Carmine G. De Pasquale

Effects of myocardial fibrosis and ventricular dyssynchrony on response to therapy in new-presentation idiopathic dilated cardiomyopathy: insights from cardiovascular magnetic resonance and echocardiography

AIMS To determine whether the extent of myocardial fibrosis by late-gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR), and echocardiographic ventricular dyssynchrony are independently associated with response to medical therapy in patients with newly diagnosed idiopathic dilated cardiomyopathy (DCM). Myocardial fibrosis and ventricular dyssynchrony are frequent findings in DCM. Previous studies focused on patients with established cardiomyopathy; however, the degree of myocardial fibrosis and ventricular dyssynchrony at presentation and their role in perpetuating left ventricular (LV) dysfunction in DCM remains unclear. Those studies of individuals with long-standing DCM did not characterize patients early in the disease course, and may not have included those with significant improvement in LV function. Thus factors contributing to LV recovery are uncertain. METHODS AND RESULTS Consecutive patients with a new diagnosis of DCM [LV ejection fraction (EF) ≤45%] made within the preceding 2 weeks were recruited. Patients underwent LGE-CMR, echocardiography, 6-minute walk testing, cardiopulmonary exercise testing, and blood sampling for measurement of serum amino-terminal pro-brain natiuretic peptide (NT-pro-BNP) concentration at baseline. Baseline patient characteristics were compared with a cohort of healthy volunteers. Myocardial fibrosis by LGE-CMR was quantified, identified by experienced observers blinded to patient outcome. Left ventricular systolic function was reassessed after 5 months of optimal medical therapy. Sixty-eight patients with DCM and 19 healthy volunteers were studied. DCM patients were studied a median 12.5 days following diagnosis. Compared with healthy controls, DCM patients exhibited greater inter- and intra-ventricular dyssynchrony. Twenty-four per cent of DCM patients exhibited LGE at diagnosis. Among DCM patients with LGE, the mean fibrosis mass was 2.2 ± 1.3 g. On multivariate analysis, strain dyssynchrony index, and fibrosis mass were independently associated with change in the LVEF over time (P≤ 0.001). Late-gadolinium enhancement cardiovascular magnetic resonance conferred additive value for modelling change in the LVEF beyond clinical and echocardiographic dyssynchrony parameters. CONCLUSION The extent of myocardial fibrosis is independently associated with lack of response to medical therapy in new-presentation DCM, and LGE-CMR may thus be an important risk-stratifying investigation in these patients. Accurate risk stratification may permit more targeted pharmacological and device therapies for patients with newly diagnosed DCM.

Prolonged alveolocapillary barrier damage after acute cardiogenic pulmonary edema

ObjectivesTo determine whether acute cardiogenic pulmonary edema is associated with damage to the alveolocapillary barrier, as evidenced by increased leakage of surfactant specific proteins into the circulation, to document the duration of alveolocapillary barrier damage in this setting, and to explore the role of pulmonary parenchymal inflammation by determining if circulating tumor necrosis factor-&agr; is increased after acute cardiogenic pulmonary edema. DesignProspective, observational study. SettingCritical care, cardiac intensive care, and cardiology wards of a tertiary-care university teaching hospital. PatientsA total of 28 patients presenting with acute cardiogenic pulmonary edema and 13 age-matched normal volunteers. InterventionsCirculating surfactant protein-A and -B and tumor necrosis factor-&agr; were measured on days 0 (presentation), 1, 3, 7, and 14. Clinical markers of pulmonary edema were documented at the same times. Measurements and Main ResultsSurfactant protein-A and -B were elevated on day 0 compared with controls (367 ± 17 ng/mL vs. 303 ± 17 and 3821 ± 266 ng/mL vs. 2747 ± 157 [mean ± sem], p < .05), and although clinical, hemodynamic and radiographic variables improved rapidly (p < .001), surfactant protein-A and -B rose further until day 3 (437 ± 22, p < .001, 4642 ± 353, p < .01). Tumor necrosis factor-&agr; was elevated at presentation (p < .05), doubled by day 1 (6.98 ± 1.36 pg/mL, p < .05), remained elevated on day 3 (5.72 ± 0.96 pg/mL, p < .05), and peak levels were related to chest radiograph extravascular lung water score (rp = 0.64, p = .003). ConclusionsAlthough the initial increase in plasma surfactant protein-A and -B may represent hydrostatic stress failure of the alveolocapillary barrier, the prolonged elevation, when hemodynamic abnormalities have resolved, and the delayed elevation of tumor necrosis factor-&agr; are consistent with pulmonary parenchymal inflammation, which may further damage the alveolocapillary barrier. This prolonged physiologic defect at the alveolocapillary barrier after acute cardiogenic pulmonary edema may partly account for the vulnerability of these patients to recurrent pulmonary fluid accumulation.

