Clinical course and therapy optimization of patients after discharge from a specialized heart failure clinic.

Aim: We aimed to describe the clinical course of patients with heart failure with reduced ejection fraction (HFrEF) after discharge from the heart failure clinics (HFC). Patients & methods: We reviewed the hospital's records of 610 patients that were discharged between 2013 and 2018 from the HFC at a single centre. Patients with no recurrent contact to ambulatory cardiac care were invited to an echocardiographic assessment. Results: Of the survivors, 72% were re-referred after discharge. Nearly 30% of the patients with no recurrent contact with ambulatory cardiac care had persistent HFrEF and further therapeutical optimizations were indicated in half of them. Conclusion: This highlights the importance to identify high-risk patients that would benefit from extended management in the HFC.

What is this summary about? In Denmark, it is standard practice to discharge patients with heart failure from heart failure clinics to primary care after achieving optimized guideline-directed medical therapy. However, little is known about their subsequent clinical course and whether their treatment could be further optimized. To answer that question, we reviewed the hospital's records of heart failure patients that were discharged between 2013 and 2018. What were the results? Of the 610 heart failure patients that were discharged from our clinic, 30% had died; 72% of the survivors were re-referred to cardiac clinics in the interim period. Nearly 30% of the patients with no recurrent contact with cardiac clinics had persistent heart failure and further therapeutical optimizations were indicated in half of them. What do the results mean? Deaths and re-referral to cardiac clinics accounted for the majority of the heart failure patients that were initially discharged; while further intervention was indicated in half of the stable patients that had no recurrent contact with cardiac ambulatory care. This highlights the challenges in identifying high-risk patients that would benefit from an extended management programme in the heart failure clinic and the importance of following up heart failure patients despite initial optimized therapy.

Limited value of pulse wave analysis in assessing arterial wave reflection and stiffness in the pulmonary artery.

We explored the use of the augmentation index (AI) based on pulse wave analysis (PWA) in the pulmonary circulation as a measure of wave reflection and arterial stiffness in individuals with and without pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Right heart catheterization was performed using a pressure and Doppler flow sensor-tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in 10 controls, 11 PAH patients, and 11 CTEPH patients. PWA was applied to the measured pressure, while wave intensity analysis (WIA) and wave separation analysis (WSA) were performed using both the pressure and velocity to determine the magnitudes and timings of reflected waves. Type C (AI < 0) pressure waveform dominated in controls and type A (AI > 12%) waveform dominated in PAH patients, while there was a mixture of types A, B, and C among CTEPH patients. AI was greater and the inflection time shorter in CTEPH compared to PAH patients. There was a poor correlation between AI and arterial wave speed as well as measures of wave reflection derived from WIA and WSA. The infection point did not match the timing of the backward compression wave in ~50% of the cases. In patients with type C waveforms, the inflection time correlated well to the timing of the late systolic forward decompression wave caused by ventricular relaxation. In conclusion quantifying pulmonary arterial wave reflection and stiffness using AI based on PWA may be inaccurate and should therefore be discouraged.

Endothelial Dysfunction and Passive Changes in the Aorta and Coronary Arteries of Diabetic db/db Mice.

Endothelial cell dysfunction and vessel stiffening are associated with a worsened prognosis in diabetic patients with cardiovascular diseases. The present study hypothesized that sex impacts endothelial dysfunction and structural changes in arteries from diabetic mice. In diabetic (db/db) and normoglycaemic (db/db+) mice, the mechanical properties were investigated in pressurized isolated left anterior descending coronary arteries and aorta segments that were subjected to tensile testing. Functional studies were performed on wire-mounted vascular segments. The male and female db/db mice were hyperglycaemic and had markedly increased body weight. In isolated aorta segments without the contribution of smooth muscle cells, load to rupture, viscoelasticity, and collagen content were decreased suggesting larger distensibility of the arterial wall in both male and female db/db mice. In male db/db aorta segments with smooth muscle cell contribution, lumen diameter was smaller and the passive stretch-tension curve was leftward-shifted, while they were unaltered in female db/db aorta segments versus control db/db+ mice. In contrast to female db/db mice, coronary arteries from male db/db mice had altered stress-strain relationships and increased distensibility. Transthoracic echocardiography revealed a dilated left ventricle with unaltered cardiac output, while aortic flow velocity was decreased in male db/db mice. Impairment of acetylcholine relaxation was aggravated in aorta from female db/db compared to control and male db/db mice, while impairment of sodium nitroprusside relaxations was only observed in aorta from male db/db mice. The remodeling in the coronary arteries and aorta suggests an adaptation of the arterial wall to the reduced flow velocity with sex-specific differences in the passive properties of aorta and coronary arteries. The findings of less distensible arteries and more pronounced endothelial dysfunction in female compared to male diabetic mice may have implications for the observed higher incidence of macrovascular complications in diabetic women.

