Wild-Type Transthyretin Amyloid Cardiomyopathy: The Gordian-Knot of Novel Therapeutic Regimens.

Wild-type TTR amyloidosis (wtATTR) represents a disease difficult to diagnose with poor prognosis. Increased clinical suspicion is key, allowing for timely diagnosis. Until recently, only off-label therapies were available but recent introduction of disease specific therapy has shown potential to alter the natural history of the disease. Tafamidis, the only currently approved drug for the therapy of wtATTR, provided significantly better survival and quality of life. However, not all subgroups of patients derived equal benefit. This, along with the increased cost of treatment raised question on whether treatment should be invariably administered through the wtATTR population. This review aims to summarize current evidence on the natural history and staging systems for wtATTR, as well as available treatment options. Special consideration is given to the selection process of patients who would be expected to gain maximum benefit from tafamidis treatment, based on an ethical and cost-effective point of view.

Left Atrial Myopathy is Associated With Exercise Incapacity and Ventilatory Inefficiency in Hypertrophic Cardiomyopathy.

BACKGROUND: Left atrial (LA) myopathy is an established component of hypertrophic cardiomyopathy (HCM); however, the data about its association with exercise incapacity or ventilatory inefficiency that may be seen in HCM patients are limited. This study aimed to explore the association between LA myopathy, evaluated by echocardiography LA strain, and exercise capacity and ventilatory efficiency, evaluated by cardiopulmonary exercise testing (CPET), in HCM patients. METHODS: This study included 241 consecutive HCM patients (aged 51.2±15.7 years 67.2% male) in sinus rhythm who underwent CPET and transthoracic echocardiography at the same visit. Exercise incapacity (maximal/predicted oxygen consumption [%peakVO2] <80%) and ventilatory inefficiency (ventilation/carbon dioxide output [VE/VCO2] slope >34) were assessed by CPET. Left atrial myopathy was examined by speckle-tracking myocardial deformation parameters: LA reservoir, conduit and booster strain. RESULTS: All three LA strain values were univariate predictors of exercise capacity and ventilatory efficiency. Among them, LA reservoir strain had the higher r correlation coefficient for predicting both %peakVO2 and VE/VCO2 slope. Left atrial reservoir strain, presence of angina and family history of HCM were independent predictors of exercise capacity. Left atrial reservoir strain, male gender and non-sustained ventricular tachycardia were independent predictors of ventilatory efficiency. Left atrial reservoir strain was a significant predictor of %peakVO2<80% with an optimal cut-off value of 27% (sensitivity 87% and specificity 31%) and VE/VCO2>34 with an optimal cut-off value of 18% (sensitivity 71% and specificity 83%). CONCLUSION: Left atrial myopathy, as reflected by the LA strain values, was associated with exercise incapacity and ventilatory inefficiency in HCM individuals. Left atrial reservoir strain was the only common independent predictor of %peakVO2 and VE/VCO2 slope.

The predictive value of left ventricular and left atrial mechanics for atrial fibrillation and heart failure in hypertrophic cardiomyopathy: a prospective cohort study.

Atrial fibrillation (AF) and heart failure (HF) represent clinical turning points, altering the natural history of HCM and influencing long-term outcome of the disease. The aim of this study was to evaluate the ability of left ventricular (LV) and left atrial (LA) myocardial deformation parameters to predict new-onset AF and HF outcomes in patients with HCM. This was a prospective study that included HCM patients without severe valvular heart disease, prior myocardial infarction or history of AF. The study sample consisted of 250 patients (mean age 50.8 ± 15.8, 67.2% male). Two-dimensional (2D) speckle tracking deformation parameters including global longitudinal strain (GLS), radial strain, circumferential strain, LA reservoir strain (LAεres), LA conduit strain (LAεcon) and LA booster strain(LAεboost) were examined. During a mean follow-up of 2.5 ± 1.2 years, 44 patients developed new-onset AF. All the LV and LA deformation parameters were significant univariate predictors of AF. GLS and LAεres had the highest C statistic among the LV and LA functional indices. In multivariable analysis, only LAεres remained an independent predictor of the arrhythmia (HR 0.91, 95% CI 0.85-0.98, p: 0.008). Similarly, GLS and LAεres had the highest predictive value among the 2D speckle tracking parameters for HF outcomes. LAεres remained an independent predictor after adjusting for significant covariates. GLS and LAεres demonstrated high predictive value for the development of AF and HF in HCM. LAεres was the only independent predictor of both outcomes.Clinical trial registration: ClinicalTrials.gov identifier: NCT04112511.

Correlation of miR-146a-5p plasma levels and rs2910164 polymorphism with left ventricle outflow tract obstruction in hypertrophic cardiomyopathy.

OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium that is characterized by phenotypic variability among patients. miR-146a is a small non-coding RNA that is well known for its role in inflammation and myocardial hypertrophy. The aim of this study is to evaluate the role of miR-146a as a candidate genetic factor influencing HCM phenotype. METHODS: In this study, 140 HCM patients and 112 control individuals were genotyped for the rs2910164 single nucleotide polymorphism (SNP) in the MIR146A gene; using this data, the correlation between different genotypes and clinical features of the disease were determined. Additionally, plasma levels of miR-146a-5p were determined in 50 HCM patients and 30 control individuals by using qPCR. RESULTS: The incidence of GC and CC genotypes were significantly lower in HCM patients (odds ratio (OR) = 0.5 [0.3-0.8], p = 0.007). The GC/CC genotypes in the dominant genetic model positively correlated with the presence of left ventricle outflow tract (LVOT) obstruction (OR = 2.3 [1.2-4.7] and p = 0.018), a higher left ventricle mass index (118 ± 47 g/m2 vs 92 ± 42 g/m2 and p = 0.02), and increased left ventricle end-diastolic diameter (4.66 ± 0.64cm vs 4.39 ± 0.7cm and p = 0.026). Atrial fibrillation was significantly higher in patients homozygous for the C allele (OR = 10.6 [2-55], p = 0.003). Interestingly, the plasma levels of miR-146a-5p were significantly increased in HCM patients with LVOT obstruction. CONCLUSION: Our findings indicate that the C allele of the rs2910164 SNP might be under negative selection in HCM patients. Additionally, plasma levels of miR-146a-5p and GC/CC genotypes are indicative of the obstructive phenotype in HCM patients.

The natural history of hypertrophic cardiomyopathy in a large Mediterranean cohort.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) represents the most common inherited cardiomyopathy and it is characterized by phenotypic and genetic heterogeneity. The purpose of our study was to investigate the natural history of HCM in a large Mediterranean cohort and to identify predictors of outcomes. METHODS: The clinical and echocardiographic characteristics of 690 patients with HCM were examined. The predictors of mortality and sudden cardiac events were examined during a mean follow-up of 8.5 years. RESULTS: Asymmetrical hypertrophy was the most common among our cohort (82.9%) followed by apical hypertrophy pattern (13.6%). Atrial fibrillation was present in 22.3%, whereas nonsustained ventricular tachycardia occurred in 10.4% of the patients. During follow-up, a total of 7.4% of patients died. Specifically, 5.5% HCM patients died from cardiovascular causes, including 2.8% from heart failure and 2% from sudden death. Obstructive phenotype did not have any effect on mortality. Atrial fibrillation, ejection fraction and right ventricular systolic pressure (RVSP) were common independent predictors for overall and cardiovascular mortality. A total of 6.1% of HCM patients suffered sudden arrhythmic events and maximal wall thickness, ejection fraction, nonsustained ventricular tachycardia, syncopal episodes and, more importantly, the presence of an apical aneurysm were all independent risk factors. CONCLUSION: HCM is a relatively benign cardiomyopathy in Greece, similarly to other countries. Apical hypertrophy pattern is more common in Greece than in the other European countries, whereas the presence of apical aneurysm is the most important risk factor for arrhythmic events on top of the established risk factors for sudden death.

Motivational interviewing to support LDL-C therapeutic goals and lipid-lowering therapy compliance in patients with acute coronary syndromes (IDEAL-LDL) study: rationale and design.

BACKGROUND: Achieving low-density lipoprotein cholesterol (LDL-C) target levels after an acute coronary syndrome (ACS) is of paramount importance, and is often burdened by undertreatment and medication or lifestyle non-adherence issues. OBJECTIVE: We examined the effect of a patient-centered, physician-led motivational intervention following ACS on relevant secondary prevention aspects. METHODS-DESIGN: The IDEAL-LDL is a single-center, randomized controlled clinical trial, conducted among patients hospitalized due to an ACS. Following discharge, all patients undergo a baseline assessment of lipid profile. Patients in the intervention group receive an in-person educational session and an informative leaflet, and also undergo two phone-based, motivational interviewing sessions at 1 and 6 months. These interventions emphasize on LDL-C goals, adherence to lipid-lowering medication, and healthy dietary-lifestyle habits, and are not provided to patients in the control group, who receive usual care. At 12 months after each patient's discharge, an in-person interview and lipid profile reassessment are performed. The primary outcomes are the assessment of LDL-C goal achievement (<70 mg/dL or >50% reduction from baseline levels) from baseline to 1 year and changes in medication adherence. Secondary outcomes relate to the incidence of the composite outcome of cardiovascular death, nonfatal myocardial infarction/stroke, need for myocardial revascularization, and recurrent hospitalization during the follow-up period. DISCUSSION: This paper describes the protocol, design, and rationale for key methodology for an ongoing clinical trial featuring a simple and feasible intervention. Similar adherence efficacy trials have not led to sufficient improvements, and there remains a gap regarding how adherence interventions should be implemented into clinical care.

Elevated plasma levels of miR-29a are associated with hemolysis in patients with hypertrophic cardiomyopathy.

BACKGROUND: miR-29a is a small non-coding RNA that is known to repress collagen synthesis. Interestingly, elevated plasma miR-29a was reported to correlate with pronounced myocardial fibrosis in patients with hypertrophic cardiomyopathy. The objective of this study was to elucidate the origin of plasma miR-29a, and evaluate its significance as a biomarker. METHODS: miR-29a expression was evaluated in plasma (n=50) and myocardial samples (n=4) from patients with hypertrophic cardiomyopathy using RT-qPCR. RESULTS: Although miR-29a was highly expressed in the myocardium, miR-29a plasma levels did not show any correlation with serum troponin I levels (rs=-0.12, p=0.43), and the heart does not release significant amounts of miR-29a into the circulation via exosome secretion. Conversely, miR-29a was present in red blood cells, and plasma levels correlated significantly with markers of hemolysis: lactic dehydrogenase (rs=0.36, p=0.01) and the absorbance of oxyhemoglobin at 414nm (rs=0.39, p=0.006). Furthermore, the association between serum haptoglobin and the maximal blood flow velocity in the left ventricle outflow tract (rs=-0.42, p=0.008) indicated that intravascular hemolysis is a manifestation of the disease. CONCLUSIONS: miR-29a is highly expressed in myocardial tissue from patients with hypertrophic cardiomyopathy. In contrast, plasma miR-29a is primarily of nonmyocardial origin and is correlated significantly with the extent of hemolysis observed in these patients.

Hepatopulmonary syndrome is associated with the presence of hepatocellular carcinoma in patients with decompensated cirrhosis.

BACKGROUND: Hepatopulmonary syndrome (HPS) is a relatively common complication in patients with decompensated cirrhosis. Our aim was to evaluate the prevalence of HPS, its clinical impact, and the possible association between HPS and characteristics of patients with decompensated cirrhosis. METHODS: Patients with stable decompensated cirrhosis admitted to our department and assessed for HPS were included. For each patient, several clinical, laboratory and echocardiographic parameters as well as renal function were recorded. The severity of liver disease was evaluated according to the Model for End-stage Liver Disease and Child-Pugh scores, and renal function was assessed using 51chromium complexed with ethylene diamine tetracetic acid. In addition, the short synacthen test was performed in each patient to evaluate the adrenal function. RESULTS: Sixty-three patients were enrolled, 26 (41.3%) of whom diagnosed with HPS. In multivariate analysis, the presence of hepatocellular carcinoma [odds ratio (OR) 8.1, 95% confidence interval (CI) 5.3-27.9, P=0.045] and salivary cortisol at T60 (60 min after the intravenous injection of 250 µg corticotropin) (OR 0.88, 95%CI 0.71-0.98, P=0.045) were the factors independently associated with HPS. T60 salivary cortisol had relatively good discriminative ability for the presence of HPS (area under the curve=0.73). The presence of HPS was not associated with the outcome (P=0.22). CONCLUSION: In our cohort of patients with decompensated cirrhosis, the presence of hepatocellular carcinoma and T60 salivary cortisol were the only factors independently associated with HPS.

Patients with intracranial bleeding and atrial fibrillation treated with left atrial appendage occlusion: Results from the Amplatzer Cardiac Plug registry.

BACKGROUND: In patients with non-valvular atrial fibrillation (NVAF), intracranial bleeding (ICB) constitutes a very challenging situation in which the rate of both ischemic and hemorrhagic events is increased. In these patients, left atrial appendage occlusion (LAAO) might represent a very valid alternative. OBJECTIVES: To investigate the procedural safety and long-term outcome of patients undergoing LAAO therapy due to previous ICB. METHODS: Data from the Amplatzer Cardiac Plug multicenter registry on 1047 consecutive patients were analyzed. Patients with previous ICB as indication for LAAO were compared to patients with other indications. RESULTS: A total of 198 patients (18.9%) with previous ICB were identified. The CHA2DS2-VASc score was similar (4.5±1.5 vs. 4.4±1.6, p=0.687) and the HAS-BLED score was higher in patients with previous ICB compared to those without (3.5±1.1 vs. 3.1±1.2, p<0.001). No significant differences in peri-procedural major adverse events were observed (2.5 vs 5.4%, p=0.1). Patients with previous ICB were more frequently on single acetylsalicylic acid therapy after LAAO (42.4% vs. 28.3%; p<0.001). With an average follow-up of 1.3years, the observed annual stroke/TIA rate (procedure and follow-up) for patients with previous ICB was 1.4% (75% relative risk reduction). The observed annual major bleeding rate (procedure and follow-up) for patients with previous ICB was 0.7% (89% relative risk reduction). CONCLUSIONS: In patients with NVAF and previous ICB, LAAO seemed to be a safe procedure and was associated with a significant reduction in stroke/TIA and a remarkably low frequency of major bleeding during follow-up.

The TRACE registry (Trans-Radial Approach in Central and northErn Greece).

OBJECTIVE: We examined trans-radial approach (TRA) use in coronary angiographies (CAs) as well as in percutaneous coronary interventions (PCIs) in specific regions of Greece, its distribution in public and private catheterization laboratories (CLs) and its preference by operators. Reliable data regarding the use of TRA are not available in Greece. METHODS: The study was performed in northern and central Greece, which constitutes 35.32% of the national population. This study focused on the years 2004, 2009 and 2013. RESULTS: There are 12 CLs. CAs performed using TRA were 0.43% in 2004, 12.28% in 2009 and 39.81% in 2013, whereas PCIs performed using TRA were 0.38%, 9.20% and 39.48%, respectively. Operators familiar with TRA, but who performed TRA electively, were 13.33% in 2004, 60.38% in 2009 and 42.37% in 2013. However, operators performing TRA routinely were 2.2%, 5.66%, and 49.15%, respectively. In 2013, there was a 3.76% decrease in CAs and 4.51% decrease in PCIs compared to 2009; in private CLs, there was a 29.63% decrease in CAs and 34.72% decrease in PCIs performed, which was contradictory to the 27.27% increase observed in CAs and 29.83% increase in PCIs in public CLs. CONCLUSIONS: This is the first study to reveal the volumes and trends in interventions performed via TRA across central and northern Greece. TRA has gained a reputation among operators in both public and private CLs. Due to the financial crisis in Greece, catheterizations have been diminished, whereas private CLs have lost a great amount of their turnover.

Feasibility and significance of preclinical diagnosis in hypertrophic cardiomyopathy.

Preclinical diagnosis in hypertrophic cardiomyopathy (HCM) refers to the detection of functional or histopathological abnormalities in subjects who carry any HCM-causing gene mutation, before or even without the development of left ventricular hypertrophy [genotype(+)/phenotype(-)subjects]. The concept that HCM pathology may exist in the absence of left ventricular hypertrophy is quite old but the ability to recognize the presence of early myocardial changes is quite new. Lessons from animal models have shown that in experimental human HCM, myocardial cell mechanical dysfunction precedes histopathological changes, such as myocyte disarray, fibrosis, and hypertrophy. Several clinical reports have demonstrated that the majority of HCM genotype(+)/phenotype(-) subjects display myocardial functional or histopathological changes, such as reduced tissue Doppler imaging-derived systolic and diastolic velocities, abnormal electrocardiogram, cardiac magnetic resonance-visualized myocardial crypts, mitral leaflet elongation, and evidence of a fibrotic state, such as increased type I procollagen synthesis, cardiac magnetic resonance-increased myocardial extracellular volume, and late gadolinium myocardial enhancement. All these signs have been proposed as preclinical markers of HCM. At present the separation of such a group of subjects in the early phase of their disease provides the opportunity to test new therapies to prevent the development of fibrosis, hypertrophy, and dysfunction.

Clinical characteristics and natural history of hypertrophic cardiomyopathy with midventricular obstruction.

BACKGROUND: The prevalence, clinical characteristics and natural history of patients with hypertrophic cardiomyopathy (HCM) and midventricular obstruction (MVO) have not been adequately studied. METHODS AND RESULTS: A single-center cohort consisting of 423 patients (mean age, 49.3±17.2 years; 66.2% male) was thoroughly followed up for a median of 84 months (7 years; range, 6-480 months). MVO, characterized by the echocardiographic appearance of midventricular muscular apposition with a simultaneous mid-cavitary gradient ≥30mmHg, was identified in 34 patients (8%). Patients with MVO tended to be more symptomatic during their initial evaluation (>90% presented with NYHA class ≥II) compared to the rest of the HCM cohort. Apical aneurysm formation was identified in more than one-fourth of patients with MVO (26.5%), being a characteristic of the group. On multivariate Cox regression hazard analysis, presence of MVO strongly predicted progression to end-stage (burnt out) HCM and related heart failure (HF) deaths (hazard ratio, [HR], 2.62; 95% confidence interval [CI]: 1.2-8.8; P=0.047), as well as sudden death and associated lethal arrhythmic events (HR, 3.3; 95% CI: 1.26-8.85; P=0.016). CONCLUSIONS: MVO is a distinct phenotype of HCM associated with unfavorable prognosis in terms of end-stage HCM, sudden death and lethal arrhythmic events. The high adverse outcome rate necessitates early recognition of MVO and appropriate therapeutic interventions.