Franz X. Kleber

Impairment of Ventilatory Efficiency in Heart Failure Prognostic Impact

BACKGROUNDnImpairment of ventilatory efficiency in congestive heart failure (CHF) correlates well with symptomatology and contributes importantly to dyspnea.nnnMETHODS AND RESULTSnWe investigated 142 CHF patients (mean NYHA class, 2.6; mean maximum oxygen consumption [VO(2)max], 15.3 mL O(2) x kg(-1) x min(-1); mean left ventricular ejection fraction [LVEF], 27%). Patients were compared with 101 healthy control subjects. Cardiopulmonary exercise testing was performed, and ventilatory efficiency was defined as the slope of the linear relationship of V(CO(2)) and ventilation (VE). Results are presented in percent of age- and sex-adjusted mean values. Forty-four events (37 deaths and 7 instances of heart transplantation, cardiomyoplasty, or left ventricular assist device implantation) occurred. Among VO(2)max, NYHA class, LVEF, total lung capacity, and age, the most powerful predictor of event-free survival was the VE versus V(CO(2)) slope; patients with a slope </=130% of age- and sex-adjusted normal values had a significantly better 1-year event-free survival (88.3%) than patients with a slope >130% (54.7%; P<0.001).nnnCONCLUSIONSnThe VE versus V(CO(2)) slope is an excellent prognostic parameter. It is easier to obtain than parameters of maximal exercise capacity and is of higher prognostic importance than VO(2)max.

Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure

OBJECTIVESnWe sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin.nnnBACKGROUNDnLevosimendan is a calcium sensitizer for treatment of acute decompensated heart failure.nnnMETHODSnA double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 microg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 microg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 microg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a > or =15% increase in stroke volume (SV) at 23 h to 24 h; 2) a > or =25% decrease in pulmonary capillary wedge pressure (PCWP) (and > or =4 mm Hg) at 23 h to 24 h; 3) a > or =40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a > or =50% decrease in PCWP during two consecutive measurements.nnnRESULTSnThe response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p< or =0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages.nnnCONCLUSIONSnDosing of levosimendan with a 10-min bolus of 6 to 24 microg/kg followed by an infusion of 0.05 to 0.2 microg/kg/min is well tolerated and leads to favorable hemodynamic effects.

Impaired ventilatory efficiency in chronic heart failure: Possible role of pulmonary vasoconstriction

BACKGROUNDnPatients with chronic heart failure show impairment of ventilatory efficiency, defined as the relation between ventilation and carbon dioxide output. It is caused by ventilation of excess physiologic dead space. We hypothesized a role of active vasoconstriction in the increase of physiologic dead space, presumed to lead to alveolar hypoperfusion.nnnMETHODS AND RESULTSnIn 57 patients with chronic heart failure (New York Heart Association classification II through IV, ejection fraction 25.6%+/-10.4%) and 7 control subjects, gas exchange at rest and on exercise was compared with hemodynamic measurements and, in a subgroup of 15 patients, with endothelin-1, epinephrine, and norepinephrine levels in the pulmonary and systemic circulation. Ventilatory efficiency at rest (VE/VCO2 ratio) correlated with ventilatory efficiency on exercise (VE vs VCO2 slope). Impairment of ventilatory efficiency correlated strongly negative with exercise tolerance (maximal oxygen uptake: r = -0.67) and cardiac output (r = -0.66) and positive with pulmonary hypertension (mean pulmonary artery pressure: r = 0.69, pulmonary vascular resistance: r = 0.60). None of the vasoconstrictors correlated with reduction of ventilatory efficiency in the subgroup studied.nnnCONCLUSIONSnImpairment of ventilatory efficiency in chronic heart failure is correlated with resting pulmonary artery pressures and associated with the impairment of exercise capacity. An imbalance of pulmonary vascular tone probably leads to both pulmonary hypertension and alveolar hypoperfusion.

