Cristina Gavina

Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium

High diastolic stiffness of failing myocardium results from interstitial fibrosis and elevated resting tension (Fpassive) of cardiomyocytes. A shift in titin isoform expression from N2BA to N2B isoform, lower overall phosphorylation of titin, and a shift in titin phosphorylation from N2B to N2BA isoform can raise Fpassive of cardiomyocytes. In left ventricular biopsies of heart failure (HF) patients, aortic stenosis (AS) patients, and controls (CON), we therefore related Fpassive of isolated cardiomyocytes to expression of titin isoforms and to phosphorylation of titin and titin isoforms. Biopsies were procured by transvascular technique (44 HF, 3 CON), perioperatively (25 AS, 4 CON), or from explanted hearts (4 HF, 8 CON). None had coronary artery disease. Isolated, permeabilized cardiomyocytes were stretched to 2.2-&mgr;m sarcomere length to measure Fpassive. Expression and phosphorylation of titin isoforms were analyzed using gel electrophoresis with ProQ Diamond and SYPRO Ruby stains and reported as ratio of titin (N2BA/N2B) or of phosphorylated titin (P-N2BA/P-N2B) isoforms. Fpassive was higher in HF (6.1±0.4 kN/m2) than in CON (2.3±0.3 kN/m2; P<0.01) or in AS (2.2±0.2 kN/m2; P<0.001). Titin isoform expression differed between HF (N2BA/N2B=0.73±0.06) and CON (N2BA/N2B=0.39±0.05; P<0.001) and was comparable in HF and AS (N2BA/N2B=0.59±0.06). Overall titin phosphorylation was also comparable in HF and AS, but relative phosphorylation of the stiff N2B titin isoform was significantly lower in HF (P-N2BA/P-N2B=0.77±0.05) than in AS (P-N2BA/P-N2B=0.54±0.05; P<0.01). Relative hypophosphorylation of the stiff N2B titin isoform is a novel mechanism responsible for raised Fpassive of human HF cardiomyocytes.

Diabetes Mellitus Worsens Diastolic Left Ventricular Dysfunction in Aortic Stenosis Through Altered Myocardial Structure and Cardiomyocyte Stiffness

Background— Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified. Methods and Results— Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-&mgr;m sarcomere length to measure resting tension (Fpassive). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM; P=0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1% versus AS-DM, 18.2±2.6%; P<0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm2 versus AS-DM, 31.4±6.1 score per 1 mm2; P=0.03), and higher Fpassive (AS, 3.5±1.7 kN/m2 versus AS-DM, 5.1±0.7 kN/m2; P=0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher Fpassive and normalization of Fpassive after in vitro treatment with protein kinase A. Conclusions— Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte Fpassive, which was related to hypophosphorylation of the N2B titin isoform.

Correlation between plasma levels of apelin and myocardial hypertrophy in rats and humans: possible target for treatment?

Objective: To investigate the effects of left ventricular (LV) pressure overload and diabetes on the apelinergic system. Research design/methods: Pressure overload was established in rats by supra-renal aortic-banding. Six weeks later, diabetes was induced by streptozotocin (65 mg/kg, intraperitoneal), resulting in four groups: sham, banded (BA), diabetic (DM) and diabetic-banded (DM-BA). Twelve weeks later, LV function and structure were evaluated by echocardiography and biopsies and plasma samples collected. Furthermore, plasma samples and LV-endomyocardial biopsies were procured from aortic stenosis and mitral stenosis patients during surgery to evaluate myocardial expression of apelin and APJ-receptor and plasma levels of apelin. Results: Direct correlations between apelin plasma levels and LV-mass index and between apelin and APJ myocardial expression were observed both in humans and rats. Expression of apelin and APJ was not significantly altered by pressure-overload in humans, being downregulated by pressure overload and even more by diabetes in rats. Finally, an inverse correlation between apelin rat plasma levels and its myocardial expression was observed. Conclusions: While apelin/APJ myocardial expression decreases, apelin plasma levels increase in LV hypertrophy. Considering apelins positive inotropic and vasodilator properties, this elevation in apelin plasma levels may represent a compensatory mechanism to maintain inotropism and cardiac output during pressure-overload or diabetic cardiomyopathy.

