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Background and Aims Adjustment of treatment based on remote monitoring of pulmonary artery (PA) pressure may reduce the risk of hospital admission for heart failure (HF). We have conducted a meta-analysis of large randomized trials investigating this question. Methods A systematic literature search was performed for randomized clinical trials (RCTs) with PA pressure monitoring devices in patients with HF. The primary outcome of interest was the total number of HF hospitalizations. Other outcomes assessed were urgent visits leading to treatment with intravenous diuretics, all-cause mortality, and composites. Treatment effects are expressed as hazard ratios, and pooled effect estimates were obtained applying random effects meta-analyses. Results Three eligible RCTs were identified that included 1898 outpatients in New York Heart Association functional class II-IV, either hospitalized for HF in the prior 12 months or with elevated plasma NT-proBNP concentrations. Mean follow-up was 14.7 months, 67.8% of the patients were men, and 65.8% had an ejection fraction ≤40%. Compared to patients in the control group, the hazard ratio (95% confidence interval) for total HF hospitalizations in those randomized to PA pressure monitoring was 0.70 (0.58-0.86) (p=0.0005). The corresponding hazard ratio for the composite of total HF hospitalizations, urgent visits and all-cause mortality was 0.75 (0.61-0.91; p=0.0037) and for all-cause mortality 0.92 (0.73-1.16). Subgroup analyses, including ejection fraction phenotype, revealed no evidence of heterogeneity in the treatment effect. Conclusions The use of remote PA pressure monitoring to guide treatment of patients with HF reduces episodes of worsening HF and subsequent hospitalizations.

Background Although multiple novel biomarkers have individually been shown to predict outcomes in patients with HFrEF, the value of these over and above conventional clinical and laboratory variables, plus natriuretic peptides, is uncertain. Purpose To test the incremental predictive value of 11 novel biomarkers added to a recent prognostic model 1 (PREDICT-HF) derived in PARADIGM-HF and validated in ATMOSPHERE and the Swedish heart failure registry. The PREDICT-HF model includes clinical variables, standard laboratory variables, and BNP or NT-proBNP. Methods 1559 participants enrolled in PARADIGM-HF had all 11 biomarkers of interest measured. These reflected different pathophysiological pathways: (i) myocyte injury (high sensitivity cardiac troponin T), (ii) cardiac remodelling and inflammation (growth stimulation expressed gene 2, growth differentiation factor-15 and galectin-3), (iii) extracellular matrix remodelling (matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1), (iv) neurohormonal pathways (aldosterone) and (v) renal dysfunction and injury (cystatin C, kidney injury molecule-1 and urinary albumin to creatinine ratio). The incremental prognostic value of these biomarkers was evaluated using Harrell's C statistic. Results The mean age of participants studied was 67.3 (SD 9.9) years, 1254 (80%) were men and 1103 (71%) were in NYHA class II. During a median follow-up of 31 months, 197 patients died and 300 experienced the primary composite outcome (cardiovascular death or heart failure hospitalization). When each candidate biomarker (log unit) was added individually to the PREDICT-HF base model, GDF-15, ST2, TIMP1, cystatin C, hsTnT and UACR were independent predictors of all-cause mortality (Table 1). GDF-15, TIMP1, hs-TnT and cystatin C consistently increased the risk of both all-cause mortality and the primary outcome. Individuals who had all 4 biomarkers elevated (compared to none elevated) had the highest risk: HR for all-cause mortality 3.65 (2.01–6.64), p Conclusion Several novel biomarkers provide meaningful additional prognostic information in patients with HFrEF. A multimarker approach incorporating biomarkers reflecting different pathophysiological pathways added most information. This approach may be useful in refining risk and targeting treatment. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The PARADIGM-HF trial was funded by Novartis.J.J.V.M is supported by a British Heart Foundation Centre of Excellence Grant

