Johannes Holzmeister

Cardiac-Resynchronization Therapy in Heart Failure with a Narrow QRS Complex

BACKGROUND Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS complex, which suggests the potential usefulness of CRT in such patients. METHODS We conducted a randomized trial involving 115 centers to evaluate the effect of CRT in patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony. All patients underwent device implantation and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death from any cause or first hospitalization for worsening heart failure. RESULTS On March 13, 2013, the study was stopped for futility on the recommendation of the data and safety monitoring board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group, as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.57; P=0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; hazard ratio, 1.81; 95% CI, 1.11 to 2.93; P=0.02). CONCLUSIONS In patients with systolic heart failure and a QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality. (Funded by Biotronik and GE Healthcare; EchoCRT ClinicalTrials.gov number, NCT00683696.).

Acetaminophen Increases Blood Pressure in Patients With Coronary Artery Disease

Background— Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. Methods and Results— The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. Conclusions— This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.

Statins and the Risk of Cancer After Heart Transplantation

Background— Although newer immunosuppressive agents, such as mTOR (mammalian target of rapamycin) inhibitors, have lowered the occurrence of malignancies after transplantation, cancer is still a leading cause of death late after heart transplantation. Statins may have an impact on clinical outcomes beyond their lipid-lowering effects. The aim of the present study was to delineate whether statin therapy has an impact on cancer risk and total mortality after heart transplantation. Methods and Results— A total of 255 patients who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year were included in the present study. The primary outcome measure was the occurrence of any malignancy; the secondary end point was overall survival. During follow-up, a malignancy was diagnosed in 108 patients (42%). The cumulative incidence of tumors 8 years after transplantation was reduced in patients receiving a statin (34% versus 13%; 95% confidence interval, 0.25–0.43 versus 0.07–0.18; P<0.003). Statin use was associated with improved cancer-free and overall survival (both P<0.0001). A Cox regression model that analyzed the time to tumor formation with or without statin therapy, adjusted for age, male sex, type of cardiomyopathy, and immunosuppressive therapy (including switch to mTOR inhibitors or tacrolimus), demonstrated a superior survival in the statin group. Statins reduced the hazard of occurrence of any malignancy by 67% (hazard ratio, 0.33; 95% confidence interval, 0.21–0.51; P<0.0001). Conclusions— Although it is not possible to adjust for all potential confounders because of the very long follow-up period, this registry suggests that statin use is associated with improved cancer-free and overall survival after cardiac transplantation. These data will need to be confirmed in a prospective trial.

Implantable cardioverter defibrillators and cardiac resynchronisation therapy

Implantable cardioverter defibrillators and cardiac resynchronisation therapy (CRT) have become standard of care in modern treatment for heart failure. Results from trials have provided ample evidence that CRT, in addition to its proven benefits in patients with symptomatic heart failure (New York Heart Association [NYHA] class III), might also reduce morbidity and mortality in those with mildly symptomatic heart failure (NYHA class II). As a result, the 2010 European Society of Cardiology guidelines now recommend CRT for both patient populations. In this review we summarise and critically assess the landmark randomised clinical trials REVERSE, MADIT-CRT, and RAFT. Furthermore, we discuss the rationale and available evidence for other emerging indications of CRT, including its use in patients with a mildly reduced left ventricular ejection fraction (>35%), in those with a narrow QRS complex (≤120 ms), and in those with concomitant bradyarrhythmic pacemaker indications. We also focus on patients who do not respond to CRT, and on CRT optimisation.

Characteristics and long-term outcome of echocardiographic super-responders to cardiac resynchronisation therapy: ‘real world’ experience from a single tertiary care centre

