Do the remodeling effects of sacubitril/valsartan treatment depend upon heart failure duration?

AIMS: The angiotensin receptor and neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) is recommended for the treatment of patients with heart failure in New York Heart Association (NYHA) class II-III and left ventricular ejection fraction (LVEF) 35% or less. We examined the effects of sacubitril/valsartan on cardiac remodeling and their correlation with heart failure duration in patients enrolled in our heart failure clinic from March 2017 to December 2019. METHODS: Echocardiographic and clinical/laboratory data were collected at baseline and at 6-month and 12-month follow-up visits in 69 patients (age 67 ±â€Š12 years, disease duration 8.4 ±â€Š5.8 years, 93% men). RESULTS: At both time points, mean NYHA class, NT-proBNP level, LVEF, LV end-systolic volume, and estimated systolic pulmonary pressure significantly (P < 0.05) improved versus baseline, as did the proportion of patients with diastolic dysfunction grade 3 or functional mitral regurgitation grade 3-4. In the subgroup with mean disease duration less than 8.5 years (n = 40), there was a significant improvement in all variables at both time points; in this group, a recovery of right ventricular function was also seen at the 12-month follow-up. On the contrary, patients with heart failure duration of at least 8.5 years (n = 29) showed only a slight improvement in LVEF and mitral regurgitation at 12 months. There were no significant changes in renal function and/or potassium levels in all patients. CONCLUSION: In patients with a relatively short disease duration, sacubitril/valsartan was associated with a strong favorable remodeling of the left ventricle and improvement in pulmonary circulation.

Assessment of left ventricular diastolic function by three-dimensional transthoracic echocardiography.

Doppler echocardiography assessment of left ventricular (LV) filling pressures at rest and during exercise is the most widely used imaging technique to assess LV diastolic function in clinical practice. However, a sizable number of patients evaluated for suspected LV diastolic function show an inconsistency between the various parameters included in the flowchart recommended by current Doppler echocardiography guidelines and results in an undetermined LV diastolic function. Current three-dimensional echocardiography technology allows obtaining accurate measurements of the left atrial volumes and functions that have been shown to improve the diagnostic accuracy and prognostic value of the algorithms recommended for assessing both LV diastolic dysfunction and heart failure with preserved ejection fraction. Moreover, current software packages used to quantify LV size and function provide also volume-time curves showing the dynamic LV volume change throughout the cardiac cycle. Examining the diastolic part of these curves allows the measurement of several indices of LV filling that have been reported to be useful to differentiate patients with normal LV diastolic function from patients with different degrees of diastolic dysfunction. Finally, several software packages allow to obtain also myocardial deformation parameters from the three-dimensional datasets of both the left atrium and the LV providing additional functional parameters that may be useful to improve the diagnostic yield of three-dimensional echocardiography for the LV diastolic dysfunction. This review summarizes the current applications of three-dimensional echocardiography to assess LV diastolic function.

A brief period of intensive cardiac rehabilitation improves global longitudinal strain and diastolic function after a first uncomplicated myocardial infarction.

Objectives In patients with abnormal left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI), cardiac rehabilitation with physical training prevents cardiac remodelling. To define the role of rehabilitation in the recovery of ventricular function in less severe cases, we studied its effects on more refined indexes of left ventricular function in uncomplicated, low-risk patients. Methods and results Fifty-five patients underwent percutaneous coronary revascularization after uncomplicated first AMI. Thirty-four started cardiac rehabilitation with counselling and physical training; 21 patients did not train, followed a counselling program and were taken as controls. Echocardiography was performed at baseline, after rehabilitation or counselling program and at six months follow-up. We measured: global strain (GS%) with speckle tracking analysis, E/e' by tissue Doppler imaging (TDI), left ventricular elastance (KLV) from the deceleration time (DT), LVEF, systolic and diastolic volumes, wall motion score index (WMSI). At baseline, groups had similar GS%, KLV, LVEF, DT, E/e', systolic and diastolic volumes, WMSI. Rehabilitation increased peak VO2 by 18% (P < 0.05) and improved GS%, KLV, LVEF, E/e' and WMSI (P < 0.02) that were unchanged in controls. The improvement persisted at six months. Conclusions After a first uncomplicated AMI, abnormalities of left systolic and diastolic ventricular function may be present persisting over time despite a normal LVEF, which are fully reverted by cardiac rehabilitation.

Intermittent levosimendan infusions in advanced heart failure: a real world experience.