Background The COAPT trial of MitraClip therapy employed a central screening eligibility committee (CSEC) of heart failure (HF) experts to ensure the use of maximally tolerated guideline-directed medical therapy (GDMT) and systematically document intolerances in all potential patients prior to approval for randomization. Purpose To describe the percentage of GDMT classes, doses tolerated, predictors of intolerance, and specific intolerances limiting GDMT among patients approved for randomization by the CSEC. Methods We analyzed baseline use, dose, and intolerances of i) angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) or angiotensin receptor neprilysin inhibitor (ARNI); ii) beta-blockers (BB); and iii) mineralocorticoid receptor antagonists (MRA) in the CSEC-approved COAPT population with HF with reduced ejection fraction (HFrEF; LVEF ≤40%). We analyzed variables associated with GDMT tolerance. Results In COAPT, 464 patients had HFrEF and complete screening medication information. Any dose of all 3, 2 or 1 GDMT classes were tolerated in 39%, 39% and 20% of patients respectively; only 2% of patients (n=9) could not tolerate any GDMT (Figure 1). BB were prescribed in the most (93%) patients followed by ACEI/ARB/ARNI (69%) and MRA (55%). Intolerances limiting each GDMT class differed, but hypotension and kidney dysfunction were most common (Figure 2). No patients tolerated goal doses of all 3 GDMT classes. For BB, only 32% tolerated ≥50% of the goal dose; while for ACEI/ARB/ARNI, no patients achieved goal doses, and only 1% tolerated ≥50% of the goal dose. For MRA, 86% of patients tolerated 25mg/day or less. Patients intolerant of BB were less likely to tolerate an ACEI/ARB/ARNI (OR 0.39, 95% CI 0.20–0.76; p=0.004) but not a MRA (p=0.21) compared with patients tolerating a low dose BB. Patients intolerant of MRA were less likely to tolerate ACEI/ARB/ARNI therapy (OR 0.37, 95% CI 0.25–0.57; p Conclusion In a contemporary trial in which HF specialists ensured GDMT optimization, many patients had medical intolerances prohibiting use of one or more GDMT classes, and few patients tolerated target doses. These findings indicate medical intolerances are the primary cause of low GDMT prescription rates in patients with moderate to severe HFrEF. Yet, use of GDMT in this very ill population was much better than “real world” registries of HFrEF suggesting that mandating careful CSEC review prior to study enrollment is important for clinical trials having the objective of randomizing a maximally treated patient cohort. Funding Acknowledgement Type of funding sources: None.

In the failing heart, several changes occur in cardiac adrenergic receptor-signal transduction pathways. The most striking of these changes occur in beta-ARs, and of the changes in beta-adrenergic receptors, beta1-receptor down-regulation is the most prominent. Other changes include uncoupling of beta2-adrenergic receptors and increased activity of the inhibitory G-protein, Gi. Most of these changes appear to be related to increased activity of the adrenergic nervous system, i.e. increased exposure to norepinephrine. Antagonists of the adrenergic nervous system improve left ventricular function and outcome in patients with heart failure. This fact supports the notion that activation of these neurohormonal systems exerts a net long-term detrimental effect on the natural history of chronic heart failure and that myocardial adrenergic desensitization phenomena are at least partially adaptive in the setting of left ventricular dysfunction.

BACKGROUND: The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying. MATERIALS AND METHODS: One approach to providing evidence for cause-effect of a disease-influencing gene is to quantitatively compare changes in phenotype to changes in gene expression by employing serial measurements in a longitudinal experimental design. We investigated the quantitative relationships between changes in gene expression and phenotype n 47 patients with idiopathic DCM. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function (beta-adrenergic receptors, sarcoplasmic reticulum Ca(2) + ATPase, and alpha- and beta-myosin heavy chain isoforms) or associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide), plus beta-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction. RESULTS: Improvement in DCM phenotype was directly related to a coordinate increase in alpha- and a decrease in beta-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of beta(1)- or beta(2)-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca(2) + ATPase and atrial natriuretic peptide. CONCLUSION: We conclude that in human DCM, phenotypic modification is selectively associated with myosin heavy chain isoform changes. These data support the hypothesis that myosin heavy chain isoform changes contribute to disease progression in human DCM.

This article reviews the current understanding of the pathophysiology and clinical spectrum of heart failure. A cascade of hemodynamic and neurohormonal derangements result from a decrease in ventricular performance or cardiac output. Because neurohormonal activation has become a target for intervention in heart failure, the role of selected systems (sympathetic nervous, renin-angiotensin-aldosterone) and of natriuretic peptides is detailed. The spectrum (from compensated to acute decompensated) within which congestive heart failure patients present is reviewed, with special attention paid to the intermediate, transitional group of patients, who pose unique diagnostic and therapeutic challenges. Given these variable presentations, there is an obligation to tailor therapy accordingly.