Effects of Iloprost Inhalation on Exercise Capacity and Ventilatory Efficiency in Patients With Primary Pulmonary Hypertension

BACKGROUNDnThe continuous infusion of prostacyclin has been shown to improve exercise capacity and survival in patients with primary pulmonary hypertension (PPH). Inhalation of iloprost, a stable analog of prostacyclin, might be an alternative therapy for PPH, selectively acting on the pulmonary vascular bed through ventilation-matched alveolar deposition of the drug. We investigated the short-term effects of iloprost inhalation on exercise capacity and gas exchange in patients with PPH.nnnMETHODS AND RESULTSnIn 11 patients with PPH, we performed 2 consecutive cardiopulmonary exercise tests before and after the inhalation of 17 microgram of iloprost. Patients had marked pulmonary hypertension (mean pulmonary artery pressure 65 mm Hg), and inhalation resulted in a decrease in pulmonary vascular resistance (1509 versus 1175 dyne. s(-1). cm(-5), P<0.05). Arterial blood gases remained unchanged (PaO(2) 69.3 versus 66.8 mm Hg; PaCO(2) 29.6 versus 28.8 mm Hg). Iloprost significantly (P<0.05) improved exercise duration (379 versus 438 seconds), peak oxygen uptake (12.8 versus 14.2 mL. kg(-1). min(-1)), VE-versus-V CO(2) slope (58 versus 51.4).nnnCONCLUSIONSnThe present data show that iloprost inhalation exerts pulmonary vasodilatation and improves symptoms and exercise capacity in patients with PPH. The data also suggest that iloprost inhalation is a suitable treatment for PPH. Whether these effects are maintained during long-term treatment and are paralleled by improvement in prognosis remains to be determined.

Ventilatory efficiency and exercise tolerance in 101 healthy volunteers

Abstract The ventilatory equivalent for CO2 defines ventilatory efficiency largely independent of metabolism. An impairment of ventilatory efficiency may be caused by an increase in either anatomical or physiological dead space, the latter being the most important mechanism in the hyperpnoea of heart failure, pulmonary embolism, pulmonary hypertension and the former in restrictive lung disease. However, normal values for ventilatory efficiency have not yet been established. We investigated 101 (56 men) healthy volunteers, aged 16–75 years, measuring ventilation and gas exchange at rest (nu2009=u200964) and on exercise (modified Naughton protocol, nu2009=u2009101). Age and sex dependent normal values for ventilatory efficiency at rest defined as the ratio ventilation:carbon dioxide output (V˙E:V˙CO2), exercise ventilatory efficiency during exercise, defined as the slope of the linear relationship between ventilation and carbon dioxide output (V˙E vs V˙CO2 slope), oxygen uptake at the anaerobic threshold and at maximum (V˙O2AT,V˙O2max, respectively) and breathing reserve were established. Ventilatory efficiency at rest was largely independent of age, but was smaller in the men than in the women [V˙E:V˙CO2 50.5 (SD 8.8) vs 57.6 (SD 12.6) P<0.05]. Ventilatory efficiency during exercise declined significantly with age and was smaller in the men than in the women (men: (V˙E vs V˙CO2 slopeu2009= 0.13u2009×u2009ageu2009+u200919.9; women: V˙E vs V˙CO2 slopeu2009= 0.12u2009×u2009ageu2009+u200924.4). The V˙O2AT and V˙O2max were 23 (SD 5) and 39 (SD 7) ml O2u2009·u2009kgu2009·u2009min−1 in the men and 18 (SD 4) and 32 (SD 7) in the women, respectively, and declined significantly with age. The V˙O2AT was reached at 58 (SD 9)% V˙O2max. Breathing reserve at the end of exercise was 41% and was independent of sex and age. It was concluded from this study that ventilatory efficiency as well as peak oxygen uptake are age and sex dependent in adults.

Iloprost als inhalative bzw. intravenöse Langzeitbehandlung von Patienten mit Primärer Pulmonaler Hypertonie – Register der Berliner Arbeitsgruppe für Pulmonale Hypertonie –

