Reduced congestion and improved response to a fluid/sodium challenge in chronic heart failure patients after initiation of sacubitril/valsartan: The NATRIUM-HF study.

AIMS: The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown. METHODS AND RESULTS: We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0-3 h), the load phase (3-6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6-9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (-0.50 [-12.7, 7.4] kg at 2 months, and -0.75 [-15.9, 7.5] kg at 3 months; both p < 0.0001). CONCLUSIONS: The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors.

Cardiogenic pulmonary edema - is it lone cardiogenic? "Missing link" between hemodynamic and other existing mechanisms.

The current traditional pathophysiologic concept of pulmonary edema of cardiogenic origin explains its development by a hydrostatic effect due to increased pulmonary capillary pressure resulting in fluid flux to alveolar and interstitial areas from capillaries. However, several experimental studies and clinical data of poor response to hemodynamic and diuretic treatment in many scenarios provide further evidence of the involvement of several other contributing factors to the development of cardiogenic pulmonary edema. Several experimental and clinical studies have found that sympathetic overactivity with elevated plasma catecholamine concentrations may play an important role in the development of cardiovascular-associated pulmonary edema. Catecholamine-induced pulmonary injury may be one of the key mechanisms in acute cardiogenic pulmonary edema triggering proinflammatory cytokine overactivation, oxidative stress and myocardial injury. In the everyday treatment of acute heart failure, physicians should consider the possibility of other noncardiogenic mechanisms involved in the progression of acute pulmonary edema, particularly catecholamine overactivity, lymphatic drainage, inflammatory and oxidative stress, high surfactant protein. The classic, hemodynamic treatment approach in pulmonary edema with the coexistence of other contributing factors may not provide adequate clinical benefit during treatment.

Heart Failure with Reduced Ejection Fraction: The Role of Cardiovascular and Lung Ultrasound beyond Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is considered a major health care problem with frequent decompensations, high hospitalization and mortality rates. In severe heart failure (HF), the symptoms are refractory to medical treatment and require advanced therapeutic strategies. Early recognition of HF sub- and decompensation is the cornerstone of the timely treatment intensification and, therefore, improvement in the prognosis. Echocardiography is the gold standard for the assessment of systolic and diastolic functions. It allows one to obtain accurate and non-invasive measurements of the ventricular function in HF. In severely compromised HF patients, advanced cardiovascular ultrasound modalities may provide a better assessment of intracardiac hemodynamic changes and subclinical congestion. Particularly, cardiovascular and lung ultrasound allow us to make a more accurate diagnosis of subclinical congestion in HFrEF. The aim of this review was to summarize the advantages and limitations of the currently available ultrasound modalities in the ambulatory monitoring of patients with HFrEF.

Takotsubo syndrome is a coronary microvascular disease: experimental evidence.

BACKGROUND AND AIMS: Takotsubo syndrome (TTS) is a conundrum without consensus about the cause. In a murine model of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion played a key role in the development of TTS. METHODS AND RESULTS: Vascular Kv1.5 channels connect coronary blood flow to myocardial metabolism and their deletion mimics the phenotype of CMD. To determine if TTS is related to CMD, wild-type (WT), Kv1.5-/-, and TgKv1.5-/- (Kv1.5-/- with smooth muscle-specific expression Kv1.5 channels) mice were studied following transaortic constriction (TAC). Measurements of left ventricular (LV) fractional shortening (FS) in base and apex, and myocardial blood flow (MBF) were completed with standard and contrast echocardiography. Ribonucleic Acid deep sequencing was performed on LV apex and base from WT and Kv1.5-/- (control and TAC). Changes in gene expression were confirmed by real-time-polymerase chain reaction. MBF was increased with chromonar or by smooth muscle expression of Kv1.5 channels in the TgKv1.5-/-. TAC-induced systolic apical ballooning in Kv1.5-/-, shown as negative FS (P < 0.05 vs. base), which was not observed in WT, Kv1.5-/- with chromonar, or TgKv1.5-/-. Following TAC in Kv1.5-/-, MBF was lower in LV apex than in base. Increasing MBF with either chromonar or in TgKv1.5-/- normalized perfusion and function between LV apex and base (P = NS). Some genetic changes during TTS were reversed by chromonar, suggesting these were independent of TAC and more related to TTS. CONCLUSION: Abnormalities in flow regulation between the LV apex and base cause TTS. When perfusion is normalized between the two regions, normal ventricular function is restored.