The importance of hypertension as a risk factor for heart failure [1, 2] reinforces the importance of preventative strategies directed towards earlier and more aggressive blood pressure control. Treatment of hypertension has been shown to improve outcomes in hypertensive subjects, particularly when the agent used not only controls blood pressure but also limits or reverses myocardial hypertrophy [2].

The success of beta-blocking agents in clinical trials of heart failure (HF) has led to a widespread call for their increased use, which assumes these agents will perform as well in the usual care setting. Given the traditional contraindication of the use of beta-blocking agents in HF, and their perception as difficult to use in HF, observing how they perform in the usual care setting could be critical in accelerating their widespread application. Carvedilol is the only beta-blocking agent currently approved in the United States for use in HF.The Coreg (brand of carvedilol; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) Heart Failure Registry (COHERE) is intended to collect data on outcomes and other clinical variables in a typical HF population and to observe experience with carvedilol in the hands of community practitioners. COHERE does not include any specific patient selection or exclusion criteria. The decision to use carvedilol is entirely at the discretion of the participant physician, based on evidence of HF as judged by assessments the practitioner usually uses. All patients will be followed for 1 year, with information on outcomes and other clinical variables collected and analyzed at baseline, the end of titration, and at 6 and 12 months after reaching the maximum tolerated dose. About 600 participant physicians selected to be as representative as possible of the community practice setting will enroll approximately 6,000 patients.COHERE will be the first and largest prospective observational experience with a new treatment, ie, carvedilol, in patients with HF managed in the usual care setting and should provide valuable information about this new treatment in this environment compared with the more rigid clinical trials setting.

The left-ventricular (LV) functional, hemodynamic, and antiadrenergic effects of metoprolol, bucindolol, and carvedilol have been compared in three concurrent placebo-controlled clinical trials in patients with symptomatic idiopathic dilated cardiomyopathy. All three drugs were well tolerated, all produced at least moderate degrees of beta-blockade as assessed by reduction in exercise heart rate, and all increased the left-ventricular ejection fraction. Compared with the beta 1-selective, second-generation compound metoprolol, the third-generation compounds bucindolol and carvedilol lowered indices of adrenergic activity and tended to improve LV function to a greater extent. In patients with chronic heart failure there may be important therapeutic response differences between second- and third-generation beta-blocking agents.

We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a "third-generation" beta -blocking agent with vasodilator properties, in chronic heart failure.Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, and high-dose carvedilol groups, respectively, compared with 2 EF units with placebo, P.001 for linear dose response) and survival (respective crude mortality rates of 6.0%, 6.7%, and 1.1% with increasing doses of carvedilol compared with 15.5% in the placebo group, P.001). When the three carvedilol groups were combined, the all-cause actuarial mortality risk was lowered by 73% in carvedilol-treated subjects (P.001). Carvedilol also lowered the hospitalization rate (by 58% to 64%, P = .01) and was generally well tolerated.In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose-related reductions in mortality and hospitalization rate.

To test the hypothesis that diminished sodium delivery to the distal tubular site of atrial natriuretic peptide (ANP) action accounts for renal ANP resistance in cirrhosis, 12 cirrhotic patients with ascites were studied at baseline and during the infusion of ANP alone (0.15 micrograms/kg/min), mannitol alone (4 g/hr), and ANP plus mannitol for 3 hours each. Distal tubular sodium delivery, as assessed by lithium clearance, was increased during the infusion of mannitol (13.8 +/- 3.4 to 23.7 +/- 5.7 mL/min; P.05) and during the ANP plus mannitol infusion (13.8 +/- 3.4 to 28.5 +/- 6.3 mL/min; P.001) in 6 patients, subsequently termed "responders." Both responders and nonresponders were resistant to the natriuretic effect of ANP infused alone, and mannitol alone did not produce an increase in urinary sodium excretion. However, in responders, the mannitol-induced increase in distal tubular sodium delivery resulted in a fivefold increase in urinary sodium excretion during ANP infusion (29 +/- 6 to 154 +/- 40 mumol/min, P.01). Urinary cyclic guanosine monophosphate (cGMP) excretion increased significantly and to a similar extent during ANP and ANP plus mannitol in all 12 patients, supporting the active biological responsiveness of renal ANP receptors. Unlike responders, nonresponders showed a significant decrease in arterial blood pressure and an increase in plasma renin activity during ANP plus mannitol, consistent with worsened arterial underfilling caused by ANP-induced vasodilation. Thus, the present results support the hypothesis that diminished distal tubular sodium delivery is a major factor contributing to ANP resistance in cirrhosis.