Impact of pulmonary endarterectomy on pulmonary arterial wave propagation and reservoir function.

High wave speed and large wave reflection in the pulmonary artery have previously been reported in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We assessed the impact of pulmonary endarterectomy (PEA) on pulmonary arterial wave propagation and reservoir function in patients with CTEPH. Right heart catheterization was performed using a combined pressure and Doppler flow sensor-tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in eight patients with CTEPH before and 3 mo after PEA. Wave intensity and reservoir-excess pressure analyses were then performed. Following PEA, mean pulmonary arterial pressure (PAPm; ∼49 vs. ∼32 mmHg), pulmonary vascular resistance (PVR; ∼11.1 vs. ∼5.1 Wood units), and wave speed (∼16.5 vs. ∼8.1 m/s), i.e., local arterial stiffness, markedly decreased. The changes in the intensity of the reflected arterial wave and wave reflection index (pre: ∼28%; post: ∼22%) were small, and patients post-PEA with and without residual pulmonary hypertension (i.e., PAPm ≥ 25 mmHg) had similar wave reflection index (∼20 vs. ∼23%). The reservoir and excess pressure decreased post-PEA, and the changes were associated with improved right ventricular afterload, function, and size. In conclusion, although PVR and arterial stiffness decreased substantially following PEA, large wave reflection persisted, even in patients without residual pulmonary hypertension, indicating lack of improvement in vascular impedance mismatch. This may continue to affect the optimal ventriculoarterial interaction, and further studies are warranted to determine whether this contributes to persistent symptoms in some patients.NEW & NOTEWORTHY We performed wave intensity analysis in the pulmonary artery in patients with chronic thromboembolic pulmonary hypertension before and 3 mo after pulmonary endarterectomy. Despite substantial reduction in pulmonary arterial pressures, vascular resistance, and arterial stiffness, large pulmonary arterial wave reflection persisted 3 mo postsurgery, even in patients without residual pulmonary hypertension, suggestive of lack of improvement in vascular impedance mismatch.

The role of aliskiren in the management of hypertension and major cardiovascular outcomes: a systematic review and meta-analysis.

The role of the direct renin inhibitor aliskiren in hypertension is not fully established and use of aliskiren in diabetic patients is especially controversial. A systematic review investigating both short-term diastolic and systolic blood pressure (DBP and SBP) reduction and long-term cardiovascular outcomes has not been conducted. Therefore, we aimed to fill this gap by investigating BP reduction, major cardiovascular outcomes, and mortality of aliskiren compared to other antihypertensive therapy. We searched PubMed and Embase databases for relevant randomized controlled trials (RCTs). Using a random-effects model, weighted mean difference (WMD) and relative risk (WRR) with 95% confidence interval (CI) were used to measure the effect of aliskiren therapy in the management of hypertension and major cardiovascular outcomes. Thirty seven RCTs with a total of 35,916 patients were included. Aliskiren induced slightly greater DBP and SBP reductions than other antihypertensive agents (WMD -0.77 mmHg, 95% CI [-2.01;0.46 mmHg] and WMD -1.14 mmHg, 95% CI [-2.78;0.50 mmHg], respectively). Aliskiren did not reduce total mortality or cardiovascular death. In patients with diabetes, aliskiren add-on therapy may have the potential to increase total mortality and cardiovascular death (WRR 1.06, 95% CI [0.88;1.28] and WRR 1.09, 95% CI [0.94;1.24], respectively). Despite superior BP-reducing effect, aliskiren is not recommended as first-line treatment in hypertensive patients as it does not reduce mortality and major cardiovascular outcomes. Dual renin-angiotensin-aldosterone system inhibition with aliskiren should be avoided in diabetic patients, while the use of aliskiren monotherapy remains to be investigated.

Impact of chronic hypoxia on proximal pulmonary artery wave propagation and mechanical properties in rats.