Heart failure with normal ejection fraction: The complementary roles of echocardiography and CMR imaging

Heart failure with normal ejection fraction (HFNEF), previously referred to as diastolic heart failure, has increased in prevalence as a cause of heart failure, now accounting for up to 50% of all cases. Contrary to initial evidence, the prognostic outlook in HFNEF may be similar to that of heart failure with reduced ejection fraction. According to current consensus statements, the diagnosis of HFNEF requires the demonstration of relatively preserved systolic left ventricular function and evidence of diastolic dysfunction. Noninvasive imaging techniques now permit evaluation of these parameters without need for cardiac catheterization in the large majority of patients. Echocardiography is the modality of choice in the evaluation of diastolic function but suffers from limitations in its assessment of systolic function. Cardiac magnetic resonance (CMR) imaging is the gold standard in the volumetric quantification of systolic function; however, it has limitations in its ability to characterize diastolic function. This report aims to review the strengths and weaknesses of both imaging modalities in the diagnosis of HFNEF. With regards to echocardiography, it will specifically describe limitations in measuring left ventricular ejection fraction, describe novel techniques to assess systolic function such as tissue velocity and strain analysis, and will review the measurements used in the evaluation of diastolic function. With respect to CMR, this review will highlight its value in the assessment of systolic left ventricular function, will review ancillary CMR findings that may support the diagnosis of HFNEF such as tissue characterization, and will provide a brief overview of CMR techniques to assess diastolic function. We propose that these 2 modalities may play a complementary role in the diagnosis of HFNEF. The importance of imaging in the diagnosis of HFNEF extends to both the individual patient and to clinical trials of therapies for this condition.

Plasma Surfactant Protein-B A Novel Biomarker in Chronic Heart Failure

Background—In chronic heart failure (CHF), elevated pulmonary microvascular pressure (Pmv) results in pulmonary edema. Because elevated Pmv may alter the integrity of the alveolocapillary barrier, allowing leakage of surfactant protein-B (SP-B) from the alveoli into the circulation, we aimed to determine plasma levels of SP-B in CHF and their relation to clinical status. Methods and Results—Fifty-three outpatients with CHF had plasma SP-B and N-terminal proBNP (NT-proBNP) assayed, in addition to a formalized clinical assessment at each clinic review over a period of 18 months. The control group comprised 19 normal volunteers. Plasma SP-B was elevated in CHF (P<0.001), and levels increased with New York Heart Association classification (P<0.001). SP-B correlated with objective clinical status parameters and NT-proBNP. During follow-up, major cardiovascular events occurred in patients with higher plasma SP-B (P<0.01) and NT-proBNP (P<0.05). Furthermore, on conditional logistic regression analysis, only SP-B was independently associated with CHF hospitalization (P=0.005). The 53 patients underwent a total of 210 outpatient visits. When the diuretic dosage was increased on clinical grounds, SP-B had increased 39% (P<0.001) and NT-proBNP had increased 32% (P<0.001). Conversely, at the next visit, SP-B fell 12% (P<0.001), whereas NT-proBNP fell 39% (P<0.001). Conclusions—Plasma SP-B is increased in CHF, and levels are related to clinical severity. Furthermore, within individual patients, SP-B levels vary with dynamic clinical status and NT-proBNP levels. Because plasma SP-B is independently associated with CHF hospitalization, it may, by virtue of its differing release mechanism to NT-proBNP, be a clinically useful biomarker of the pulmonary consequences of raised Pmv.