The unifying hypothesis of body fluid volume regulation explains the renal handling of sodium and water in health and in various disease states associated with edema formation and no intrinsic renal parenchymal disease. According to this hypothesis, underfilling of the arterial vascular compartment, resulting from either a decrease in cardiac output or peripheral arterial vasodilation, initiates a sequence of events that results in activation of the sympathetic nervous and renin-angiotensin-aldosterone systems and the nonosmotic release of AVP. Activation of these neurohormonal vasoconstrictor systems causes diminished renal hemodynamics and renal sodium and water retention that persist despite an increase in total extracellular and blood volume. In edematous patients, a vasoconstrictor-mediated increase in proximal tubular sodium reabsorption results in diminished sodium delivery to the distal tubular sites of action of aldosterone and ANP; this explains the failure of such patients to escape from the sodium-retaining effects of aldosterone and the resistance to the natriuretic and diuretic effects of ANP. In pregnancy, an early decrease in systemic vascular resistance associated with activation of the neurohormonal vasoconstrictor systems precedes the normal expansion of blood and plasma volumes and is consistent with the arterial underfilling hypothesis. The loss of this peripheral vasodilatory response in some pregnancies may contribute to the development of preeclampsia and eclampsia.

The pathogenesis of renal sodium and water retention in cardiac failure, cirrhosis, and the nephrotic syndrome may be explained by the unifying hypothesis of body fluid volume regulation. According to this hypothesis, underfilling of the arterial vascular compartment initiates a sequence of events, including activation of various neurohormonal vasoconstrictor systems, which results in enhanced renal sodium and water reabsorption, the failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. In patients with low-output cardiac failure, a decrease in cardiac output results in arterial underfilling. Peripheral arterial vasodilation diminishes the fullness of the arterial vascular compartment in patients with high-output cardiac failure and cirrhosis. In the nephrotic syndrome, the decrease in plasma oncotic pressure due to hypoalbuminemia initiates arterial underfilling. The factors that are responsible for the peripheral arterial vasodilation in patients with cirrhosis remain obscure. Diuretics are initially effective in reducing the excess of total-body sodium and water in edematous patients. Loop diuretics, with or without metolazone or a thiazide diuretic, are quite useful in patients with heart failure. In cirrhosis and the nephrotic syndrome, the specific aldosterone antagonist spironolactone, alone or in combination with other diuretics, has proven to be highly efficacious. However, in all instances, the emergence of diuretic resistance represents a major limitation of diuretic therapy for the edematous patient. This diuretic resistance may be mediated by further activation of vasoconstrictor, antinatriuretic neurohormones.

Acute renal failure (ARF) may be defined as an abrupt decrease in previously stable renal function sufficient to result in retention of nitrogenous waste, e.g. blood urea nitrogen (BUN) and creatinine, in the body. Acute renal failure is commonly encountered in the hospital setting. The incidence of ARF is largely dependent on the patient population. A prospective study of general medical and surgical inpatients showed an incidence of almost 5% (Hou et al. 1983). A higher frequency of occurrence is encountered in selected clinical settings, particularly, an incidence of 15%-25% is seen in the Intensive Therapy Unit (ITU) (Wilkins and Faragher 1983). The mortality of patients presenting with ARF alone is 8%. However, the overall mortality of patients with ARF in the setting of the Intensive Therapy Unit still averages 60% or more, despite improvements in monitoring, diagnostics, and therapy (Brunner et al. 1986; Frankel et al. 1983; Stott et al. 1972). Thus, ARF remains a special challenge for the ITU physician.