The main factor and source causing AHF symptoms is congestion rather than low CO [14, 28, 114, 115]. Only a minority of patients (clearly less than 10%) admitted with AHF feature signs and symptoms of clinically relevant, significantly compromised peripheral circulation, hypoperfusion, and/or clinically meaningful hypotension [116–118]. As such, both entities (HFpEF and HFrEF) share one of the main pathophysiological issues indicating and promoting acute heart failure: acutely and substantially elevated left, and generally subsequent right [15, 119–121], ventricular filling pressures, which are associated with pulmonary and systemic venous congestion (with and without low CO) [14, 15, 122–124]. Left- and right-sided filling pressure is largely determined by (a) the amount of blood flow (venous return) to the heart and (b) by the diastolic cardiac properties, e.g. chamber and myocardial stiffness [125]. Accordingly, a considerable high blood volume flow to the heart (preload) alone may precipitate pulmonary edema as seen in completely normal hearts of patients suffering from acute glomerulonephritis, causing acute, oligo/anuric kidney disease [125]. On the other hand, worsening diastolic dysfunction (DD) is shown to provoke pulmonary edema even in the absence of relevant volume retention [113, 126, 127].

Backward transmission of the elevated left-sided filling pressures, causing pulmonary venous hypertension augmenting RV afterload [4, 128–130] and diastolic ventricular interaction [131, 132], decisively affect and, in turn, lead to marked increases in RVEDPs consecutively displaying systemic (peripheral) congestion [133, 134]. As such, congestion attributed to high LVEDP is responsible for and causes the foremost clinical symptoms, dyspnoea (acute dyspnoea at rest, orthopnoea or paroxysmal nocturnal dyspnoea, breathlessness on exertion), and signs and symptoms associated with peripheral edema development, like swollen legs, ascites, renal dysfunction and gut discomfort [17, 30, 49, 50, 69]. Considerable evidence indicates that elevated, high LVEDPs causally underlie the development and presence of congestion [123]. Moreover, every relevant acute rise in LVEDP may precipitate pulmonary congestion or even flash pulmonary edema [67, 135]. Patients suffering from diastolic dysfunction are particularly at risk to develop pulmonary congestion or edema as any (additional) pathological effect affecting the heart muscle potentially worsens diastolic stiffness [126]. Typical conditions are acute ischemic episodes [136] and abrupt increases in BP [4, 113, 127, 137]. Ischemia causes (further) ventricular diastolic stiffening [138, 139] as acute myocardial ischemia slows ventricular relaxation and increases myocardial wall stiffness [140–142], consequently LVEDP increases [62, 63, 142]. Rising BP is, in any case, associated with elevated sympathetic tone, augmented afterload, increases in LVEDP, and may result in fluid redistribution and further neurohormonal activation [15, 143, 144]. Increases in afterload generally cause a rise in LVEDP [113, 127, 145, 146]. As such, HFpEF patients, found to be highly sensitive to changes in loading conditions (volume and pressure load) [113, 147, 148], are especially predisposed to develop pulmonary congestion or actually flash pulmonary edema [67, 113, 127, 149]. This is even true in the case of only mild, acute increases in BP [67, 113, 127, 149] or yet undetectable volume expansions [148]. In a rigid heart chamber, which is unable to properly accommodate to increasing blood flows and intracardiac volumes [150], already small increases in end-diastolic filling volume are accompanied by substantial, exponential (the diastolic pressure-volume relationship follows an exponential equation) increases in LVEDP [150]. Indeed, rising and elevated BPs or increasing LV filling volumes may lead, in the setting of combined ventriculo-arterial stiffening, to further increases in ventricular stiffness [113, 148, 151], thereby worsen diastolic dysfunction [152] which will result in disproportionate rises in LVEDP [113, 148]. Worsening diastolic function due to hypertensive dysregulations, uncontrolled hypertension, and myocardial ischemia, but hyperglycemia as well, are predominant causes for AHF development in HFpEF patients and in diabetic patients with diabetic cardiomyopathy [40, 41, 152]. However, new onset of atrial fibrillation (AF) is, as well, a frequent trigger [42]. As a result of the loss of atrial function, a compensatory increase in LVEDP in order to maintain end-diastolic filling volume and thus CO (via Frank-Starling mechanism) is reported. Subsequently the neurohormonal systems will be activated [152]. Both, reduced diastolic filling and abnormal left atrial function, may result in neurohormonal stimulation [152]. Increases in LVEDP are demonstrated to happen more rapidly in HFpEF than in HFrEF, attributed to the blunted diastolic distensibility, a typical property of HFpEF (in contrary, HFrEF patients show an increased diastolic distensibility) [123].

Accordingly, elevated LVEDPs causing central, pulmonary and systemic congestion are in the vast majority of AHFS the critical underlying pathology and the reason for presentation [5, 122, 153, 154]. Remarkably, central and peripheral congestion usually arise concurrently [155, 156].

Enhanced levels of left ventricular filling pressures unfortunately display a range of adverse effects, including enhanced myocardial oxygen demand, compromised coronary perfusion with concomitant risk of angina, global and subendocardial ischemia [157–159], progressive mitral [15] and often tricuspid regurgitation, activation of the adrenergic and the renin-angiotensin-aldosterone system, thus activating the neurohormonal systems (NHs), and stimulate the cytokine system [160]. As such, high LVEDPs may evoke and contribute to disease progression [104, 161–164]. Indeed, features typically associated with and characteristic of AHF are neurohormonal activation [165–168], stimulated inflammation [169–172] and activated endothelial function, commonly termed endothelial dysfunction (ED) [173, 174]. Inflammation and ED generally accompany each other as they are closely interrelated and interconnected [175–177] and go along with enhanced levels of oxidative stress (ROS) [178, 179].