Load independent impairment of reverse remodeling after valve replacement in hypertensive aortic stenosis patients

BACKGROUND We evaluated the impact of hypertension on the left ventricular mass regression in aortic stenosis after aortic valve replacement. METHODS We prospectively studied 135 patients with severe aortic stenosis at baseline and 1 year after surgery. In 32 patients we analyzed myocardial gene expression of collagen types I and III, connective tissue growth factor, transforming growth factor-β1, metalloproteinase-2 and its tissue inhibitor and compared its levels vs controls. RESULTS Seventy-six patients (56.3%) had a history of hypertension. Hypertensive patients were older, had higher Euroscore-II and NYHA class, with no differences in stenosis severity. At 1 year follow-up there was a median decrease of mass index of 14.2% (P25-75: -4.3%-30.4%; p<0.001). Mass regression was significantly higher in patients without hypertension, with a median decrease of 25.9% (P25-75: 12.0%-38.7%) vs 5.4% (P25-75: -12.5%-20.1%; p=0.001), despite similar increase in effective orifice area and no differences in valvuloarterial impedance. After 1 year, higher baseline left ventricular mass index (p=0.005) and the absence of hypertension (p=0.002) or diabetes (p=0.041) were the only independent predictors of mass regression higher than the median. Comparing with controls, aortic stenosis patients had an increased expression of collagen types I and III, but only hypertensive patients had higher relative expression of collagen type I vs III. In hypertensive patients TIMP2 expression was up-regulated and correlated with higher baseline left ventricular mass index (r=0.61; p=0.020). CONCLUSIONS In aortic stenosis, hypertension impairs mass regression one year after valve replacement, independently of total afterload. Differences in the expression of extracellular matrix remodeling genes might contribute to this finding.

Determinants of clinical improvement after surgical replacement or transcatheter aortic valve implantation for isolated aortic stenosis

BackgroundTranscatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement (SAVR) in patients with aortic stenosis (AS) and high surgical risk. Hemodynamic performance after TAVI is superior, but the impact of reverse remodeling on clinical improvement is controversial. We aim to address the differences in hemodynamic changes between SAVR and TAVI, and its correlation with LV remodeling and clinical improvement at 6 months follow-up.MethodsForty-two patients treated by TAVI were compared with 45 SAVR patients with a stented bioprosthesis. Clinical, 2D and 3D echocardiographic data were prospectively obtained before and six months after intervention.ResultsPatients had similar distribution for sex, body surface area and AS severity. TAVI patients were older, more symptomatic and had more comorbidities. They also had higher LV filling pressures, larger 3D indexed left atrium volume, but similar 3D indexed LV mass. At 6 months, TAVI patients had greater clinical improvement and higher effective orifice area index (EAOI), but only SAVR patients already had a significant decrease in 3D indexed LV mass and diastolic volume. In univariate analysis older age, NYHA class ≥ III, increase in EAOI and TAVI were related with functional class improvement. After multivariate analysis only NYHA class ≥ III (OR 8.81, CI:2.13-36.52; p = 0.003) and an increase in EAOI ≥ 105% (OR 3.87, CI:1.02-14.70; p = 0.04) were predictors of clinical improvement.ConclusionsAt 6 months, functional class improvement was greater after TAVI. Higher initial NYHA class and an increase in EAOI ≥ 105% were independently associated with functional enhancement. It is debatable if left ventricular remodeling is determinant for functional class improvement.

Understanding the Molecular and Cellular Changes Behind Aortic Valve Stenosis

Morbidity from degenerative aortic valve disease (AVS) is increasing worldwide, concomitant with the ageing of the population and the growing consumption of high caloric and cholesterol diets of the western countries. Despite the increasing prevalence of AVS, with its high mortality and morbidity, studies on the molecular and cellular mechanisms underlying the onset of aortic valve degeneration have only advanced in the last 15 years. The result of this effort is now beginning to reveal several mechanisms with great therapeutic targeting potential that may alter the natural history of this progressive pathology. Indeed, the view of this disease has changed from being an unmodifiable degenerative disease to an active biological process regulated by highly conserved cellular pathways. The progression of AVS includes inflammation, angiogenesis and remodelling of the extracellular matrix leading to osteogenesis in the aortic valve and revealing many mechanisms and risk factors similar to atherosclerosis. Therefore statins and angiotensin II antagonists seemed promising treatment options; however, experimental results are still controversial. Nonetheless, valvular degeneration results in dramatic myocardial changes induced by chronic pressure overload such as left ventricular hypertrophy as well as other paramount myocardial extracellular changes. Currently, a strong impulse for future research to investigate the pathophysiological mechanisms and their modulation in order to prevent/delay the onset or progression of valve degeneration is needed. In the present review, we focused on the molecular and cellular mechanisms underlying degenerative AVS and its myocardial impact.