Background The individual benefit from cardiac resynchronisation therapy (CRT) varies largely among patients. Aims To compare different definitions of echocardiographic super-response to CRT regarding their ability to predict the incidence of adverse events. Methods Three definitions of super-response to CRT were evaluated in 110 consecutive patients with CRT implantation: (1) an absolute increase in ejection fraction of ≥10%; (2) a decrease in left ventricular end-systolic volume of ≥30%; and (3) a decrease in left ventricular end-diastolic volume of ≥20%. The primary endpoint was a combination of time to death, heart transplantation, ventricular assist device implantation and hospitalisation for heart failure. Secondary endpoints included time to first appropriate implantable cardioverter defibrillator (ICD) discharge during follow-up. Results All three definitions of super-response were highly predictive of a reduced risk for reaching the primary combined endpoint (3-year estimators: 64%±7% vs 82%±7% for ejection fraction ≥10%; 63%±8% vs 92%±5% for end-systolic volume ≥30%; and 62%±8% vs 94%±4% for end-diastolic volume ≥20%; all p<0.001). In all three analyses, super-responders had a significantly shorter time from diagnosis of heart failure until the time point of CRT implantation. However, even super-responders, independent of the definition, did experience appropriate ICD discharges during follow-up. Conclusions All three definitions of super-response are highly predictive for a favourable outcome after CRT. However, even patients with pronounced reverse left ventricular remodelling experience appropriate ICD discharges during follow-up.

Association of intraventricular mechanical dyssynchrony with response to cardiac resynchronization therapy in heart failure patients with a narrow QRS complex

Aims Current criteria for cardiac resynchronization therapy (CRT) are restricted to patients with a wide QRS complex (>120 ms). Overall, only 30% of heart failure patients demonstrate a wide QRS complex, leaving the majority of heart failure patients without this treatment option. However, patients with a narrow QRS complex exhibit left ventricular (LV) mechanical dyssynchrony, as assessed with echocardiography. To further elucidate the possible beneficial effect of CRT in heart failure patients with a narrow QRS complex, this two-centre, non-randomized observational study focused on different echocardiographic parameters of LV mechanical dyssynchrony reflecting atrioventricular, interventricular and intraventricular dyssynchrony, and the response to CRT in these patients. Methods and results A total of 123 consecutive heart failure patients with a narrow QRS complex (<120 ms) undergoing CRT was included at two centres. Several widely accepted measures of mechanical dyssynchrony were evaluated: LV filling ratio (LVFT/RR), LV pre-ejection time (LPEI), interventricular mechanical dyssynchrony (IVMD), opposing wall delay (OWD), and anteroseptal posterior wall delay with speckle tracking (ASPWD). Response to CRT was defined as a reduction ≥15% in left ventricular end-systolic volume at 6 months follow-up. Measures of dyssynchrony can frequently be observed in patients with a narrow QRS complex. Nonetheless, for LVFT/RR, LPEI, and IVMD, presence of predefined significant dyssynchrony is <20%. Significant intraventricular dyssynchrony is more widely observed in these patients. With receiver operator characteristic curve analyses, both OWD and ASPWD demonstrated usefulness in predicting response to CRT in narrow QRS patients with a cut-off value of 75 and 107 ms, respectively. Conclusion Mechanical dyssynchrony can be widely observed in heart failure patients with a narrow QRS complex. In particular, intraventricular measures of mechanical dyssynchrony may be useful in predicting LV reverse remodelling at 6 months follow-up in heart failure patients with a narrow QRS complex, but with more stringent cut-off values than currently used in ‘wide’ QRS patients.

Electrocardiographic changes in early recognition of Fabry disease

Background Fabry disease (FD) is an inherited X-chromosomal lysosomal storage disease resulting in intracellular storage of globotriaosylceramide. Cardiac involvement is most frequently manifested as left ventricular hypertrophy (LVH). However, patients with FD may also have various conduction abnormalities before LVH develops. The present study was designed to analyse early conduction abnormalities on baseline ECG of patients with FD and to investigate their diagnostic value. Methods and results Baseline electrocardiographic (ECG) and echocardiographic measurements of patients with FD (n=30) were compared with those of heart rate and age-matched healthy individuals (n=50). The PQ-interval (131±18 vs 155±20 ms, p<0.000001) and the QRS width (83±11 vs 90±9 ms, p<0.05) were significantly shorter and repolarisation dispersion was more pronounced in patients with FD (QTc dispersion: 66±32 vs 40±24 ms, p<0.001, Tpeak−Tend dispersion: 56±20 vs 37±16 ms, p<0.0005). Moreover, P-wave duration was significantly shorter (74±16 vs 105±14 ms, p<0.000001) in FD and accounted predominantly for the shortening of the PQ-interval. P-wave duration showed a 92% sensitivity and 80% specificity for the diagnosis of FD. Conclusions P-wave duration, PQ-interval and QRS width are shorter and repolarisation dispersion more pronounced in patients with FD compared with heart rate and age-matched controls. The significant shortening of the PQ-interval in FD occurs because of a marked shortening of the P-wave duration, which in itself demonstrated a high sensitivity and specificity for early detection and treatment of this disease.

