Bicuspid aortic valve (BAV) is a common (0.5-2.0% of general population) congenital heart defect with increased prevalence of aortic dilatation and dissection. BAV has an autosomal dominant ...inheritance with reduced penetrance and variable expressivity. BAV has been described as an isolated trait or associated with syndromic conditions e.g., Marfan Marfan syndrome or Loeys-Dietz syndrome (MFS, LDS). Identification of a syndromic condition in a BAV patient is clinically relevant to personalize aortic surgery indication. A 4-fold increase in BAV prevalence in a large cohort of unrelated MFS patients with respect to general population was reported, as well as in LDS patients (8-fold). It is also known that BAV is more frequent in patients with thoracic aortic aneurysm (TAA) related to mutations in
, and
genes. Moreover, in 8 patients with BAV and thoracic aortic dilation, not fulfilling the clinical criteria for MFS,
mutations in 2/8 patients were identified suggesting that
or other genes involved in syndromic conditions correlated to aortopathy could be involved in BAV. Beyond loci associated to syndromic disorders, studies in humans and animal models evidenced/suggested the role of further genes in non-syndromic BAV. The transcriptional regulator
has been associated with the development and acceleration of calcium deposition. Genome wide marker-based linkage analysis demonstrated a linkage of BAV to loci on chromosomes 18, 5, and 13q. Recently, a role for
/
in aortic valve morphogenesis and endocardial cell differentiation has been reported. BAV has also been associated with a reduced
gene expression or involvement of a locus containing
/
. Much remains to be understood about the genetics of BAV. In the last years, high-throughput sequencing technologies, allowing the analysis of large number of genes or entire exomes or genomes, progressively became available. The latter issue together with the development of "BigData" analysis methods improving their interpretation and integration with clinical data represents a promising opportunity to increase the disease knowledge and diagnosis in monogenic and multifactorial complex traits. This review summarized the main knowledge on the BAV genetic bases, the role of genetic diagnosis in BAV patient managements and the crucial challenges for the comprehension of genetics of BAV in research and diagnosis.
Objectives This study sought to assess the impact of body mass index (BMI) on cardiac phenotypic and clinical course in a multicenter hypertrophic cardiomyopathy (HCM) cohort. Background It is ...unresolved whether clinical variables promoting left ventricular (LV) hypertrophy in the general population, such as obesity, may influence cardiac phenotypic and clinical course in patients with HCM. Methods In 275 adult HCM patients (age 48 ± 14 years; 70% male), we assessed the relation of BMI to LV mass, determined by cardiovascular magnetic resonance (CMR) and heart failure progression. Results At multivariate analysis, BMI proved independently associated with the magnitude of hypertrophy: pre-obese and obese HCM patients (BMI 25 to 30 kg/m2 and >30 kg/m2 , respectively) showed a 65% and 310% increased likelihood of an LV mass in the highest quartile (>120 g/m2 ), compared with normal weight patients (BMI <25 kg/m2 ; hazard ratio HR: 1.65; 95% confidence interval CI: 0.73 to 3.74, p = 0.22 and 3.1; 95% CI: 1.42 to 6.86, p = 0.004, respectively). Other features associated with LV mass >120 g/m2 were LV outflow obstruction (HR: 4.9; 95% CI: 2.4 to 9.8; p < 0.001), systemic hypertension (HR: 2.2; 95% CI: 1.1 to 4.5; p = 0.026), and male sex (HR: 2.1; 95% CI: 0.9 to 4.7; p = 0.083). During a median follow-up of 3.7 years (interquartile range: 2.5 to 5.3), obese patients showed an HR of 3.6 (95% CI: 1.2 to 10.7, p = 0.02) for developing New York Heart Association (NYHA) functional class III to IV symptoms compared to nonobese patients, independent of outflow obstruction. Noticeably, the proportion of patients in NYHA functional class III at the end of follow-up was 13% among obese patients, compared with 6% among those of normal weight (p = 0.03). Conclusions In HCM patients, extrinsic factors such as obesity are independently associated with increase in LV mass and may dictate progression of heart failure symptoms.
Nonobstructive hypertrophic cardiomyopathy (HCM) has been regarded as the predominant hemodynamic form of the disease on the basis of assessment of outflow gradient under resting conditions. We ...sought to prospectively define the prevalence, clinical profile, and significance of left ventricular (LV) outflow tract obstruction under resting conditions and with physiological exercise in a large HCM cohort.
