant connective-tissue disorder affecting approximately 1 in 5000 people, is caused by mutations in the gene encoding fibrillin-1 (
FBN1
).
1
,
2
FBN1
mutations lead to defects in multiple organ systems, of which the most life-threatening is progressive enlargement and dissection of the aortic root.
3
,
4
Current medical management of Marfan's syndrome is focused on serial cardiac-imaging studies and the use of pharmacologic agents to reduce hemodynamic stress on the aortic wall. Pharmacologic treatment often involves the use of beta-adrenergic–receptor antagonists (beta-blockers), although other agents, such as angiotensin-converting–enzyme (ACE) inhibitors and calcium-channel blockers, have been used . . .
Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression ...accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor—β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal—regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.
For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical ...heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.
We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers.
...Pathogenic mutations in desmosomal and non-desmosomal genes were identified in 577 patients (241 families) from USA and Dutch ARVD/C cohorts. Patients with sudden cardiac death (SCD)/ventricular fibrillation (VF) at presentation (n = 36) were younger (median 23 vs. 36 years; P < 0.001) than those presenting with sustained monomorphic ventricular tachycardia (VT). Among 541 subjects presenting alive, over a mean follow-up of 6 ± 7 years, 12 (2%) patients died, 162 (30%) had sustained VT/VF, 78 (14%) manifested left ventricular dysfunction (EF < 55%), 28 (5%) experienced heart failure (HF), and 10 (2%) required cardiac transplantation. Patients (n = 22; 4%) with >1 mutation had significantly earlier occurrence of sustained VT/VF (mean age 28 ± 12 years), lower VT-/VF-free survival (P = 0.037), more frequent left ventricular dysfunction (29%), HF (19%) and cardiac transplantation (9%) when compared with those with only one mutation. Desmoplakin mutation carriers experienced more than four-fold occurrence of left ventricular dysfunction (40%) and HF (13%) than PKP2 carriers. Missense mutation carriers had similar death-/transplant-free survival and VT/VF penetrance (P = 0.137) when compared with those with truncating or splice site mutations. Men are more likely to be probands (P < 0.001), symptomatic (P < 0.001) and have earlier and more severe arrhythmic expression.
Presentation with SCD/VF occurs at a significantly younger age when compared with sustained monomorphic VT. The genotype of ARVD/C mutation carriers impacts clinical course and disease expression. Male sex negatively modifies phenotypic expression.
Filamin C truncating variants (
) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of
remain incompletely explored. We aimed to ...develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of
carriers.
carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with
and 60 with
-related arrhythmogenic cardiomyopathies were used for prognostic comparison.
Eighty-five patients carrying
were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of
carriers did not significantly differ from
carriers and
carriers. In
carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD.
Among patients referred to tertiary referral centers,
arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.
Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is ...particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive.
The DCM Precision Medicine Study developed
, a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the
booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband.
Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive
(n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the
arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the
arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the
arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 1-sided 95% CI, 1.08-∞). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata (
=0.90).
, a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of these patients.
URL: https://www.
gov; Unique identifier: NCT03037632.
Transthyretin-cardiac amyloidoses (ATTR-CA) are an underdiagnosed but increasingly recognized cause of heart failure. Extracellular deposition of fibrillary proteins into tissues due to a variety of ...inherited transthyretin mutations in ATTRm or due to advanced age in ATTRwt eventually leads to organ failure. In the heart, amyloid deposition causes diastolic dysfunction, restrictive cardiomyopathy with progressive loss of systolic function, arrhythmias, and heart failure. While traditional treatments have consisted of conventional heart failure management and supportive care for systemic symptoms, numerous disease-modifying therapies have emerged over the past decade. From organ transplantation to transthyretin stabilizers (diflunisal, tafamidis, AG-1), TTR silencers (ALN-ATTR02, ISIS-TTR(Rx)), and degraders of amyloid fibrils (doxycycline/TUDCA), the potential for effective transthyretin amyloid therapy is greater now than ever before. In light of these multiple agents under investigation in human clinical trials, clinicians should be familiar with the systemic cardiac amyloidoses, their differing pathophysiology, natural histories, and unique treatment strategies.