Reduction of Hospitalization and Mortality by Echocardiography-Guided Treatment in Advanced Heart Failure.

In advanced heart failure (AHF) clinical evaluation fails to detect subclinical HF deterioration in outpatient settings. The aim of the study was to determine whether the strategy of intensive outpatient echocardiographic monitoring, followed by treatment modification, reduces mortality and re-hospitalizations at 12 months. Methods: 214 patients with ejection fraction < 30% and >1 hospitalization during the last year underwent clinical evaluation and echocardiography at discharge and were divided into intensive (IMG; N = 143) or standard monitoring group (SMG; N = 71). In IMG, volemic status and left ventricular filling pressure were assessed 14, 30, 90, 180 and 365 days after discharge. HF treatment, particularly diuretic therapy, was temporarily intensified when HF deterioration signs and E/e' > 15 were detected. In SMG, standard outpatient monitoring without obligatory echocardiography at outpatient visits was performed. Results: We observed lower hospitalization (absolute risk reduction [ARR]-0.343, CI-95%: 0.287−0.434, p < 0.05; number needed to treat [NNT]-2.91) and mortality (ARR-0.159, CI 95%: 0.127−0.224, p < 0.05; NNT-6.29) in IMG at 12 months. One-year survival was 88.8% in IMG and 71.8% in SMG (p < 0.05). Conclusion: In AHF, outpatient monitoring of volemic status and intracardiac filling pressures to individualize treatment may potentially reduce hospitalizations and mortality at 12 months follow-up. Echocardiography-guided outpatient therapy is feasible and clinically beneficial, providing evidence for the larger application of this approach.

Asymptomatic COVID-19 and ST-elevation myocardial infarction in young adults: lessons learned from two similar cases.

We present two cases of acute myocardial infarction in young patients with asymptomatic COVID-19 infection and ST-elevation myocardial infarction (STEMI), complicated by severe acute heart failure and ventricular fibrillation, resulting cardiopulmonary resuscitation and mechanical ventilatory support. Urgent primary percutaneous coronary intervention with further complex treatment was effective in both cases with critical cardiovascular state and co-morbid COVID-19 infection. This report illustrates the challenges in clinical severity of STEMI with COVID-19 infection, despite of young age and absence of clinical symptoms and chronic co-morbidities. STEMI patients with even asymptomatic COVID-19 infection may be presented with significantly higher rates of severe acute heart failure.

Optimization of multi-organ failure for successful coronary angioplasty in acute myocardial infarction after pneumonectomy.

Pneumonectomy is a procedure that possesses several chronic complications most commonly associated with cardiovascular and respiratory systems. Acute myocardial infarction in patients after pneumonectomy and with other comorbidities represents high risk of interventional complications and mortality. We present a case of effective percutaneous coronary angioplasty in a 75-year-old patient with acute non-STEMI infarction, previous pneumonectomy and multi-organ pathology. Choice of treatment strategy and clinical decision making were further complicated by the presence of multiple risk factors, including impaired respiratory function and advanced age of the patient. However, after the short term stabilization of cardiac and respiratory failure symptoms, the patient underwent successful angioplasty with implantation of a drug eluting stent on the right coronary artery. The patient demonstrated a significant improvement of the symptoms and multiorgan failure parameters after angioplasty. This report shows the effective management strategy of patient with acute myocardial infarction and concomitant multi organ failure with indication for percutaneous coronary intervention.

Lung ultrasound-guided therapy reduces acute decompensation events in chronic heart failure.