Objective To analyse the effects of levosimendan infusions in advanced heart failure. Methods Patients with advanced heart failure treated with repeated levosimendan infusions were retrospectively compared with controls. Clinical, blood and echocardiographic parameters were obtained at baseline and after 12 months, and before and after each levosimendan infusion. Hospitalizations for heart failure and in-hospital length of stay in the 6 months before enrolment and after 6 and 12 months were recorded, along with 1-year mortality. Results Twenty-five patients treated with levosimendan and 25 controls were studied. After each levosimendan infusion, ventricular function and various clinical and metabolic parameters were improved. After 12 months, left ventricular ejection fraction (LVEF) had improved compared with baseline in the levosimendan group. The 1-year mortality rate was similar in both groups. During the 6 months before enrolment, hospitalizations were fewer in controls compared with the levosimendan group; after 6 and 12 months they increased in controls and decreased in the levosimendan group. Seven patients were super-responders to levosimendan, with LVEF improving more than 20% and hospitalizations being reduced at 12 months compared with the rest of the levosimendan group. Conclusion Intermittent levosimendan improved LVEF and decreased hospitalizations in advanced heart failure and represents a therapeutic option for patients whose disease is worsening.

Effects of hypobaric hypoxia exposure at high altitude on left ventricular twist in healthy subjects: data from HIGHCARE study on Mount Everest.

AIMS: Previous studies investigating the effect of hypoxia on left ventricle focused on its global function, an approach that may not detect a selective dysfunction of subendocardial layers that are most sensitive to an inadequate oxygen supply. In the HIGHCARE study, aimed at exploring the effects of high altitude hypoxia on multiple biological variables and their modulation by an angiotensin receptor blocker, we addressed the effects of hypobaric hypoxia on both systolic and diastolic left ventricular geometry and function, focusing on echocardiographic assessment of left ventricle twist to indirectly examine subendocardial left ventricular systolic function. METHODS AND RESULTS: In 39 healthy subjects, physiological and echocardiographic variables, including left ventricular twist and a simplified torsion-to-shortening ratio (sTSR), were recorded at sea level, at 3400 m, and at 5400 m altitude (Mount Everest base camp). Both left ventricular twist and sTSR were greater at 5400 m than at sea level (12.6° vs. 9.6° and 0.285 vs. 0.202, P < 0.05 for both), were linearly related to the reduction in arterial oxygen partial pressure (P < 0.01 for both), and were associated with significant changes in LV dimensions and contractility. No effects of angiotensin receptor blockade were observed on these variables throughout the study. CONCLUSION: Our study, for the first time, demonstrates an increase in left ventricular twist at high altitude in healthy subjects exposed to high altitude hypoxia, suggesting the occurrence of subendocardial systolic dysfunction in such condition.

Diastolic dysfunction and abnormal exercise ventilation predict adverse outcome in elderly patients with chronic systolic heart failure.

BACKGROUND: Heart failure is increasing in the elderly and represents a socioeconomic burden requiring the correct management for which risk stratification is mandatory. Among younger patients, echocardiogram and cardiopulmonary exercise test are useful in prognostic stratification. Few studies have analyzed the utility of these tests in elderly patients. METHODS: We report on 90 patients over 70 years old, on whom cardiopulmonary tests and echocardiograms were performed between 1998 and 2006 (67 M, 23 F; 75 ± 3 years; ejection fraction (EF) 30 ± 6%; NYHA 2.1 ± 0.8; 60% ischemic; therapy according to international guidelines). Echocardiographic variables were (1) left ventricular ejection fraction (EF); (2) severity of diastolic dysfunction on multiparametric examination of Doppler and TDI parameters; (3) severity of functional mitral regurgitation. Cardiopulmonary variables were (1) peak VO(2); (2) peak O(2) pulse; (3) peak respiratory quotient (RQ); (4) VE/VCO(2) slope. Endpoint considered was mortality of any cause at three-years follow-up. RESULTS: Mortality was 21%. At univariate analysis, survivors (n = 71) and deceased (n = 19) were similar for age, NYHA class, peakVO(2) and RQ; they differed for EF, severity of mitral regurgitation, severity of diastolic dysfunction, O(2) pulse and VE/VCO(2) slope. At multivariate analysis, only VE/VCO(2) slope and severe diastolic dysfunction (restrictive filling pattern) discriminated between the two groups. In particular, the association of restrictive filling pattern and VE/VCO(2) slope ≥ 45 predicted 3-year mortality with sensitivity of 84% and specificity of 88%. CONCLUSIONS: Echocardiographic and cardiopulmonary data can identify high-risk elderly patients with systolic heart failure, who may need aggressive clinical management.