We prospectively analyzed 320 consecutive HCM patients (age, 47+/-17 years), measuring LV outflow gradient at rest, with Valsalva maneuver, and with exercise echocardiography. LV outflow obstruction was present at rest and/or with exercise in 225 patients (70%); 119 had rest gradients > or = 50 mm Hg and were not exercised. Of the other 201 patients with gradients < 50 mm Hg at rest (average, 4+/-9 mm Hg), 106 developed mechanical obstruction to LV outflow resulting from mitral valve-septal contact after exercise (80+/-43 mm Hg), including 76 with marked gradients > or = 50 mm Hg and 46 with heart failure symptoms. The remaining 95 patients (30%) had no or small gradients (< 30 mm Hg) both at rest and with exercise. Valsalva maneuver underestimated the presence and magnitude of exercise-induced obstruction.
Among those patients who come to clinical evaluation, HCM is a predominantly obstructive disease in which LV outflow gradients, frequently associated with heart failure symptoms and often identified only with exercise, are evident in most patients (ie, 70%). Identification of LV outflow obstruction with exercise echocardiography may broaden management options in HCM by identifying symptomatic patients not otherwise regarded as potential candidates for septal reduction therapy. Assessment of subaortic gradients with exercise should be a routine component of the evaluation of HCM patients without outflow obstruction under resting conditions.
Assessment and Significance of Left Ventricular Mass by Cardiovascular Magnetic Resonance in Hypertrophic Cardiomyopathy Iacopo Olivotto, Martin S. Maron, Camillo Autore, John R. Lesser, Luigi Rega, ...Giancarlo Casolo, Marcello De Santis, Giovanni Quarta, Stefano Nistri, Franco Cecchi, Carol J. Salton, James E. Udelson, Warren J. Manning, Barry J. Maron, Left ventricular (LV) mass was assessed by cardiovascular magnetic resonance in 264 patients with hypertrophic cardiomyopathy (HCM), and compared with LV mass in 606 healthy control subjects. The LV mass index in HCM patients significantly exceeded that of control subjects, but was within normal range in 56 patients (21%), and only mildly increased in 18 (16%). Left ventricular mass was weakly related to maximal LV thickness (r2 = 0.38; p < 0.001). During follow-up, markedly increased LV mass index proved a more sensitive predictor of outcome than extreme maximal wall thickness. In distinction to prior perceptions, increased LV mass is not required to establish the clinical diagnosis of HCM.
Genetic variants in transforming growth factor beta (TGF-β) receptors type 1 (TGFBR1) and type 2 (TGFBR2) genes have been associated with different hereditary connective tissue disorders sharing ...thoracic aortic aneurysm and dissection (TAA/D). Mutations in both TGFBR1/2 genes have been described in patients with TAA/D and Marfan syndrome (MFS), and they are associated consistently with Loeys-Dietz syndrome. The existing literature shows discordant data resulting from mutational screening of TGFBR1/2 genes in patients with MFS. The aim of the study was to investigate the role of TGFBR1/2 genetic variants in determining and/or modulating MFS clinical phenotype.
We investigated 75 unrelated patients with MFS referred to the Center for Marfan Syndrome and Related Disorders (Careggi University Hospital, Florence) who were subjected to FBN1 and TGFBR1/2 Sanger mutational screening.
Forty-seven patients with MFS (63%) carried a pathogenetic FBN1 mutation. No pathogenetic mutations were detected in TGFBR1/2 genes. Ten common polymorphisms were identified in TGFBR2 and 6 in TGFBR1. Their association with cardiovascular manifestations was evaluated. Carriers of the A allele of rs11466512, delA allele of c.383delA or delT allele of c.1256-15del1T polymorphisms had a trend toward or significantly reduced z-scores (median interquartile range (IQR), 2.2 1.13-4.77; 2.1 1.72-3.48; 2.5 1.85-3.86) with respect to homozygous patients with wild-type MFS (median IQR, 4.20 2.39-7.25; 3.9 2.19-7.00; 3.9 2.14-6.93). Carriers of the A allele of the rs2276767 polymorphism showed a trend toward increased z-score (median IQR, 4.9 2.14-7.16) with respect to patients with wild-type MFS (median IQR, 3.3 1.75-5.45). The protective effect of TGFBR1/2 genetic score including all the 4 variants was also evaluated. Patients with MFS with two or more protective alleles included in the score had statistically significant reduced aortic z-scores (median IQR, 2.20 1.48-3.37) with respect to patients with 1 or no protective alleles (median IQR, 4.20 2.48-7.12; P = .007). Patients with severe aortic manifestations (aortic z-score ≥ 2 or aortic surgery) showed a significantly lower prevalence of subjects with two or more protective alleles included in the genetic score (29.7%) than patients with no or milder cardiovascular involvement (63.6%; P = .029). The genetic score protective effect on global aortic manifestations severity (aortic z-score ≥ 2 or aortic surgery) was also observed at the logistic regression analysis adjusted for the presence of FBN1 gene mutations (odds ratio, 0.21; 95% CI, 0.05-0.84; P = .028).