Cardiac 123I-MIBG scintigraphy and arrhythmic risk in left ventricular noncompaction

Left ventricular noncompaction is an unusual but increasingly recognized cardiomyopathy, the etiology of which is still not definitely established. Clinical presentation includes a wide spectrum of scenarios, including heart failure, thromboembolism and malignant arrhythmias, with half of deaths occurring suddenly. Early detection of LVNC is therefore essential to prevent sudden cardiac death. To our knowledge, this is the first report of the presence of cardiac sympathetic nervous dysfunction, assessed by 123iodine-metaiodobenzylguanidine myocardial scintigraphy, in a patient with LVNC, preserved left ventricular systolic function and exercise-induced nonsustained ventricular tachycardia. This finding may be related to the increased arrhythmic risk observed in this cardiomyopathy, giving a new insight into the pathophysiology of LVNC.

Left Ventricular Hypertrophy in Isolated Aortic Stenosis: Primetime for the Ventricle

Aortic stenosis is the most common type of valvular heart disease and its recent increase is related to aging. The decreased aortic valve area imposes a chronic systolic pressure overload to the left ventricle. In response, the ventricle hypertrophies in an attempt to normalize the increased wall stress, but this response is not uniform in patients with similar degrees of stenosis and its regression after surgical correction is variable, suggesting that several factors, other than load, can explain these differences. These findings are particularly important since the presence of left ventricular hypertrophy after aortic valve replacement is an independent predictor of worse outcome, probably because it indicates irreversible remodeling. Age, gender, hypertension, patient-prosthesis mismatch and interstitial remodeling also play an important role in this setting, raising the possibility of intervention beyond valve replacement. The possibility of combining estrogen treatment, antihypertensive agents, antioxidants and modulators of the renin-angiotensin-aldosterone system with surgical treatment to promote reverse remodeling is very appealing. On the other hand, a preventive strategy to intervene earlier in patients with significant left ventricular mass and avoid patient-prosthesis mismatch, especially in the younger and those with systolic dysfunction, can have a significant impact on prognosis. Further evidence, with well designed clinical trials, is needed but the spotlight must be in the ventricle, not the valve.

Giant high-pressure pulmonary artery aneurysm in an elderly patient with chronic obstructive pulmonary disease

The authors report the case of a 74-year-old man, with a history of chronic obstructive pulmonary disease (COPD), GOLD grade 3, stable for the past two decades, who was admitted to our center with severe right heart failure. The chest radiograph showed moderate heart enlargement mainly of the right atrium and pulmonary artery, similar to previous chest radiographs in the previous 20 years. The transthoracic echocardiogram showed a pulmonary artery aneurysm (PAA), dilatation of the right chambers with pulmonary artery systolic pressure of 52 mmHg, and preserved right ventricular systolic function. A thoracic computed tomography scan confirmed the presence of a giant PAA 72 mm in diameter. The patient was started on high-dose diuretics, with significant clinical improvement. After optimization of medical therapy right heart catheterization was carried out with the patient in optimal clinical condition, which revealed mild precapillary pulmonary hypertension with a mean pulmonary artery pressure of 26 mmHg. On the basis of the clinical and imaging findings a stable, giant, high-pressure, PAA was diagnosed secondary to pulmonary hypertension induced by COPD, with a 20-year follow-up without need for surgical repair, which helped in our decision to maintain medical surveillance. The recent onset of heart failure is explained by the unfavorable evolution of COPD. This case may change the attitude expressed in previous studies favoring the choice of an invasive approach to treat giant high-pressure PAAs, instead supporting the maintenance of medical treatment.

Recomendações da Sociedade Portuguesa de Cirurgia Cárdio‐Torácica e Vascular e da Sociedade Portuguesa de Cardiologia sobre tempos de espera para cirurgia cardíaca

Appointed jointly by the Portuguese Society of Cardiothoracic and Vascular Surgery (SPCCTV) and the Portuguese Society of Cardiology (SPC), the Working Group on Waiting Times for Cardiac Surgery was established with the aim of developing practical recommendations for clinically acceptable waiting times for the three critical phases of the care of adults with heart disease who require surgery or other cardiological intervention: cardiology appointments; the diagnostic process; and invasive treatment. Cardiac surgery has specific characteristics that are not comparable to other surgical specialties. It is important to reduce maximum waiting times and to increase the efficacy of systems for patient monitoring and tracking. The information in this document is mainly based on available clinical information. The methodology used to establish the criteria was based on studies on the natural history of heart disease, clinical studies comparing medical treatment with intervention, retrospective and prospective analyses of patients on waiting lists, and the opinions of experts and working groups. Following the first step, represented by publication of this document, the SPCCTV and SPC, as the bodies best suited to oversee this process, are committed to working together to define operational strategies that will reconcile the clinical evidence with the actual situation and with available resources.