Plasma surfactant protein-B: a novel biomarker in chronic heart failure

Background—In chronic heart failure (CHF), elevated pulmonary microvascular pressure (Pmv) results in pulmonary edema. Because elevated Pmv may alter the integrity of the alveolocapillary barrier, allowing leakage of surfactant protein-B (SP-B) from the alveoli into the circulation, we aimed to determine plasma levels of SP-B in CHF and their relation to clinical status. Methods and Results—Fifty-three outpatients with CHF had plasma SP-B and N-terminal proBNP (NT-proBNP) assayed, in addition to a formalized clinical assessment at each clinic review over a period of 18 months. The control group comprised 19 normal volunteers. Plasma SP-B was elevated in CHF (P<0.001), and levels increased with New York Heart Association classification (P<0.001). SP-B correlated with objective clinical status parameters and NT-proBNP. During follow-up, major cardiovascular events occurred in patients with higher plasma SP-B (P<0.01) and NT-proBNP (P<0.05). Furthermore, on conditional logistic regression analysis, only SP-B was independently associated with CHF hospitalization (P=0.005). The 53 patients underwent a total of 210 outpatient visits. When the diuretic dosage was increased on clinical grounds, SP-B had increased 39% (P<0.001) and NT-proBNP had increased 32% (P<0.001). Conversely, at the next visit, SP-B fell 12% (P<0.001), whereas NT-proBNP fell 39% (P<0.001). Conclusions—Plasma SP-B is increased in CHF, and levels are related to clinical severity. Furthermore, within individual patients, SP-B levels vary with dynamic clinical status and NT-proBNP levels. Because plasma SP-B is independently associated with CHF hospitalization, it may, by virtue of its differing release mechanism to NT-proBNP, be a clinically useful biomarker of the pulmonary consequences of raised Pmv.

Reduced Surface Tension Normalizes Static Lung Mechanics in a Rodent Chronic Heart Failure Model

RATIONALE Chronic elevation of pulmonary microvascular pressure in chronic heart failure results in compensatory changes in the lung that reduce alveolar fluid filtration and protect against pulmonary microvascular rupture. OBJECTIVES To determine whether these compensatory responses may have maladaptive effects on lung function. METHODS Six weeks after myocardial infarction (chronic heart failure model) rat lung composition, both gross and histologic; air and saline mechanics; surfactant production; and immunological mediators were examined. MEASUREMENTS AND MAIN RESULTS An increase in dry lung weight, due to increased insoluble protein, lipid and cellular infiltrate, without pulmonary edema was found. Despite this, both forced impedance and air pressure-volume mechanics were normal. However, there was increased tissue stiffness in the absence of surface tension (saline pressure-volume curve) with a concurrent increase in both surfactant content and alveolar type II cell numbers, suggesting a novel homeostatic phenomenon. CONCLUSIONS These studies suggest a compensatory reduction in pulmonary surface tension that attenuates the effect of lung parenchymal remodeling on lung mechanics, hence work of breathing.

Pulmonary Hypertension and Right Heart Dysfunction in Chronic Lung Disease

Group 3 pulmonary hypertension (PH) is a common complication of chronic lung disease (CLD), including chronic obstructive pulmonary disease (COPD), interstitial lung disease, and sleep-disordered breathing. Development of PH is associated with poor prognosis and may progress to right heart failure, however, in the majority of the patients with CLD, PH is mild to moderate and only a small number of patients develop severe PH. The pathophysiology of PH in CLD is multifactorial and includes hypoxic pulmonary vasoconstriction, pulmonary vascular remodeling, small vessel destruction, and fibrosis. The effects of PH on the right ventricle (RV) range between early RV remodeling, hypertrophy, dilatation, and eventual failure with associated increased mortality. The golden standard for diagnosis of PH is right heart catheterization, however, evidence of PH can be appreciated on clinical examination, serology, radiological imaging, and Doppler echocardiography. Treatment of PH in CLD focuses on management of the underlying lung disorder and hypoxia. There is, however, limited evidence to suggest that PH-specific vasodilators such as phosphodiesterase-type 5 inhibitors, endothelin receptor antagonists, and prostanoids may have a role in the treatment of patients with CLD and moderate-to-severe PH.

CIRCULATING SURFACTANT PROTEIN-B LEVELS INCREASE ACUTELY IN RESPONSE TO EXERCISE-INDUCED LEFT VENTRICULAR DYSFUNCTION

1. As a result of its enormous surface area and necessary thinness for gas exchange, the alveolocapillary barrier is vulnerable to mechanical disruption from raised pulmonary microvascular pressure (Pmv).

Ventricular arrhythmias triggered by alerting stimuli in conscious rabbits pre-treated with dofetilide

Abstract.We tested whether normally benign alerting/arousing stimuli provoke cardiac arrhythmias in conscious rabbits with electrically unstable myocardium. Alerting stimuli (loud sound, tapping and moving the cage, pinprick, inhalation of formaldehyde vapour) were presented before and after administration of dofetilide to conscious unrestrained rabbits (New Zealand White). Dofetilide (0.28–3.0 mg/kg i. v.) caused prolongation of QT interval (from 131 ± 9 to 217 ± 11 ms; p < 0.01, n = 6) and Tpeak-Tend interval (from 34 ± 5 to 81 ± 9 ms; p < 0.01, n = 6), altered ventricular conductance, and caused appearance of spontaneous ventricular ectopic beats. Alerting stimuli elicited ventricular ectopic beats in 18/30 trials in all dofetilide-treated animals, with a short latency (3.1 ± 0.4 s). Formaldehyde vapour, in addition, elicited profound bradycardia, and precipitated non-sustained polymorphic ventricular tachycardia (torsades de points) lasting 0.6–8.5 s in 5/6 animals. These arrhythmias occurred also with a short latency (mean 8.7 ± 1.6 s). Betaadrenergic blockade with propranolol (1.5 mg/kg i. v.) abolished spontaneous ventricular ectopy, suppressed torsades de points precipitated by formaldehyde, and significantly (p < 0.05) reduced the number of ventricular ectopic beats triggered by alerting stimuli. In predisposed hearts, alerting stimuli precipitate arrhythmias by producing transient increases in sympathetic discharge in the ventricular myocardium. Vagally induced bradycardia with concurrent ventricular beta-adrenoreceptor activation may underlie development of torsades de points in patients with long QT syndrome precipitated by swimming, diving or facial immersion.

Early effects of transcatheter aortic valve implantation and aortic valve replacement on myocardial function and aortic valve hemodynamics: Insights from cardiovascular magnetic resonance imaging

OBJECTIVES There remains a paucity of mechanistic data on the effect of transcatheter aortic valve implantation (TAVI) on early left and right ventricular function and quantitative aortic valve regurgitation. We sought to assess and compare the early effects on myocardial function and aortic valve hemodynamics of TAVI and aortic valve replacement (AVR) using serial cardiovascular magnetic resonance (CMR) imaging and echocardiography. METHODS A prospective comparison study of 47 patients with severe aortic stenosis undergoing either TAVI (n = 26) or high-risk AVR (n = 21). CMR (for left ventricle/right ventricle function, left ventricular mass, left atrial volume, and aortic regurgitation) was carried out before the procedure and early postprocedure (<14 days). RESULTS Groups were similar with respect to Society of Thoracic Surgeons score (TAVI, 7.7 vs AVR, 5.9; P = .11). Preoperative left ventricular (TAVI, 69% ± 13% vs AVR, 73% ± 10%; P = .10) and right ventricular (TAVI, 61% ± 11% vs AVR, 59% ± 8%; P = .5) ejection fractions were similar. Postoperative left ventricular ejection fraction was preserved in both groups. In contrast, decline in right ventricular ejection fraction was more significant in the TAVI group (61%-54% vs 59%-58%; P = .01). Postprocedure aortic regurgitant fraction was significantly greater in the TAVI group (16% vs 4%; P = .001), as was left atrial size (110 vs 84 mL; P = .02). Further analysis revealed a significant relationship between the increased aortic regurgitant fraction and greater left atrial size (P = .006), and a trend toward association between the decline in right ventricle dysfunction and increased postprocedure aortic regurgitation (P = .08). CONCLUSIONS There was no significant difference in early left ventricular systolic function between techniques. Whereas right ventricle systolic function was preserved in the AVR group, it was significantly impaired early after TAVI, possibly reflecting a clinically important pathophysiologic consequence of paravalvular aortic regurgitation.