Follow-up data for 81 consecutive patients with primary pulmonary hypertension (PPH) and pulmonary hypertension related to connective tissue diseases or liver cirrhosis, entered into a multicenter registry in Berlin between 1/96 and 11/99, are described. At entry into the registry the diagnosis of PPH was known for 22±32 months. Hemodynamically, these patients were characterized by a right atrial pressure of 8.6±5 mmHg, a mean pulmonary arterial pressure of 58.9±17 mmHg, a cardiac index of 1.8±0.6 l/min/m2 and a pulmonary vascular resistance of 1574±787dyn×s×cm–5. In about one third of the patients, a restrictive and/or obstructive pulmonary physiology was found while the majority showed signs compatible with small airway disease. Furthermore, diffusion abnormalities were found in about 65% of the patients. When added to conventional medical therapy the treatment with inhaled or continuously infused prostanoids represents a major improvement in the treatment of patients with PPH. Aerosolized iloprost therapy was started in 51 patients and was continued for 12 and 24 months in 20 and 6 patients, respectively. This therapy was well tolerated without any significant changes in pulmonary function or signs of toxicity. About 25% of these patients had to be switched to continuous intravenous therapy due to progressive clinical and hemodynamic deterioration. About two thirds of these “rescue patients” could be stabilized on intravenous therapy and discharged from the hospital. Based on the currently available evidence, the continuous infusion of prostanoids represents an important part of the standard therapy in the treatment of patients with PPH. These first long-term data on inhaled iloprost therapy in this patient group illustrate the potential value of this well-tolerated and effective treatment within the concept of a differentiated treatment plan for patients with PPH. However, the true importance of prostanoid inhalation in comparison to continuous intravenous therapy in PPH remains to be determined in randomized controlled trials. Wir berichten über 81 Patienten mit Primärer Pulmonaler Hypertonie bzw. Pulmonaler Hypertonie assoziiert mit einer Kollagenose oder Leberzirrhose, bei denen die Diagnose seit 22±32 Monate bekannt war. Die Hämodynamik bei Erstvorstellung war durch einen mittleren rechtsatrialen bzw. pulmonalarteriellen Druck von 8,6±5 bzw. 58,9±17 mmHg, einen Cardiac Index von 1,8±0,6 l/min/m2 und einen pulmonalvaskulären Widerstand von 1574±787 dyn×s×cm-5 gekennzeichnet. Bei jeweils einem Drittel der Patienten wurden restriktive und obstruktive Ventilationsstörungen dokumentiert. Spirometrisch konnten bei der Mehrzahl der Patienten endexspiratorische Veränderungen im Sinne einer „small airways disease“ erfasst werden. Zusätzlich zeigten zwei Drittel aller untersuchten Patienten eine Diffusionsstörung. Die spiroergometrisch gemessene kardiopulmonale Leistungsfähigkeit war bei 46 Prozent der Patienten hochgradig eingeschränkt. Bei 51 Patienten wurde im Rahmen eines „bridging to transplant“ Konzeptes eine inhalative Therapie mit Iloprost begonnen. Diese Behandlung wurde bei 20 Patienten mehr als ein Jahr und bei sechs Patienten länger als zwei Jahre durchgeführt. Bei etwa einem Viertel dieser Patienten musste trotz anfänglich erfolgreicher Inhalation die Umstellung zur intravenösen Iloprostapplikation begonnen werden. Darunter konnten zwei Drittel der Patienten soweit stabilisiert werden, dass eine Überführung in die ambulante Betreuung möglich wurde. Ein Drittel verstarb in der Wartezeit auf die Transplantation, was wir u.a. auf das bereits weit fortgeschrittene Krankheitsstadium der Patienten zurückführen. Die Behandlung mit inhalativem und intravenösem Iloprost bei Patienten mit Pulmonaler Hypertonie stellt eine wesentliche Erweiterung der konservativen Behandlung dar. Neben der bereits etablierten intravenösen Therapie mit Prostanoiden für Patienten mit PPH im NYHA-Stadium III/IV kann der endgültige Stellenwert der inhalativen Gabe von Iloprost erst nach Abschluss der zur Zeit laufenden kontrollierten Studien beurteilt werden.

Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure Rationale and Design of the Randomized Trial to REDUCE Elevated Left Atrial Pressure in Heart Failure (REDUCE LAP-HF I)

Heart failure with preserved ejection fraction (HFpEF), a major public health problem with high morbidity and mortality rates, remains difficult to manage because of a lack of effective treatment options. Although HFpEF is a heterogeneous clinical syndrome, elevated left atrial pressure—either at rest or with exertion—is a common factor among all forms of HFpEF and one of the primary reasons for dyspnea and exercise intolerance in these patients. On the basis of clinical experience with congenital interatrial shunts in mitral stenosis, it has been hypothesized that the creation of a left-to-right interatrial shunt to decompress the left atrium (without compromising left ventricular filling or forward cardiac output) is a rational, nonpharmacological strategy for alleviating symptoms in patients with HFpEF. A novel transcatheter interatrial shunt device has been developed and evaluated in patients with HFpEF in single-arm, nonblinded clinical trials. These studies have demonstrated the safety and potential efficacy of the device. However, a randomized, placebo-controlled evaluation of the device is required to further evaluate its safety and efficacy in patients with HFpEF. In this article, we give the rationale for a therapeutic transcatheter interatrial shunt device in HFpEF, and we describe the design of REDUCE Elevated Left Atrial Pressure in Heart Failure (REDUCE LAP-HF I), the first randomized controlled trial of a device-based therapy to reduce left atrial pressure in HFpEF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02600234.