Clinical relevance of cardiac structure and function abnormalities in patients with Cushing's syndrome before and after cure.

OBJECTIVES: Sustained hypercortisolism impacts cardiac function, and, indeed, cardiac disease is one of the major determinants of mortality in patients with Cushing's syndrome. The aim of this study was to assess the clinical relevance of cardiac structure and function alterations by echocardiography in patients with active Cushing's syndrome and after disease remission. STUDY DESIGN: Seventy-one patients (61 women, 10 men) with Cushing's syndrome and 70 age-, sex- and blood pressure-matched controls were enrolled. Echocardiography was performed in 49 patients with active disease and at several time points after remission in 44 patients (median follow-up 46.4 months), and prevalence of abnormal left ventricular mass measurements and systolic and diastolic functions indices was compared between patients with active disease, after remission and controls. Twenty-two patients were evaluated both before and after remission. RESULTS: Up to 70% of patients with active Cushing's syndrome presented abnormal left ventricular mass parameters; 42% presented concentric hypertrophy and 23% concentric remodelling. Major indices of systolic and diastolic functions, i.e. ejection fraction and E/A ratio, respectively, were normal. Upon remission of hypercortisolism, left ventricular mass parameters ameliorated considerably, although abnormal values were still more frequent than in controls. Both cortisol excess and hypertension contribute to cardiac mass alterations and increase the prevalence of target organ damage. CONCLUSIONS: Cushing's syndrome is associated with an increased risk for abnormalities of cardiac mass, which ameliorates, but does not fully disappear after remission. Systolic and diastolic functions are largely within the normal range in these patients.

Acute effects of levosimendan on mitral regurgitation and diastolic function in patients with advanced chronic heart failure.

BACKGROUND: We analyzed the inodilator properties of levosimendan in patients with chronic heart failure and severe functional mitral regurgitation. METHODS: We studied 20 patients under optimal treatment and in stable clinical condition (New York Heart Association 3.19 + or - 0.66; 70 + or - 7 years). Levosimendan was infused as a bolus (12 microg/kg in 10 min) followed by a 24-h infusion (0.1-0.2 microg/kg per min). Before and after infusion, Doppler echocardiography, brain natriuretic peptide determination and noninvasive hemodynamic monitoring with bioimpedance cardiography were performed. RESULTS: Levosimendan improved left ventricular ejection fraction (ejection fraction 31 + or - 4 from 27 + or - 4, P < 0.05), decreased brain natriuretic peptide (333 + or - 139 from 629 + or - 63 pg/ml, P < 0.01), reduced mitral valve effective regurgitant orifice area to 27 + or - 5 from 36 + or - 7 mm (P < 0.01) and the velocity of displacement of mitral annulus [ratio between E and E' waves on Doppler and tissue Doppler (E/E') from 22.7 + or - 1.6 to 13.1 + or - 0.6, P < 0.01]. Noninvasive hemodynamic monitoring showed increased acceleration index (a marker of inotropism), and reduced peripheral resistances and thoracic fluid content (P < 0.01). After 4 weeks of washout, some of these effects were still evident. CONCLUSION: In patients with chronic heart failure and functional mitral regurgitation, levosimendan acutely improved systolic and diastolic function, reduced mitral regurgitation and modulated neurohormonal activation, with a tendency for these changes to persist over a short-term follow-up.

Transthoracic bioimpedance and brain natriuretic peptide levels accurately indicate additional diastolic dysfunction in patients with chronic advanced systolic heart failure.

AIMS: Diastolic dysfunction in patients with heart failure has prognostic relevance, possibly because of its relationship with worsening haemodynamic status. In the quest for simpler indexes of haemodynamic status in patients, brain natriuretic peptide (BNP) levels have been proposed as a surrogate of diastolic function. To date, the value of combining BNP levels with non-invasive haemodynamic monitoring by transthoracic electric bioimpedance (TEB) for the prediction of diastolic function has not been evaluated. METHODS AND RESULTS: We compared left ventricular diastolic function measured by tissue Doppler imaging (TDI) with TEB results and BNP levels in 120 patients with chronic advanced systolic heart failure on optimal treatment (70 +/- 9 years, NYHA 2.4 +/- 0.8, ejection fraction 31 +/- 5%). Of the TEB variables measured, we only considered thoracic fluid content (TFC). To describe diastolic function, we used the TDI of the velocity of displacement of the mitral annulus (E') and the ratio E/E'. In all patients, E/E' was significantly related to TFC and to BNP levels (P < 0.001). Moreover, the combination of BNP > or = 350 pg/mL and TFC > or = 35/kOmega identified patients with diastolic dysfunction (defined as E/E' > or = 15) with high sensitivity and specificity (95 and 94%, respectively). CONCLUSION: The combination of transthoracic bioimpedance monitoring and BNP measurement accurately indicated the presence of diastolic dysfunction in most patients. These user-friendly and operator-independent tools may be useful as a screening assessment for diastolic dysfunction, and consequently abnormal central haemodynamic status, either in ambulatory patients or when an adequate echocardiographic evaluation is not readily available.