Arterial stiffness and wave reflection are important components of the ventricular afterload. Therefore, we aimed to assess the arterial wave characteristics and mechanical properties of the proximal pulmonary arteries (PAs) in the hypoxic pulmonary hypertensive rat model. After 21 days in normoxic or hypoxic chambers (24 animals/group), animals underwent transthoracic echocardiography and PA catheterization with a dual-tipped pressure and Doppler flow sensor wire. Wave intensity analysis was performed. Artery rings obtained from the pulmonary trunk, right and left PAs, and aorta were subjected to a tensile test to rupture. Collagen and elastin content were determined. In hypoxic rats, proximal PA wall thickness, collagen content, tensile strength per unit collagen, maximal elastic modulus, and wall viscosity increased, whereas the elastin-to-collagen ratio and arterial distensibility decreased. Arterial pulse wave velocity was also increased, and the increase was more prominent in vivo than ex vivo. Wave intensity was similar in hypoxic and normoxic animals with negligible wave reflection. In contrast, the aortic maximal elastic modulus remained unchanged, whereas wall viscosity decreased. In conclusion, there was no evidence of altered arterial wave propagation in proximal PAs of hypoxic rats while the extracellular matrix protein composition was altered and collagen tensile strength increased. This was accompanied by altered mechanical properties in vivo and ex vivo. NEW & NOTEWORTHY In rats exposed to chronic hypoxia, we have shown that pulse wave velocity in the proximal pulmonary arteries increased and pressure dependence of the pulse wave velocity was steeper in vivo than ex vivo leading to a more prominent increase in vivo.

Wave Intensity Analysis Provides Novel Insights Into Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: In contrast to systemic hypertension, the significance of arterial waves in pulmonary hypertension (PH) is not well understood. We hypothesized that arterial wave energy and wave reflection are augmented in PH and that wave behavior differs between patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: Right heart catheterization was performed using a pressure and Doppler flow sensor-tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery. Wave intensity analysis was subsequently applied to the acquired data. Ten control participants, 11 patients with PAH, and 10 patients with CTEPH were studied. Wave speed and wave power were significantly greater in PH patients compared with controls, indicating increased arterial stiffness and right ventricular work, respectively. The ratio of wave power to mean right ventricular power was lower in PAH patients than CTEPH patients and controls. Wave reflection index in PH patients (PAH: ≈25%; CTEPH: ≈30%) was significantly greater compared with controls (≈4%), indicating downstream vascular impedance mismatch. Although wave speed was significantly correlated to disease severity, wave reflection indexes of patients with mildly and severely elevated pulmonary pressures were similar. CONCLUSIONS: Wave reflection in the pulmonary artery increased in PH and was unrelated to severity, suggesting that vascular impedance mismatch occurs early in the development of pulmonary vascular disease. The lower wave power fraction in PAH compared with CTEPH indicates differences in the intrinsic and/or extrinsic ventricular load between the 2 diseases.

Pulmonary Artery Occlusion and Mediastinal Fibrosis in a Patient on Dopamine Agonist Treatment for Hyperprolactinemia.

Unusual forms of pulmonary hypertension include pulmonary hypertension related to mediastinal fibrosis and the use of serotonergic drugs. Here, we describe a patient with diffuse mediastinal fibrosis and pulmonary hypertension while she was on dopamine agonist therapy. A young woman, who was treated with cabergoline and bromocriptine for hyperprolactinemia, presented with progressive dyspnea over several months. Based on the clinical investigation results, in particular, elevated pulmonary arterial pressures and significant perfusion defects on computed tomography (CT) pulmonary angiography and ventilation/perfusion (V/Q) scintigraphy, chronic thromboembolic pulmonary hypertension (CTEPH) was initially considered the most plausible diagnosis. However, during an attempted pulmonary endarterectomy, loose fibrous tissues were observed in the mediastinum and cryosection of the right pulmonary artery showed fibrosis and chronic inflammation. Subsequent investigations revealed that diffuse mediastinal fibrosis with concurrent pulmonary hypertension, and not CTEPH, was the most likely diagnosis and cabergoline and bromocriptine may have triggered the fibrotic changes. Both drugs are ergot-derived dopamine agonists, which are known to cause cardiac valve fibrosis and less frequently, non-cardiac fibrotic changes. The underlying mechanism is attributed to their interactions with serotonin receptors. There is much evidence that serotonin, a potent vasoconstrictor and mitogen, is involved in the pathogenesis of pulmonary hypertension. In conclusion, as CT and V/Q scintigraphy findings can occasionally be deceptive, physicians should be particularly aware of differential diagnoses in patients without obvious history of venous thromboembolism that are suspected of having chronic thromboembolic pulmonary hypertension.

Pulmonary artery wave propagation and reservoir function in conscious man: impact of pulmonary vascular disease, respiration and dynamic stress tests.

KEY POINTS: Wave travel plays an important role in cardiovascular physiology. However, many aspects of pulmonary arterial wave behaviour remain unclear. Wave intensity and reservoir-excess pressure analyses were applied in the pulmonary artery in subjects with and without pulmonary hypertension during spontaneous respiration and dynamic stress tests. Arterial wave energy decreased during expiration and Valsalva manoeuvre due to decreased ventricular preload. Wave energy also decreased during handgrip exercise due to increased heart rate. In pulmonary hypertension patients, the asymptotic pressure at which the microvascular flow ceases, the reservoir pressure related to arterial compliance and the excess pressure caused by waves increased. The reservoir and excess pressures decreased during Valsalva manoeuvre but remained unchanged during handgrip exercise. This study provides insights into the influence of pulmonary vascular disease, spontaneous respiration and dynamic stress tests on pulmonary artery wave propagation and reservoir function. ABSTRACT: Detailed haemodynamic analysis may provide novel insights into the pulmonary circulation. Therefore, wave intensity and reservoir-excess pressure analyses were applied in the pulmonary artery to characterize changes in wave propagation and reservoir function during spontaneous respiration and dynamic stress tests. Right heart catheterization was performed using a pressure and Doppler flow sensor tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in control subjects and patients with pulmonary arterial hypertension (PAH) at rest. In controls, recordings were also obtained during Valsalva manoeuvre and handgrip exercise. The asymptotic pressure at which the flow through the microcirculation ceases, the reservoir pressure related to arterial compliance and the excess pressure caused by arterial waves increased in PAH patients compared to controls. The systolic and diastolic rate constants also increased, while the diastolic time constant decreased. The forward compression wave energy decreased by ∼8% in controls and ∼6% in PAH patients during expiration compared to inspiration, while the wave speed remained unchanged throughout the respiratory cycle. Wave energy decreased during Valsalva manoeuvre (by ∼45%) and handgrip exercise (by ∼27%) with unaffected wave speed. Moreover, the reservoir and excess pressures decreased during Valsalva manoeuvre but remained unaltered during handgrip exercise. In conclusion, reservoir-excess pressure analysis applied to the pulmonary artery revealed distinctive differences between controls and PAH patients. Variations in the ventricular preload and afterload influence pulmonary arterial wave propagation as demonstrated by changes in wave energy during spontaneous respiration and dynamic stress tests.

The vascular-disrupting agent, combretastatin-A4-phosphate, enhances neurogenic vasoconstriction in rat small arteries.

Combretastatin-A4-phosphate (CA4P/CA4), an anti-cancer drug, induces tumour hypoxia by destabilizing the cytoskeleton in tumour endothelial cells. Hypertensive side effects have been observed. We hypothesized that CA4P/CA4 lead to endothelial dysfunction followed by increased vasoconstriction. Mesenteric small arteries and femoral arteries isolated from male Wistar rats were mounted in microvascular myographs for isometric tension recordings and electrical field stimulation (EFS). Immunoblotting of endothelial nitric oxide synthase (eNOS) was performed on human umbilical vein endothelial cells (HUVECs). CA4P failed per se to change vascular tone. In femoral arteries, endothelial cell removal, l-nitro-arginine (l-NNA, an inhibitor of eNOS) and CA4P enhanced phenylephrine-induced vasoconstriction, while in mesenteric arteries only l-NNA leftward shifted concentration-response curves for phenylephrine. CA4P enhanced vasoconstriction induced by low frequency (0.5-4Hz) EFS in femoral arteries, but not in mesenteric arteries. Neurogenic contractions were inhibited by prazosin, an α(1)-adrenoceptor antagonist. In mesenteric arteries, CA4P and l-NNA inhibited vasorelaxation induced by vanadate, a tyrosine phosphatase inhibitor. CA4P did not affect acetylcholine-induced relaxation. In HUVECs, CA4P increased phosphorylation at eNOS-Thr(495), a negative regulatory site, while the positive phosphorylation site eNOS-Ser(1177) was not affected. CA4 neither influenced the actions of phenylephrine, vanadate nor acetylcholine in femoral and mesenteric arteries. In conclusion, our findings suggest that CA4P, but not CA4, enhances sympathetic adrenergic vasoconstriction probably by increasing eNOS-Thr(495) phosphorylation, in a tissue selective manner. These findings encourage further investigation to show that the hypertension and regional organ ischemia induced by CA4P can be avoided by concomitant treatment with an α(1)-adrenoceptor antagonist.