OBJECTIVE: Pulmonary congestion is the main cause of hospital admission in patients with heart failure (HF). Lung ultrasound (LUS) is a useful tool to identify subclinical pulmonary congestion. We evaluated the usefulness of LUS in addition to physical examination (PE) in the management of outpatients with HF. METHODS: In this randomised multicentre unblinded study, patients with chronic HF and optimised medical therapy were randomised in two groups: 'PE+LUS' group undergoing PE and LUS and 'PE only' group. Diuretic therapy was modified according to LUS findings and PE, respectively. The primary endpoint was the reduction in hospitalisation rate for acute decompensated heart failure (ADHF) at 90-day follow-up. Secondary endpoints were reduction in NT-proBNP, quality-of-life test (QLT) and cardiac mortality at 90-day follow-up. RESULTS: A total of 244 patients with chronic HF and optimised medical therapy were enrolled and randomised in 'PE+LUS' group undergoing PE and LUS, and in 'PE only' group. Thirty-seven primary outcome events occurred. The hospitalisation for ADHF at 90 day was significantly reduced in 'PE+LUS' group (9.4% vs 21.4% in 'PE only' group; relative risk=0.44; 95% CI 0.23 to 0.84; p=0.01), with a reduction of risk for hospitalisation for ADHF by 56% (p=0.01) and a number needed to treat of 8.4 patients (95% CI 4.8 to 34.3). At day 90, NT-proBNP and QLT score were significantly reduced in 'PE+LUS' group, whereas in 'PE only' group both were increased. There were no differences in mortality between the two groups. CONCLUSIONS: LUS-guided management reduces hospitalisation for ADHF at mid-term follow-up in outpatients with chronic HF.

Optimization of heart rate lowering therapy in hospitalized patients with heart failure: Insights from the Optimize Heart Failure Care Program.

BACKGROUND: Hospitalization is an opportunity to optimize heart failure (HF) therapy. As optimal treatment for hospitalized HF patients in sinus rhythm with heart rate≥70bpm is unclear, we investigated the impact of combined beta-blocker (BB) and ivabradine versus BBs alone on short and longer term mortality and rehospitalization. METHODS AND RESULTS: A retrospective analysis was performed on 370 hospitalized HF patients with heart rate≥70bpm (150 BB+ivabradine, 220 BB alone) in the Optimize Heart Failure Care Program in Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Russia, Ukraine, and Uzbekistan, from October 2015 to April 2016. RESULTS: At 1month, 3months, 6months and 12months, there were fewer deaths, HF hospitalizations and overall hospitalizations in patients on BB+ivabradine vs BBs alone. At 12months, all-cause mortality or HF hospitalization was significantly lower with BB+ivabradine than BBs (adjusted hazard ratio [HR] 0.45 (95% confidence interval [CI] 0.32-0.64, P<0.0001). Significantly greater improvement was seen in quality of life (QOL) from admission to 12months with BB+ivabradine vs BBs alone (P=0.0001). With BB+ivabradine, significantly more patients achieved ≥50% target doses of BBs at 12months than on admission (82.0% vs 66.6%, P=0.0001), but the effect was non-significant with BBs alone. CONCLUSIONS: Heart rate lowering therapy with BB+ivabradine started in hospitalized HF patients (heart rate≥70bpm) is associated with reduced overall mortality and re-hospitalization over the subsequent 12months. A prospective randomized trial is needed to confirm the advantages of this strategy.

Cardiomyopathies: Evolution of pathogenesis concepts and potential for new therapies.

Cardiomyopathies are defined as diseases of the myocardium with associated structural and functional abnormalities. Knowledge of these pathologies for a long period was not clear in clinical practice due to uncertainties regarding definition, classification and clinical diagnosis. In recent decades, major advances have been made in the understanding of the molecular and genetic issues, pathophysiology, and clinical and radiological assessment of the diseases. Progress has been made also in management of several types of cardiomyopathy. Advances in the understanding of these diseases show that cardiomyopathies represent complex entities. Here, special attention is given to evolution of classification of cardiomyopathies, with the aim of assisting clinicians to look beyond schematic diagnostic labels in order to achieve more specific diagnosis. Knowledge of the genotype of cardiomyopathies has changed the pathophysiological understanding of their etiology and clinical course, and has become more important in clinical practice for diagnosis and prevention of cardiomyopathies. New approaches for clinical and prognostic assessment are provided based on contemporary molecular mechanisms of contribution in the pathogenesis of cardiomyopathies. The genotype-phenotype complex approach for assessment improves the clinical evaluation and management strategies of these pathologies. The review covers also the important role of imaging methods, particularly echocardiography, and cardiac magnetic resonance imaging in the evaluation of different types of cardiomyopathies. In summary, this review provides complex presentation of current state of cardiomyopathies from genetics to management aspects for cardiovascular specialists.

Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study.

OBJECTIVES: The aim of this cohort study was to retrospectively evaluate, in patients with chronic heart failure (CHF), the long term effect of trimetazidine (TMZ) on morbidity and mortality. BACKGROUND: Previous small studies in patients with CHF have shown that TMZ can improve left ventricular function, exercise capacity and NYHA class compared to placebo. However, no data on the effects of TMZ on survival in patients with CHF have ever been produced. METHODS: In this international multicentre retrospective cohort study data from 669 patients were analyzed. 362 patients were on TMZ due to symptom persistence despite up-titration of optimal CHF therapy, while the remaining patients continued conventional CHF therapy alone. Propensity score analysis was performed in order to minimize selection bias between the two groups. RESULTS: Kaplan-Meier analysis for global mortality showed 11.3% improved global survival (p=0.015) and 8.5% improved survival for cardiovascular (CVD) death (p=0.050) in the TMZ group. Cox regression analysis for global mortality showed a significant risk reduction for TMZ treated patients with a hazard ratio (HR)=0.189 (confidence interval - CI 95%: 0.017-0.454; p=0.0002). TMZ also showed a good risk reduction profile for CVD death causes (HR=0.072, CI 95%: 0.019-0.268, p=0.0001). The rate of hospitalization for cardiovascular causes was reduced by 10.4% at 5 years (p<0.0005) with increased hospitalization-free survival of 7.8 months. CONCLUSION: TMZ is effective in reducing mortality and event-free survival in patients with CHF. The addition of TMZ on top of optimal medical therapy improves long term survival in CHF patients.

A double-blind, randomized, parallel, placebo-controlled study examining the effect of cross-linked polyelectrolyte in heart failure patients with chronic kidney disease.

AIMS: This double-blind, randomized, parallel, placebo-controlled investigation evaluated the effects of cross-linked polyelectrolyte (CLP) on serum potassium and measures of congestion in patients with heart failure (HF) and chronic kidney disease (CKD). METHODS AND RESULTS: The primary endpoint was change in serum potassium over time. Exploratory endpoints included: weight, physician and patient assessment of exertional dyspnoea, effect on N-terminal pro brain natriuretic peptide (NT-proBNP) levels, New York Heart Association (NYHA) classification, 6 min walk test (6MWT), and quality of life by Kansas City Cardiomyopathy Questionnaire (KCCQ). Serum potassium was similar in CLP (n =59) and placebo (n =52) groups throughout the 8-week study. Weight loss was greater in the CLP than in the placebo group at Weeks 1 (P =0.014) and 2 (P =0.004), and this trend continued until the end of the study. After 8 weeks, by physician assessment, the percentage of patients experiencing marked or disabling dyspnoea tended to be lower in the CLP than in the placebo group (7.3% vs. 23.9%, P =0.128). Fewer patients in the CLP than in the placebo group had NT-proBNP levels >1000 pg/mL at Week 4 (P =0.039) and Week 8 (P =0.065). The proportion of patients improving by at least one NYHA functional class over the study was higher in the CLP than in the placebo group (48.8% vs. 17.4%; P =0.002). Effects on 6MWT at Week 8 (p =0.072) and quality of life (overall KCCQ score) at Week 4 (p =0.005) and 8 (P =0.062) all favoured the CLP cohort. Four treatment-unrelated deaths occurred in the CLP group and none in the placebo group (P =0.056). CONCLUSION: In advanced, symptomatic HF with CKD, CLP is associated with beneficial clinical effects without significant serum potassium changes. TRIAL REGISTRATION: NCT01265524.

Chemopreventive doses of resveratrol do not produce cardiotoxicity in a rodent model of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), one of the most lethal cancers, results in more than one million fatalities worldwide every year. In view of the limited therapeutic alternatives and poor prognosis of liver cancer, preventive control approaches, notably chemoprevention, have been considered to be the best strategy in lowering the present prevalence of the disease. Resveratrol, a naturally occurring antioxidant and antiinflammatory agent found in grapes and red wine, inhibits carcinogenesis with a pleiotropic mode of action. Recently, we have reported that dietary resveratrol significantly prevents chemically-induced liver tumorigenesis in rats. One of the mechanisms of resveratrol-mediated chemoprevention of hepatocarcinogenesis could be related to its antiinflammatory action through hepatic cyclooxygenase (COX-2) inhibition. Although several COX-2 inhibitors are known to exert chemopreventive efficacy, not all are considered ideal candidates for chemoprevention due to the risk of adverse cardiovascular events. Accordingly, the objective of the present study was to evaluate the role of resveratrol on cardiac performance during experimental hepatocarcinogenesis initiated with diethylnitrosamine and promoted by phenobarbital. Rats had free access to diet supplemented with resveratrol four weeks before the carcinogen injection and 14 weeks thereafter. The cardiotoxicity of resveratrol was assessed by monitoring the cardiac function using transthoracic echocardiography as well as Western blot analysis of cardiac tissue. Long-term dietary administration of resveratrol dose-dependently suppressed hepatic tumor multiplicity, the principal endpoint for evaluating the chemopreventive potential of a candidate agent. The chemopreventive effects of resveratrol were also reflected in histopathological assessment of hepatic tissues. Resveratrol did not exhibit any cardiotoxicity but rather improved the cardiac function in a dose-responsive fashion. Our results indicate that resveratrol-mediated chemoprevention of rat liver carcinogenesis is devoid of any adverse cardiovascular events. Resveratrol may be developed as a chemopreventive as well as therapeutic drug for human HCC.

The effect of trimetazidine on left ventricular systolic function and physical tolerance in patients with ischaemic cardiomyopathy.

OBJECTIVE: Trimetazidine (TMZ) is the first of novel antianginal drugs with a cardioprotective effect, selectively inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. This study tested the hypothesis that the cytoprotective beneficial effect of this agent can lead to the improvement of left ventricular (LV) systolic function and tolerance to physical activity in patients with ischaemic cardiomyopathy. METHODS AND RESULTS: In 82 consecutive patients with ischaemic cardiomyopathy, a subgroup of patients (n = 42) was assigned to receive a modified form of TMZ (35 mg twice daily) in addition to the conventional therapy for the duration of three months. All patients underwent clinical, echocardiographic examination and a six-minute walk test at baseline and after a three-month treatment. The therapy with TMZ significantly improved the functional class in these patients. Left ventricular ejection fraction (LVEF) increased by 3.5 +/- 6.72% (from 34.5 +/- 3.8% to 38.0 +/- 4.8%) in the TMZ group vs. 0.8 +/- 8.06% (from 32.4 +/- 5.6% to 33.2 +/- 5.8%) in the control group (P = 0.05). The tolerance to physical activity improved by 30.0 +/- 20.7 m in the TMZ group (from 215 +/- 17.5 m to 245 +/- 20.7 m) vs. 2.0 +/- 18.85 m (from 208.2 +/- 12.4 m to 210.2 +/- 14.2 m) in the control group (P < 0.001). CONCLUSIONS: A therapeutic intervention with TMZ in conjunction with the standard therapy, over a three-month period, is associated with an increase in LVEF and improved tolerance to physical activity in patients with ischaemic cardiomyopathy.