Improvement in left ventricular diastolic stiffness induced by physical training in patients with dilated cardiomyopathy.

BACKGROUND: Diastolic dysfunction in long-term heart failure is accompanied by abnormal neurohormonal control and ventricular stiffness. The diastolic phase is determined by a balance between pressure gradients and intrinsic ventricular wall properties: according to a mathematical model, the latter (ie, left ventricular [LV] elastance, K(LV)) may be calculated by the formula: K(LV) = (70/[DT-20])(2) mm Hg/mL, where DT is the transmitral Doppler deceleration time. METHODS AND RESULTS: In 54 patients with chronic systolic heart failure (39 men, 15 women; age 65 +/- 10 years; New York Heart Association [NYHA], 2.3 +/- 0.9; ejection fraction [EF], 32% +/- 5%), we analyzed the relationship between K(LV) and an index of neurohormonal derangement (levels of brain natriuretic peptide [BNP]), and investigated whether 3 months of physical training could modulate diastolic operating stiffness. Patients were randomized to physical training (n = 27) or to a control group (n = 27). Before and after training, patients underwent Doppler echocardiogram and cardiopulmonary stress test. At baseline, ventricular stiffness was related to BNP levels (P < .01). Training improved NYHA class, exercise performance, and estimated pulmonary pressure. BNP was reduced. Ventricular volumes, mean blood pressure, and EF remained unchanged. A 27% reduction of elastance was observed (K(LV), 0.111 +/- 0.044 from 0.195 +/- 0.089 mm Hg/mL; P < .01), whose magnitude was related to changes in BNP (P < .05) and to K(LV) at baseline (P < .01). No changes in K(LV) were observed in controls after 3 months (0.192 +/- 0.115 from 0.195 +/- 0.121 mm Hg/mL). CONCLUSIONS: In heart failure, left ventricular diastolic stiffness is related to neurohormonal derangement and is modified by physical training. This improvement in LV compliance could result from a combination of hemodynamic improvement and regression of the fibrotic process.

Different ventricular remodelling and autonomic modulation after long-term beta-blocker treatment in hypertensive, ischaemic and idiopathic dilated cardiomyopathy.

OBJECTIVE: In this retrospective analysis, we investigated the influence of aetiology on autonomic modulation and reverse ventricular remodelling induced by beta-blockade in heart failure. METHODS: Twenty-three heart failure patients without comorbidities (mean age 61 +/- 4 years, New York Heart Association class 3.1 +/- 0.1, treated with angiotensin-converting enzyme inhibitors and diuretics) were divided into three groups according to aetiology: hypertensive (group 1, n = 7), ischaemic (group 2, n = 6), and idiopathic (group 3, n = 10). Before and after 6 months of carvedilol (53 +/- 10 mg/day), patients underwent cardiopulmonary test, echocardiography and autonomic evaluation with spectral analysis of RR variability (10 min of rest plus 10 min of standing: the low frequency/high frequency ratio between low and high frequency components of each spectrum was the index of sympathovagal balance). RESULTS: Carvedilol improved New York Heart Association class and exercise performance. In group 1, ejection fraction and left ventricular end-diastolic volume normalised, and interventricular septum thickness increased. No remodelling occurred in group 2. In group 3, interventricular septum thickness was unchanged, ejection fraction and left ventricular end-diastolic volume improved. Also autonomic modulation differed. At baseline, adrenergic activation was observed either at rest or during standing. After carvedilol treatment, group 1 did not show any change in the low frequency/high frequency ratio in both conditions, whereas groups 2 and 3 showed reduced adrenergic activation at rest and normal response to standing. CONCLUSIONS: Despite favourable ventricular remodelling, the poor autonomic modulation observed with beta-blockade indicates a persistent central adrenergic activation in hypertensive heart failure patients.