Association of persistent or worsened echocardiographic dyssynchrony with unfavourable clinical outcomes in heart failure patients with narrow QRS width: a subgroup analysis of the EchoCRT trial

AIMS EchoCRT was a randomized trial of cardiac resynchronization therapy (CRT) in severely symptomatic heart failure (HF) patients with narrow QRS width <130 ms, ejection fraction ≤35%, and echocardiographic dyssynchrony. All received CRT implants which were then randomized to CRT-On or CRT-Off. While the trial showed no benefit of CRT to these patients, the aim of this subgroup analysis was to test the hypothesis that persistent or worsening dyssynchrony is associated with unfavourable clinical outcomes. METHODS AND RESULTS We studied 614 EchoCRT patients with baseline and 6-month echocardiograms. Baseline dyssynchrony required for study inclusion was either tissue Doppler imaging longitudinal velocity delay ≥80 ms or speckle-tracking radial strain delay ≥130 ms. Persistent dyssynchrony at 6 months was observed similarly in both groups (77% in CRT-On; 76% in CRT-Off). Persistent dyssynchrony was associated with a significantly higher primary end point of death or HF hospitalization (HR = 1.54, 95% CI 1.03-2.30, P = 0.03), and in particular secondary endpoint of HF hospitalization (HR = 1.66, 95% CI 1.07-2.57, P = 0.02). HF hospitalizations were also associated with worsening longitudinal dyssynchrony (HR = 1.45, 95% CI 1.02-2.05, P = 0.037), and worsening radial dyssynchrony (HR = 1.81, 95% CI 1.16-2.81, P = 0.008). Associations of persistent or worsening dyssynchrony with outcomes were similar in CRT-Off and CRT-On groups. CONCLUSIONS Persistent or worsening echocardiographic dyssynchrony in HF patients with narrow QRS width was a marker for unfavourable clinical outcomes unaffected by CRT. In particular, echocardiographic dyssynchrony on follow-up was strongly associated with HF hospitalizations and appears to be a prognostic marker of disease severity.

PQ Interval in Patients With Fabry Disease

Fabry disease (FD) is an X-chromosomal inherited lysosomal storage disease resulting in intracellular storage of globotriaosylceramide. Cardiac involvement is most frequently manifested as left ventricular hypertrophy. However, patients with FD may also have from various conduction abnormalities particularly affecting atrioventricular (AV) conduction. The present study was designed to analyze primarily AV conduction abnormalities on baseline electrocardiograms of patients with FD and to investigate the correlation with echocardiographic findings. Electrocardiograms at rest of 207 patients with FD were compared to echocardiograms. PQ-interval shortening and first-degree AV block could be found in only 29 cases (14%) and 3 cases (1.4%), respectively. No echocardiographic differences could be found in patients with and without PQ-interval shortening, including left ventricular hypertrophy, atrial size, and diastolic parameters. Furthermore, no correlation of the PQ interval with any echocardiographic parameters was detected. There was no difference between men and women in baseline clinical and electrocardiographic parameters. In conclusion, shortening of the PQ interval was not a common electrocardiographic finding in patients newly diagnosed with FD. Furthermore, no correlation with typical echocardiographic findings or disease stage in FD at baseline could be found.

Rationale for and design of the TRUE-AHF trial: The effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure

The TRUE‐AHF is a randomized, double‐blind, parallel‐group, placebo‐controlled trial which is evaluating the effects of a 48‐h infusion of ularitide (15 ng/kg/min) on the short‐ and long‐term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long‐term follow‐up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event‐driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in‐hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE‐AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure.