Abstract Introduction Heart failure (HF) is associated with hemodynamic lung congestion that leads to dyspnea and excessive respiratory effort. Purpose We hypothesized that this HF induced excessive respiratory effort adversely affects both ventricles loading conditions, leading to a vicious cardiopulmonary cycle and progressive cardiac deterioration, and that this vicious cardiopulmonary cycle is independent of HF etiology. Methods The hemodynamic and respiratory indices were simultaneously measured in patients undergoing right heart catheterization for the diagnosis of dyspnea. The pulmonary wedge pressure (PCWP) is modulated by the changes in the intrathoracic pressure. The latter is determined by the respiratory effort. To quantify the respiratory effort, the PCWP was decomposed into cardiac and respiratory waves. The respiratory effort (Presp) was defined as the peak to peak amplitude of the respiratory wave that modulated the PCWP. The immediate effects of the respiratory effort on the pulmonary capillary wedge pressures (PCWP) were scrutinized by asking the patients to perform intentional vigorous breathing and short apneic events. Results The HF patients (N=50) exhibited a high Presp of 9.3±5.0 mmHg, ∼3.5-fold higher than the normal respiratory effort. The baseline end-expiratory PCWP (PCWPee) and end-expiratory pulmonary artery pressure of the HF patients have linear relationship with the baseline Presp with slops of 0.78±0.05 and 1.42±0.09 respectively. The changes in PCWPee appeared immediately, within a single breathing-cycle (t =1.65±0.39 sec) in all patients, when each patient intentionally changed the respiratory effort from apnea to his maximum Presp of 19.8±8.6 mmHg. The PCWP during apnea underestimated the HF severity and yielded lower PCWPee while severe respiratory effort markedly increased the PCWPee. Interestingly, similar slope of the instantaneous relationship between the varying Presp and observed PCWPee was obtained for all the patients, independently of the baseline PCWPee-. The PCWPee rose immediately by 0.43±0.15 for every 1 mmHg of Presp. Similar slope was observed in HF patients with ischemic (N=24) and non-ischemic (N=26, p=0.36) HF diseases (p=0.26), and in those with preserved (N=35) or reduced (N=15) ejection fractions (p=0.91). Conclusions The respiratory effort has immediate effects on the hemodynamic congestion and the workloads of the heart, and this adverse effects are independent of HF etiology. The observations support the existence of a vicious cardiopulmonary cycle that can lead to decompensation, where the respiratory effort plays a pivotal role. It may explain the similar prognosis of patients with various ejection fractions and etiologies, but with similar dyspnea severity and clinical symptoms. Funding Acknowledgement Type of funding sources: None.

Introduction: Right heart catheterization (RHC) provides objective assessment of heart failure (HF) severity. However, it is strongly affected by respiratory fluctuations, therefore various methods were suggested to correct these fluctuations. In contrast, we hypothesized that measurement of the respiratory effort in addition to the standard indices provides additional valuable information. Moreover, it can assist in the interpretations of the standard indices. Methods: We simultaneously measured the hemodynamic and respiratory indices in HF patients undergoing RHC. The pulmonary wedge pressure (PCWP) is modulated by the changes in the intrathoracic pressure. The latter is determined by the respiratory effort. To quantify the respiratory effort, the PCWP was decomposed into cardiac and respiratory waves. The respiratory effort (P RESP ) was defined as the peak to peak amplitude of the respiratory wave that modulated the PCWP. Results: HF patients (N=45) exhibited a high P RESP of 9.1±5.3 mmHg, ~3.5-fold higher than the reported normal respiratory modulations, while they are lying and at rest [Range: from 2.0 mmHg to 23.3 mmHg]. In some patients the P RESP exceeded the amplitude of cardiac `a` and `v` waves. The difference between end expiratory PCWP (PCWP EE ) and mean PCWP increased linearly with P RESP , by slop of 0.380±0.001 (R 2 = 0.76, p<0.001). The end expiratory PCWP rose with P RESP , by 0.68±0.05 mmHg for every 1 mmHg of P RESP (p<0.01). Interestingly, identical changes in the PCWP with P RESP were obtained in all the patients, independently of the HF etiology. The P RESP sheds light on the severity of dyspnea. It enables simple and precise evaluation of the PCWP EE from regular breathing. Lung congestion severity is determined by the transmural gradient between the intravascular pressure and the tissue surrounding pressure. Correction for P RESP yields more accurate evaluation of this transmural pulmonary vascular pressure. Conclusions: P RESP provides additional essential dimension on the severity of dyspnea and HF. It simplifies the measurement method and enables to derive the PCWP EE . The latter deviates from the mean PCWP in cases of severe dyspnea. It assists in evaluating the real transmural pulmonary vascular pressure.

Introduction: An increase in the pulmonary wedge pressure (PCWP) is associated with an increase in the respiratory effort and the sensation of dyspnea. Hypothesis: We investigated the inverse cause and effect relationship, whether an increase in the respiratory effort can by itself aggravate the hemodynamic congestion. Methods: We scrutinized the cardiopulmonary interactions by simultaneously measuring hemodynamic and respiratory indices in heart failure (HF) patients undergoing right heart catheterization. The immediate effects of the respiratory effort on the hemodynamic indices were analyzed by asking the patients to perform short events of apnea and intentional vigorous breathing. The cardiac waves are superimposed on the respiratory waves in the PCWP. To quantify the respiratory effort, the PCWP was decomposed into cardiac and respiratory waves. The respiratory effort (PRESP) was defined as the peak to peak swing in the respiratory wave that modulated the PCWP. Results: HF patients (n=38) exhibited a high PRESP of 9.0±3.2 mmHg, ~3.5-fold higher than the reported normal respiratory effort. The end-expiratory PCWP rose with PRESP, by 0.83±0.06 mmHg for every 1 mmHg of PRESP (p<0.01). The pulmonary artery pressure (PAP) rose with PRESP by 1.40±0.09 mmHg for every 1 mmHg of PRESP. The changes in the respiratory effort had immediate effect on PCWP, within a single breathing-cycle (t =1.67±0.40 s) in all patients. Interestingly, similar changes in the PCWP with PRESP were obtained in all the patients, independently of the HF etiology. Conclusions: An increase in the respiratory effort is not just a result of cardiac decompensation. The respiratory effort has immediate detrimental effects on the PCWP, PAP and the workloads of the heart. The results highlight the existence of a cardiopulmonary vicious cycle the can lead to progressive decompensation, where the respiratory effort plays a pivotal role.

Abstract Background Hemodynamic congestion appears days prior to the development of clinical congestion. Lung congestion is associated with increased respiratory effort and dyspnoea. The effects of increased respiratory effort on pulmonary circulation were not well-defined. Purpose The study investigates the cardiopulmonary interactions and the role of the respiratory effort in the development of decompensation. It is well-accepted that lung congestion affects the lung mechanics and increases the respiratory effort. On the other hand, changes in the intrathoracic and alveolar pressures, due to the increase in the respiratory effort, may have detrimental effects on the pulmonary circulation and the workloads of the heart. Methods We have simultaneously measured the hemodynamic indices and the respiratory mechanics in patients undergoing right heart catheterization (n=56) for the diagnosis of dyspnoea. The patients were classified either as heart failure (HF) or lung disease, according to their clinical history, symptoms and signs. The pulmonary capillary wedge pressure (PCWP) was decomposed into cardiac and respiratory waves. The respiratory effort (Presp) was defined as the respiratory wave amplitude that modulates the PCWP. Lung compliance was calculated as the ratio of the tidal volume to Presp. Results and discussion The HF patients (n=35) exhibited huge Presp of 9.6±3.7 mmHg [2.6–16.7], ∼4 fold the normal Presp, of about 2–3 mmHg (figure below). Their lung compliance decreased with increasing PCWP (2.0±0.4%/mmHg of PCWP). Both PCWP and pulmonary artery pressure (PAP) rose with Presp, by 0.92±0.36 mmHg and 1.68±0.47 mmHg, for 1 mmHg of Presp, respectively (Figure below). Interestingly, PCWP always exceeded Presp, leading to the stipulation of a novel fundamental constraint/law: the continuous pulmonary flow throughout the respiratory cycle requires that PCWP > Presp (above the identity line in figure A), otherwise the capillary pressure will decrease below the surrounding alveolar pressure and the pulmonary circulation will collapse, especially during inspiration. This constraint imposes a positive feedback of Presp on the pulmonary circulatory pressures. It is also supported by the increase in PWCP with Presp in the patients with lung diseases (Figure A). The bigger rise in PAP than in PWCP is attributed to the increase in the pulmonary vascular resistance (PVR) with Presp (0.3±0.06 wood units for 1mmHg Presp). The latter constructs additional positive feedback of Presp on the cardiac workload. A decrease in the intrathoracic pressure that surrounds the heart increases the LV apparent afterload. The increase in PAP and PVR elevates the right ventricle afterload. PCWP (A) and PAP (B) vs. Presp Conclusions The respiratory effort is not just a hallmark of HF but plays a pivotal role in the cardiopulmonary vicious cycle. An increase in the respiratory effort increases the PWCP, PAP, PVR, and the afterloads of both ventricles, and thereby may accelerate cardiac decompensation.

OBJECTIVES We sought to study relationship between cardiorespiratory fitness and C-reactive protein (CRP) in subjects with the metabolic syndrome. BACKGROUND Recent studies have shown an association between the metabolic syndrome and chronic subclinical inflammation, as determined by elevated CRP. Cardiorespiratory fitness is associated with a lower risk of diabetes and improved insulin resistance. METHODS Physical fitness was assessed in 1,640 subjects using the Bruce treadmill protocol and expressed as maximal metabolic equivalents. The level of CRP was measured using a high-sensitivity assay. RESULTS Geometric mean CRP was calculated across quartiles of fitness after adjustment for age, gender, smoking, use of medications, and coronary disease. A strong inverse trend toward decreasing CRP levels with increasing fitness quartiles was present in subjects without metabolic abnormalities, subjects with one or two metabolic abnormalities, and subjects with the metabolic syndrome (all p 0.001). The effect of fitness was particularly robust among subjects with the metabolic syndrome. The adjusted mean CRP in subjects in the upper and lower fitness quartiles was 1.48 versus 0.93 mg/dl in subjects without metabolic abnormalities, 2.40 versus 1.66 mg/dl in subjects with one or two metabolic abnormalities, and 4.62 versus 2.20 mg/l in subjects with the metabolic syndrome (p 0.049 for the interaction between fitness and number of metabolic abnormalities). CONCLUSIONS Subjects with the metabolic syndrome who maintain a high fitness level have markedly lower CRP concentrations, as compared with those with a low fitness level. (J Am Coll Cardiol ublished by Elsevier Inc. doi:10.1016/j.jacc.2004.08.030

AimsReactive pulmonary hypertension (PH) is a severe form of PH secondary to left‐sided heart failure (HF). Given the structural and functional abnormalities in the pulmonary vasculature that occur in reactive PH, we hypothesized that pulmonary artery capacitance (PAC) may be profoundly affected, with implications for clinical outcome.Methods and resultsWe studied 393 HF patients of whom 124 (32%) were classified as having passive PH and 140 (36%) as having reactive PH, and 91 patients with pulmonary arterial hypertension (PAH). Mean PAC was highest in patients without PH (4.5 ± 2.1 mL/mmHg), followed by the passive PH group (2.8 ± 1.4 mL/mmHg) and was lowest in those with reactive PH (1.8 ± 0.7 mL/mmHg) (P = 0.0001). PAC and pulmonary vascular resistance (PVR) fitted well to a hyperbolic inverse relationship (PAC = 0.25/PVR, R2 = 0.70), with reactive PH patients dispersed almost predominantly on the flat part of the curve where a reduction in PVR is associated with a small improvement in PAC. Elevated PCWP was associated with a significant lowering of PAC for any PVR (P = 0.036). During a median follow‐up of 31 months, both reactive PH [hazard ratio (HR) 2.59, 95% confidence interval (CI) 1.14–4.46, P = 0.02] and reduced PAC (HR 0.72 per 1 mL/mmHg increase, 95% CI 0.59–0.88, P = 0.001) were independent predictors of mortality.ConclusionsThe development of reactive PH is associated with a marked reduction in PAC. PAC is a strong independent haemodynamic marker of mortality in HF and may contribute to the increased mortality associated with reactive PH.

The sympathetic and parasympathetic innervation of the heart plays a major role in the regulation of cardiac function. Sympathetic nerve activity is associated with unfavorable prognosis of left ventricular dysfunction [1,2]. Iodine-123 labeled metaiodobenzyl-guanidine (MIBG) shares many cellular uptake and storage properties with norepinephrine (NE), and has been used to evaluate cardiac sympathetic nervous distribution and function [3]. Myocardial distribution and washout of MIBG from the heart differ significantly between controls and patients with severe, nonischemic, dilated cardiomyopathy [4].

The aim of this study was to assess the effect of attenuation correction (AC) on left ventricular (LV) volumes and LV transient ischemic dilatation (TID) during dual-isotope single-photon emission computer tomographic (SPECT) myocardial perfusion imaging (MPI). Ninety-six patients (mean age 58 ± 11 years, 15% women, 38 patients completed exercise and 58 dipyridamole pharmacologic stress tests) assessed for known or suspected coronary artery disease underwent dual-isotope thallium-201 rest and technetium-99m sestamibi stress SPECT MPI with computed tomography-based AC. The TID ratio was calculated separately for non-AC and AC SPECT MPI studies as the ratio of the LV endocardial volume at stress divided by LV endocardial volume at rest. The mean and range of the gated LV ejection fraction during exercise and pharmacologic stress was 54 ± 12% (29% to 80%) and 58 ± 12% (27% to 80%), respectively. In the exercise stress group, the same mean LV endocardial volumes in non-AC and AC stress (76.4 ± 30 and 76.5 ± 28) and rest (66.3 ± 26 and 66.4 ± 24) studies were found (p = 0.90). There was no statistical difference between the mean exercise TID ratio in non-AC and AC studies (1.27 vs 1.31, respectively, p = 0.10). The same mean LV endocardial volumes in non-AC and AC in pharmacologic stress (79.9 ± 42 and 80 ± 41) and rest (71.4 ± 41 and 72.3 ± 37), respectively, were found (p = 0.50). There was no statistical difference between the mean dipyridamole TID ratio in non-AC and AC studies (1.20 vs 1.17, respectively, p = 0.10). In conclusion, LV volumes and TID indexes obtained on SPECT MPI with exercise or pharmacologic stress using dipyridamole are not affected by AC.

Background Despite advent of rapid arterial revascularization as 1st line treatment for acute myocardial infarction (AMI), incomplete restoral of flow at the microvascular level remains a problem and is associated with adverse prognosis, including pathological ventricular remodeling. We aimed to study the association between multidetector row computed tomography (MDCT) perfusion defects and ventricular remodeling post-AMI. Methods In a prospective study, 20 patients with ST-elevation AMI, treated by primary angioplasty, underwent arterial and late phase MDCT as well as radionuclide scans to study presence, size and severity of myocardial perfusion defects. Contrast echocardiography was performed at baseline and at 4 months follow-up to evaluate changes in myocardial function and remodeling. Results Early defects (ED), late defects (LD) and late enhancement (LE) were detected in 15, 7 and 16 patients, respectively and radionuclide defects in 15 patients. The ED area (r = 0.74), and LD area (r = 0.72), and to a lesser extent LE area (r = 0.62) correlated moderately well with SPECT summed rest score. By univariate analysis, follow-up end-systolic volume index and ejection fraction were both significantly related to ED and LD size and severity, but not to LE size or severity. By multivariate analysis, end-systolic volume index was best predicted by LD area (p < 0.05) and ejection fraction by LD enhancement ratio. Conclusions LD size and severity on MDCT are most closely associated with pathological ventricular remodeling after AMI and may thus play a role in early identification and treatment of this condition.

Early risk stratification in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) is important since the benefit from more aggressive and costly treatment strategies is proportional to the risk of adverse clinical events. In the present study we assessed whether hybrid single photon emission computed tomography (SPECT)/coronary computed tomography angiography (CCTA) technology could be an appropriate tool in stratifying patients with NSTE-ACS.

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The purpose of this study is to define the relationship between SPECT and CTA measured parameters of left ventricular (LV) function and volumes obtained in a single session using SPECT/64-slice CT hybrid imaging device, and in addition, to assess the reproducibility of LV parameters measured using 64-slice CTA.Materials and methods: Seventy-six patients with suspected or known coronary artery disease underwent cardiac CTA and GSPECT in one session using a hybrid SPECT/CT device.LV end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) were measured on each component of the hybrid device. For the CTA component, these parameters were re-measured by the same investigator and by a second investigator with an interval of 3-54 weeks. Corresponding GSPECT and CTA measured parameters were compared. For CTA, intra-observer and inter-observer variability of LV function and volume measurements were calculated.Results: A very good correlation was found between the GSPECT and CTA measured LVEF (r = 0.81), ESV (r = 0.90) and EDV (r = 0.82). There was a small positive difference by CTA measured LVEF (3.9 +/- 14.2%), and more prominent positive differences by CTA measured ESV and EDV (9.8 +/- 14.8 and 44.9 +/- 23.1 cm(3), respectively). There was excellent reproducibility in the measurements of all parameters with very low intra-and inter-observer variability (r = 0.93 for EF and 0.98 for EDV and ESV).Conclusions: Although a good correlationwas found between the EF measurements obtained from CTA and SPECT, interchangeable use of EF measurements between the two modalities should be done cautiously and interchangeable use of LV EDV and ESV should be avoided. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Objective To compare the diagnostic performance of a new dedicated ultrafast solid-state cardiac camera (Discovery NM 530c [DNM]) with standard dual detector cameras (S-SPECT) in myocardial perfusion imaging. The primary goal was a per-patient analysis of diagnostic performance of the DNM using S-SPECT as the reference standard. Methods and results In total, 168 patients underwent one-day Tc-99m tetrofosmin rest/stress myocardial perfusion SPECT. DNM and S-SPECT images were obtained with the same injected doses. The DNM camera uses an array of cadmium zinc telluride pixilated detectors and a multipinhole collimator simultaneously imaging all cardiac views with no moving parts. Rest and stress acquisition times were 4 and 2 minutes for DNM and 14 and 12 minutes for S-SPECT. Two blinded readers independently interpreted all scans on a patient level and on a vascular territory level using a standard five-point scale. Interobserver differences were resolved by a third observer. Agreement between DNM and S-SPECT for presence or absence of myocardial perfusion defects on a per-patient analysis was 91.9% and 92.5%, respectively. Correlation coefficients of rest and stress left ventricular ejection fractions were 0.87 ( P < .01) and 0.90 ( P < .01). Conclusion The diagnostic performance of DNM is comparable to that of S-SPECT on a per-patient basis. However, superior image quality can be achieved with significantly shorter acquisition times with DNM because of improved count sensitivity and image contrast over S-SPECT.