Diagnosis and Treatment of Obstructive Hypertrophic Cardiomyopathy

Left ventricular outflow obstruction (LVOTO) and diastolic dysfunction are the main pathophysiological characteristics of hypertrophic cardiomyopathy (HCM)LVOTO, may be identified in more than half of HCM patients and represents an important determinant of symptoms and a predictor of worse prognosis. This review aims to clarify the LVOTO mechanism in, diagnosis of, and therapeutic strategies for patients with obstructive HCM

Protein Thermodynamic Destabilization in the Assessment of Pathogenicity of a Variant of Uncertain Significance in Cardiac Myosin Binding Protein C.

In the era of next generation sequencing (NGS), genetic testing for inherited disorders identifies an ever-increasing number of variants whose pathogenicity remains unclear. These variants of uncertain significance (VUS) limit the reach of genetic testing in clinical practice. The VUS for hypertrophic cardiomyopathy (HCM), the most common familial heart disease, constitute over 60% of entries for missense variants shown in ClinVar database. We have studied a novel VUS (c.1809T>G-p.I603M) in the most frequently mutated gene in HCM, MYBPC3, which codes for cardiac myosin-binding protein C (cMyBPC). Our determinations of pathogenicity integrate bioinformatics evaluation and functional studies of RNA splicing and protein thermodynamic stability. In silico prediction and mRNA analysis indicated no alteration of RNA splicing induced by the variant. At the protein level, the p.I603M mutation maps to the C4 domain of cMyBPC. Although the mutation does not perturb much the overall structure of the C4 domain, the stability of C4 I603M is severely compromised as detected by circular dichroism and differential scanning calorimetry experiments. Taking into account the highly destabilizing effect of the mutation in the structure of C4, we propose reclassification of variant p.I603M as likely pathogenic. Looking into the future, the workflow described here can be used to refine the assignment of pathogenicity of variants of uncertain significance in MYBPC3.J.A.C. was funded by the Ministerio de Ciencia, Innovación y Universidades (MCNU) through grants BIO2017-83640-P (AEI/FEDER, UE) and RYC-2014-16604, the European Research Area Network on Cardiovascular Diseases (ERA-CVD/ISCIII, MINOTAUR, AC16/00045), the Comunidad de Madrid (P2018/NMT-4443) and the CNIC-Severo Ochoa intramural grant program (03-2016 IGP). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), MCNU and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). G.F. was funded by the Ministero dell’Istruzione, dell’Università e della Ricerca-Rome PS35-126/IND.S

Rapid Evolution of an Aortic Endocarditis

Cardiac surgery is necessary in almost 50% of patients with endocarditis. Early surgery, i.e., the surgery performed during the first hospitalization, is required in the following cases: heart failure secondary to valve regurgitation; S. aureus, fungal organism, or other highly resistant organism infection; heart block, annular or aortic abscess, or destructive penetrating lesions; evidence of persistent infection as manifested by persistent bacteremia or fevers lasting >5 days after onset of appropriate antimicrobial therapy. A 62-year-old man developed a fever (38 °C) 3 days after a transaortic electrophysiological study; blood cultures were positive for S. aureus, and were sensitive to vancomycin and ceftaroline. Antibiotic therapy was started, controlling the fever and the patient's infective and inflammatory profiles well; however, 3 days later, acute aortic regurgitation developed. At transesophageal echocardiography (TEE), a rare condition was revealed-vegetation was attached to the aortic wall, impeding correct aortic valve closure. Cardiac operation was carried out and the time for surgery was discussed; based on the patient's clinically stable condition, and on the infection, which was controlled well by antibiotics therapy, surgery was not performed in emergency circumstance (within 24-48 h)-rather, it was programmed during the hospitalization. A TEE surveillance was initiated, and after 7 days, TEE revealed a new picture, with images of an aortic abscess with small perforation in the right atrium, requiring emergency surgery, carried out 20 h later. In our case, the rapid evolution of the vegetation attached to the aortic wall suggested the following: (1) that the time for the surgery cannot be guided only by clinical procedure but must also be guided by imaging pictures; (2) that strictly TEE surveillance is mandatory in patients with aortic endocarditis not initially referred for emergency surgery

Impact of Age and Heart Rate on Strain-Derived Myocardial Work in a Population of Healthy Subjects

The influence of age and gender on strain-imaging-derived myocardial work (MW) was recently investigated in healthy subjects. No information is available on the impact of heart rate (HR) on MW

Depressed Myocardial Energetic Efficiency Increases Risk of Incident Heart Failure: The Strong Heart Study

An estimation of myocardial mechano-energetic efficiency (MEE) per unit of left ventricular (LV) mass (MEEi) can significantly predict composite cardiovascular (CV) events in treated hypertensive patients with normal ejection fraction (EF), after adjustment for LV hypertrophy (LVH). We have tested whether MEEi predicts incident heart failure (HF), after adjustment for LVH, in the population-based cohort of a "Strong Heart Study" (SHS) with normal EF. We included 1,912 SHS participants (age 59 ± 8 years; 64% women) with preserved EF (≥50%) and without prevalent CV disease. MEE was estimated as the ratio of stroke work to the "double product" of heart rate times systolic blood pressure. MEEi was calculated as MEE/LV mass, and analyzed in quartiles. During a follow-up study of 9.2 ± 2.3 years, 126 participants developed HF (7%). HF was preceded by acute myocardial infarction (AMI) in 94 participants. A Kaplan-Meier plot, in quartiles of MEEi, demonstrated significant differences, substantially due to the deviation of the lowest quartile (p < 0.0001). Using AMI as a competing risk event, sequential models of Cox regression for incident HF (including significant confounders), demonstrated that low MEEi predicted incident HF not due to AMI (p = 0.026), after adjustment for significant effect of age, LVH, prolonged LV relaxation, diabetes, and smoking habits with negligible effects for sex, hypertension, antihypertensive therapy, obesity, and hyperlipemia. Low LV mechano-energetic efficiency per unit of LVM, is a predictor of incident, non-AMI related, HF in subjects with initially normal EF

Severity of Coronary Atherosclerosis and Risk of Diabetes Mellitus

Cardio-vascular target organ damage predicts the onset of type 2 diabetes mellitus (DM) in hypertensive patients. Whether an increased incidence of DM is also in relation to the severity of coronary atherosclerosis is unknown

Myocardial fibrosis and diastolic dysfunction in patients on chronic haemodialysis

BACKGROUND: Left ventricular (LV) diastolic dysfunction is linked to myocardial collagen content in many cardiac diseases. There are no data regarding such relationship in patients with end-stage renal disease (ESRD) undergoing haemodialysis. METHODS: Twenty-five patients with ESRD undergoing haemodialysis were studied by echocardiography. LV diastolic function was investigated by Doppler echocardiography, by analysing LV filling velocities at rest and during loading manoeuvres, which represent an estimate of LV filling pressure. According to the Doppler pattern, LV filling pressure in a given patient was judged to be normal or slightly increased or to be moderately or severely increased. The presence of myocardial fibrosis was estimated by ultrasound tissue characterization with integrated backscatter, which in diastole correlates with the collagen content of the myocardium. RESULTS: Integrated backscatter was higher in patients with moderate or severely increased than in patients with normal or slightly increased LV filling pressure (integrated backscatter: 51.0 +/- 9.8 vs 41.6 +/- 5.6%; P = 0.008). Integrated backscatter was a strong and independent determinant of diastolic dysfunction (odds ratio = 1.212; P = 0.040). CONCLUSION: Our data support the hypothesis that, in a selected population of patients with ESRD undergoing haemodialysis, myocardial fibrosis is associated with LV diastolic myocardial propertie

A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells

There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). In the present work, we propose a new tool to combat drug resistance. We propose to treat OC cell lines, both Pt-sensitive and -resistant, with dual combinations of one of the four chemotherapeutic agents that are widely used in the clinic, and the new peptide, hTS inhibitor, [D-Gln4]LR. This binds hTS allosterically and, unlike classical inhibitors that bind at the catalytic pocket, causes cell growth inhibition without inducing hTS overexpression. The dual drug combinations showed schedule-dependent synergistic antiproliferative and apoptotic effects. We observed that the simultaneous treatment or 24h pre-treatment of OC cells with the peptide followed by either agent produced synergistic effects even in resistant cells. Similar synergistic or antagonistic effects were obtained by delivering the peptide into OC cells either by means of a commercial delivery system (SAINT-PhD) or by pH sensitive PEGylated liposomes. Relative to non-PEGylated liposomes, the latter had been previously characterized and found to allow macrophage escape, thus increasing their chance to reach the tumour tissue. The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and/or 5-FU and/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs

Multimodality Imaging in Cardiomyopathies with Hypertrophic Phenotypes

Multimodality imaging is a comprehensive strategy to investigate left ventricular hypertrophy (LVH), providing morphologic, functional, and often clinical information to clinicians. Hypertrophic cardiomyopathy (HCM) is defined by an increased LV wall thickness not only explainable by abnormal loading conditions. In the context of HCM, multimodality imaging, by different imaging techniques, such as echocardiography, cardiac magnetic resonance, cardiac computer tomography, and cardiac nuclear imaging, provides essential information for diagnosis, sudden cardiac death stratification, and management. Furthermore, it is essential to uncover the specific cause of HCM, such as Fabry disease and cardiac amyloidosis, which can benefit of specific treatments. This review aims to elucidate the current role of multimodality imaging in adult patients with HCM

Left Ventricular Hypertrophy Regression During Antihypertensive Treatment in an Outpatient Clinic (the Campania Salute Network)

BACKGROUND: Regression of left ventricular (LV) hypertrophy (LVH) has been a goal in clinical trials. This study tests the external validity of results of clinical trials on LVH regression using a large registry from a tertiary care center, to identify phenotypes less likely to achieve regression of LVH. METHODS AND RESULTS: Patients from the Campania Salute Network, free of prevalent cardiovascular disease, but with echocardiographic LVH (defined as LV mass index [LVMi] >47 g/m2.7 in women and >50 g/m2.7 in men) were included. During a median follow-up of 67 months, clear-cut regression of LVH was documented in 14% of patients (13±8% reduction of initial LVMi) or 23% when also considering those with a reduction of LVMi ≥5 g/m2.7. Patients with persistent LVH were older with longer duration of hypertension, suboptimal blood pressure (BP) control, larger body mass index, LV mass, and carotid intima-media thickness and included more women and subjects with diabetes mellitus, isolated systolic hypertension, and metabolic syndrome (all P<0.05). Number and class of antihypertensive drugs during follow-up did not differ between groups. In multiple logistic regression analysis, older age, female sex, obesity, higher baseline LVMi and carotid intima-media thickness, and suboptimal BP control were significant covariates of persistent LVH (all P≤0.01), independent of diabetes, duration of hypertension, isolated systolic hypertension, follow-up time and number and class of antihypertensive drugs. CONCLUSIONS: Early initiation of antihypertensive treatment, aggressive BP control, and attention to metabolic aspects are critical to avoid irreversible LVH