Torsades de pointes caused by Mibefradil.

We report a case of symptomatic Torsades de pointes due to QTc prolongation by Mibefradil, which potentially explains unexpected deaths related to this drug. Multiple episodes of Torsades de pointes were documented in a 76‐year‐old woman with significant QTc prolongation of 0.53 s. After discontinuation of Mibefradil QTc intervals normalized and no further ventricular tachyarrythmias were observed. We conclude that Mibefradil can cause QTc prolongation and life threatening ventricular dysrhythmias.

Angiotensin-Converting Enzyme Inhibitors in Preventing Remodeling and Development of Heart Failure After Acute Myocardial Infarction: Results of the German Multicenter Study of the Effects of Captopril on Cardiopulmonary Exercise Parameters (ECCE)

Early action of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction (MI) has been shown in large scale clinical trials to reduce mortality over the first weeks. However, the mechanisms involved are yet unclear and several trials showed a tendency toward a small, albeit unexpected, rise in cardiogenic shock or mortality. Since cardiopulmonary exercise testing (CPX) has become a gold standard in assessing the severity of heart failure, we studied--after finishing a pilot trial--the effect of captopril versus placebo in 208 patients who were individually titrated (titrated dose, mean 46/69 mg/day after 7 days/4 weeks, respectively) in order to preserve their blood pressure in the acute phase of myocardial infarction; we followed the development of congestive heart failure (CHF) over 4 weeks by measuring oxygen consumption. After 4 weeks, overall oxygen consumption at the anaerobic threshold (VO2-AT; 13.7 vs 13.1), maximal oxygen consumption (VO2max 19.3 vs 18.9 mL/kg per min) and exercise duration (896 vs 839 sec) showed a nonsignificant difference in favor of the captopril group. The predefined, categorized, combined endpoint of severe heart failure or death (heart failure necessitating ACE inhibition, VO2max < 10 mL/kg per min, or death) was significantly reduced in the captopril group (n = 7/104) versus placebo (n = 18/104; p = 0.03). Differences were mainly caused by fewer CHF events (delta n = 10). We conclude that ACE inhibition with individualized dose titration markedly reduces the 4-week incidence of severe heart failure or death; > 10 patients per 100 treated gained major benefits from this therapy.

Current guidelines for the treatment of congestive heart failure

SummaryOvert congestive heart failure (CHF) has a prevalence of 1% of the population. The predominant symptoms of patients with CHF are fatigue and dyspnoea. Fatigue is thought to result from changes in peripheral muscle metabolism secondary to decreased vasodilative capacity and physical inactivity. An increase of peripheral perfusion by vasodilator therapy and physical activity are therefore recommended. Beside overt decompensation, where dyspnoea results from acute pulmonary congestion due to backward failure, increased physiological dead space ventilation caused by pulmonary ventilation/perfusion mismatch accounts, to a large degree, for dyspnoea, and can be improved by vasodilator therapy.According to the pathophysiology of CHF, normalisation of loading conditions and myocardial inotropy are the parameters addressed by various pharmacological agents in order to alleviate symptoms and slow progression of the disease. Diuretics are rapidly acting and effective agents to improve congestion and decrease filling pressures. Digitalis improves haemodynamics and symptomatology by increasing inotropy and slowing resting heart rate in atrial fibrillation; however, prognostic effects have yet to be proved. The introduction of vasodilators has significantly improved the prognosis of the disease, and the administration of ACE inhibitors in particular has been shown to slow progression of CHF. This results in a substantial decrease in morbidity and mortality.The present article appraises the role of the currently used drugs in the treatment of CHF, considering effects on pathophysiology and clinical outcome and provides an approach to a differential drug regimen.