In conclusion, our data reappraise the role of TGFBR1 and TGFBR2 as major genes in patients with MFS, and suggest that TGFBR1/2 genetic variants (in particular when evaluated as a burden by score) might play a role in modulating the severity of cardiovascular manifestation in MFS.
Our article provides a useful contribution in defining the role of TGFBR1 and TGFBR2 genes in Marfan syndrome, because inconclusive results from literature concerning their association with this disorder are still present. Our data do not support the role of mutations in TGFBR1 and TGFBR2 genes as major determinants of MFS phenotype; nevertheless, they suggest a role of these genes as modulator of cardiovascular manifestations' severity in patients with Marfan syndrome, thus underlining the importance of the deep understanding of the genetic background in monogenic syndromic disorders.
Surgical myectomy (SM) and alcohol septal ablation (ASA) are two invasive therapies for symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM), despite medical therapy. This ...meta-analysis aims to compare the efficacy of the two procedures. We searched all electronic databases until February 2020 for clinical trials and cohorts comparing clinical outcomes of ASA and SM treatment of patients with HOCM. The primary endpoint was all-cause mortality, cardiovascular (CV) mortality, sudden cardiac death (SCD), re-intervention, and complications. Secondary endpoints included relief of clinical symptoms and drop of left ventricular outflow tract (LVOT) gradient. Twenty studies (4547 patients; 2 CTs and 18 cohorts) comparing ASA vs. SM with a mean follow-up of 47 ± 28.7 months were included. Long term (8.72 vs. 7.84%, p = 0.42) and short term (1.12 vs. 1.27%, p = 0.93) all-cause mortality, CV mortality (2.48 vs. 3.66%, p = 0.26), SCD (1.78 vs. 0.76%, p = 0.20) and stroke (0.36 vs. 1.01%, p = 0.64) were not different between procedures. ASA was associated with lower peri-procedural complications (5.57 vs. 10.5%, p = 0.04) but higher rate of re-interventions (10.1 vs. 0.27%; p < 0.001) and pacemaker dependency (12.4 vs. 4.31%, p = 0.0004) compared to SM. ASA resulted in less reduction in LVOT gradient (−47.8 vs. −58.4 mmHg, p = 0.01) and less improvement of clinical symptoms compared to SM (New York Heart Association (NYHA) class III/IV, 82.4 vs. 94.5%, p < 0.001, angina 53.2 vs. 84.2%, p = 0.02). Thus, ASA and SM treatment of HOCM carry a similar risk of mortality. Peri-procedural complications are less in alcohol ablation but re-intervention and pacemaker implantations are more common. These results might impact the procedure choice in individual patients, for the best clinical outcome.
We present a case report of an older patient with aortic stenosis who was managed before and after transcatheter aortic valve implantation by a team of cardiologists but without the support of a ...geriatrician. We first describe the patient's post-interventional complications from a geriatric perspective and afterwards, discuss the unique approach that the geriatrician would have provided. This case report was written by a group of geriatricians working in an acute hospital, along with a clinical cardiologist who is an expert in aortic stenosis. We discuss the implications for modifying conventional practice in tandem with existing literature.
Objectives The purpose of this study was to assess myocardial blood flow (MBF) using positron emission tomography in patients with hypertrophic cardiomyopathy (HCM) according to genetic status. ...Background Coronary microvascular dysfunction is an important feature of HCM, associated with ventricular remodeling and heart failure. We recently demonstrated the increased prevalence of systolic dysfunction in patients with HCM with sarcomere myofilament gene mutations and postulated an association between genetic status and coronary microvascular dysfunction. Methods Maximum MBF (intravenous dipyridamole, 0.56 mg/kg; Dip-MBF) was measured using13 N-labeled ammonia in 61 patients with HCM (age 38 ± 14 years), genotyped by automatic DNA sequencing of 8 myofilament-encoding genes (myosin-binding protein C, beta-myosin heavy chain, regulatory and essential light chains, troponin T, troponin I, troponin C, alpha-tropomyosin, and alpha-actin). In 35 patients, cardiac magnetic resonance imaging was performed. Results Fifty-three mutations were identified in 42 of the 61 patients (genotype positive; 69%). Despite similar clinical profiles, genotype-positive patients with HCM showed substantially lower Dip-MBF compared with that of genotype-negative patients (1.7 ± 0.6 ml/min/g vs. 2.4 ± 1.2 ml/min/g; p < 0.02). A Dip-MBF <1.5 ml/min/g had 81% positive predictive value for genotype-positive status and implied a 3.5-fold independent increase in likelihood of carrying myofilament gene mutations (hazard ratio: 3.52; 95% confidence interval: 1.05 to 11.7; p = 0.04). At cardiac magnetic resonance imaging, the prevalence of late gadolinium enhancement was greater in genotype-positive patients (22 of 23 96% compared with 8 of 12 67% genotype-negative patients; p = 0.038). Conclusions Patients with HCM with sarcomere myofilament mutations are characterized by more severe impairment of microvascular function and increased prevalence of myocardial fibrosis, compared with genotype-negative individuals. These findings suggest a direct link between sarcomere gene mutations and adverse remodeling of the microcirculation in HCM, accounting for the increased long-term prevalence of ventricular dysfunction and heart failure in genotype-positive patients.
OBJECTIVE To determine the influence of a positive genetic test for hypertrophic cardiomyopathy (HCM) on clinical outcome. PATIENTS AND METHODS A cohort of 203 unrelated patients with HCM (mean ± SD ...age, 50±18 years) was enrolled from January 1, 2002, through December 31, 2003. They were followed up for a mean ± SD time of 4.0±1.7 years after genetic testing of the 8 HCM-susceptibility genes that encode key sarcomeric/myofilament proteins. The clinical phenotype of those with a positive genetic test (myofilament-positive HCM) was compared with those with a negative genetic test (myofilament-negative HCM). RESULTS In this cohort of 203 patients, 87 mutations were identified in 126 patients (myofilament-positive HCM, 62%); the remaining 77 patients (38%) were myofilament-negative. Despite similar baseline features, patients with myofilament-positive HCM showed increased risk of the combined end points of cardiovascular death, nonfatal stroke, or progression to New York Heart Association class III or IV compared with the patients with myofilament-negative HCM (25% vs 7%, respectively; independent hazard ratio, 4.27; P =.008). These end points occurred at any age among patients with myofilament-positive HCM (range, 14-86 years), but only in those aged 65 years and older among patients with myofilament-negative HCM. Moreover, patients with myofilament-positive HCM showed greater probability of severe left ventricular systolic and diastolic dysfunction, defined as an ejection fraction of less than 50% and a restrictive filling pattern ( P =.02 and P <.02, respectively, vs myofilament-negative HCM). CONCLUSION Screening for sarcomere protein gene mutations in HCM identifies a broad subgroup of patients with increased propensity toward long-term impairment of left ventricular function and adverse outcome, irrespective of the myofilament (thick, intermediate, or thin) involved.
The presence of left ventricular (LV) diastolic dysfunction (DD) as characterized by Doppler echocardiography is associated with worse overall mortality both in symptomatic and asymptomatic patients. ...However, available data on this topic come from referral centers and have been obtained by different, validated algorithms for each single study. Thus, we aimed at determining the feasibility of comprehensive evaluation of LVDD in a primary care outpatient setting and at testing the concordance of different methodological approaches in grading diastolic dysfunction. Eight hundred eighty-five consecutive outpatients, in sinus rhythm, prospectively underwent Doppler echocardiography according to a predetermined protocol. Feasibility of each LV diastolic index and concordance between 3 methods to determine the degree of LVDD, namely the American Society of Echocardiography/European Association of Echocardiography (ASE/EAE) recommendations, the Olmstead County, and the Canberra Study protocols, were tested. Feasibility of all diastolic indexes was high, ranging from 93% of Valsalva maneuver to ≥99% for mitral inflow and tissue Doppler parameters. Diastolic function was not classifiable in 6% to 19% of patients. The concordance for LV diastolic dysfunction degree was fair when comparing the classification of the ASE/EAE with those from Olmstead County (κ = 0.25; reclassification rate 51%) and Canberra Study (κ = 0.27; reclassification rate 43.7%), and was good for the comparison between the Olmstead County and Canberra classifications (κ = 0.68, reclassification rate 27%). In conclusion, feasibility of LV diastolic function measurements is very high and grading diastolic dysfunction is possible in most patients in primary care settings. Substantial differences, however, exist when concordance is tested among 3 documented criteria, resulting in poor concordance of data interpretation and hence patient stratification and clinical management.
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