Objective
To determine the utility of skin biopsies as a biomarker of disease severity in subjects with amyloid neuropathy.
Methods
Five groups of patients were studied: (1) transthyretin (TTR) ...familial amyloidotic polyneuropathy (FAP; n = 20), (2) TTR mutation carriers without peripheral neuropathy (TTR‐noPN; n = 10), (3) healthy controls (n = 20), (4) diabetic neuropathy disease controls (n = 20), and (5) patients with light‐chain (AL) amyloid (n = 2). All subjects underwent neurological examination and 3mm skin biopsies. Sections were stained with anti‐PGP9.5, anti‐TTR, and Congo red. Intraepidermal (IENFD), sweat gland (SGNFD), and pilomotor nerve fiber densities (PMNFD) were measured. Correlations between the amount of amyloid present (amyloid burden), fiber subtype, and Neuropathy Impairment Score in the Lower Limbs (NIS‐LL) were evaluated.
Results
IENFD, SGNFD, and PMNFD were all significantly reduced in TTR‐FAP patients versus healthy controls, whereas TTR‐noPN subjects had intermediate reductions. Lower nerve fiber densities were associated with NIS‐LL (p < 0.001). Congo red staining revealed brilliant red amyloid deposits confirmed by apple‐green birefringence within dermal collagen, sweat glands, and arrector pili that engulfed axons. The diagnostic sensitivity and specificity to detect amyloid in skin were 70% and 100%. Both AL amyloidosis and 2 of 10 TTR‐noPN subjects were Congo red–positive. Amyloid burden correlated with IENFD (r = −0.63), SGNFD (r = −0.67), PMNFD (r = −0.50), and NIS‐LL (r = −0.57). Wild‐type TTR staining was less prominent in TTR‐FAP patients.
Interpretation
Cutaneous amyloid was detected in 70% of TTR‐FAP and 20% of TTR‐noPN subjects. Amyloid burden correlated strongly with reductions in IENFD, SGNFD, PMNFD, and NIS‐LL. Skin is an attractive tissue to establish an amyloid diagnosis, and amyloid burden has potential as a biomarker to detect treatment effect in TTR‐FAP drug trials. Ann Neurol 2017;82:44–56
Endurance exercise is associated with adverse outcomes in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Exercise recommendations for family members remain ...undetermined.
The purposes of this study were to determine if (1) endurance exercise (Bethesda class C) and exercise intensity (metabolic equivalent hours per year MET-Hr/year) increase the likelihood of fulfilling 2010 Task Force Criteria and ventricular arrhythmias/implantable cardioverter-defibrillator shock (ventricular tachycardia/ventricular fibrillation VT/VF), and (2) exercise restriction to the American Heart Association (AHA)-recommended minimum for healthy adults is associated with favorable outcomes of at-risk family members.
Twenty-eight family members of 10 probands inheriting a PKP2 mutation were interviewed about exercise from age 10. Exercise threshold to maintain overall health was based on the 2007 AHA guidelines of a minimum 390 to 650 MET-Hr/year.
After adjustment for age, sex, and family membership, both participation in endurance athletics (odds ratio OR 7.4, P = .03) and higher-intensity exercise (OR = 4.2, P = .004) were associated with diagnosis (n = 13). Endurance athletes were also significantly more likely to develop VT/VF (n = 6, P = .02). Family members who restricted exercise at or below the upper bound of the AHA goal (≤650 MET-Hr/year) were significantly less likely to be diagnosed (OR = 0.07, P = .002) and had no VT/VF. At diagnosis and first VT/VF, family members had accumulated 2.8-fold (P = .002) and 3.5-fold (P = .03), respectively, greater MET-Hr exercise than the AHA-recommended minimum. Those who developed VT/VF had performed particularly high-intensity exercise in adolescence compared to unaffected family members (age 10-14: P = .04; age 14-19: P = .02).
The results of this study suggest restricting unaffected desmosomal mutation carriers from endurance and high-intensity athletics but potentially not from AHA-recommended minimum levels of exercise for healthy adults.
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