It should be noted that acute severe left heat failure may occasionally, in individual cases, not be accompanied by high filling pressures (markedly dilated ventricles, often with severely impaired systolic function) featuring a normal or even low LVEDP and no pulmonary edema, although they do suffer from severe acute left heart failure [180–182]—this is the so-called ! “forward failure” as described by the ESC [4].

The neurohormonal systems, NHs, perform necessary and pivotal control and modulating functions and exert a substantial integrative impact on cardio-circulatory physiology [183–185]. Neuro-hormones carry hemodynamic and biological effects on the heart and the vascular system [186]: Augmented sympathetic discharge is not only exerting vasoconstrictive, positive inotropic and chronotropic effects, but is going along with blunted parasympathetic drive causing abnormal cardiopulmonary reflex control, including attenuated baroreflex and boosted peripheral and central chemoreflexes [168]. As such, autonomic imbalance (excess sympathetic discharge and coexisting withdrawal of parasympathetic tone) is a characteristic feature in heart failure [187]. Stimulated renin-angiotensin-aldosterone system [165] and augmented non-osmotic release of arginine-vasopressin, promote other than systemic and local vasoconstrictive effects, especially renal functional changes, namely declined ultrafiltration and retained sodium and H₂O, thus facilitate fluid accumulation [166, 186]. Endothelin-1 causes marked vasoconstriction (enhancing vascular tone) [188], while elevated concentrations of natriuretic peptides especially counteract the vasoconstrictive (show venodilative and peripheral arterial resistance lowering effects) and the fluid retaining effects of the NH mediators and hormones [167, 189–191]. However, their ameliorating effects on the sympathetic and RAAS discharge appear to be clinically of minor potency in acute heart failure [164, 192], and their clinical importance is attached to their diagnostic and prognostic power [193–195]. Of special note, elevated A II and aldosterone levels contribute (aside from their well-known and characteristic vasoconstrictive effects, which directly augment the systemic vascular resistance and as such the afterload [196], and their sodium and water retaining impact [197–199]), through endothelial activation and enhanced ROS generation,¹ to the considerably diminished NO bioavailability [202–206], typically emerging in AHF [174, 206]. As such, A II promotes endothelial dysfunction and augmented ROS generation, and thereby a markedly diminished NO bioavailability ensues [161, 202, 206]. This results in significantly impaired endothelial NO dependent vasodilatation causing increased vascular tone (vasoconstriction) and disturbed regulation of ventricular function: “NO dependent regulation of ventricular function and vascular tone determines hemodynamics in AHF” [174]. The important NO-cGMP-PKG signalling pathway (NO is a pivotal paracrine and autocrine signalling molecule [207]), is a universal cascade of cellular communication regulating, via protein phosphorylation, gene expressions [208–210]. This signalling pathway will be affected resulting in (a) altered smooth muscle cell relaxation which concomitantly impacts local and systemic blood flows and blood pressure [211], causing vascular dysfunction, and (b), related to an afflicted cardiac endothelium, disturbed titin phosphorylation within the cardiomyocytes [208–210]. Titin hypophosphorylation leads to cardiomyocyte stiffening and thus precipitates diastolic dysfunction [78, 112, 210, 212]. Hence, vascular compliance (namely of the central larger vessels) is diminished (vasoconstriction in arteriolar vessels reduces arterial compliance [213]) causing increased vascular stiffness and subsequently enhanced LV (RV)-afterload thereby also facilitating diastolic dysfunction [147, 148, 174, 214–216]. Furthermore, a rise in systolic ventricular elastance is induced and as such augmented ventricular (end-)systolic stiffness [214, 217] impairing systolic performance/reducing systolic reserve capacity [199, 218]. Indeed, augmented arterial stiffness is associated with both, systolic and diastolic dysfunction [219–221], and moreover, considerably impaired NO bioavailability and worsening endothelial dysfunction are even suggested to propagate the development and/or progression of heart failure [175, 222, 223].

Without doubt, in the early phase of AHF, enhanced neurohormonal activity allows stabilization of the compromised hemodynamic conditions and disrupted homeostasis jeopardizing suitable tissue and organ nutrient and oxygen supply [224]. Ventricular filling pressures increase with increasing sympathetic tone [225] and thereby may assure appropriate ventricular filling volume in order to maintain CO in the failing heart. On the other hand, they may contribute and provoke pulmonary congestion or edema [226]. Over time, the effects of the NHs, if persistent and chronically activated, are considered and appraised to be maladaptive, deleterious for the circulation, and leading to disease progression [54, 118, 164, 192, 224, 227].

Moreover, very recent publications suggest that the stimulated neuro-endocrine hormonal systems are even “over-activated” and are overwhelming the counter-regulatory cascades, decisively contributing to, mediating, and maybe even precipitating acute heart failure [60, 162–164, 183, 186, 227, 228] as they considerably modulate myocardio-mechanical properties [229].

Endothelial activation (EA)/dysfunction (ED) being present in AHF is evidenced by elevated levels of biomarkers indicative for EA including vascular adhesion molecules (VCAM-1) and intercellular adhesion molecules ICAM-1 [230–232], cytokines such as IL-6 and IL-1β, and tumor necrosis factor TNFα [233–235]. ED is meanwhile acknowledged taking a central and crucial role in the pathophysiology and pathogenesis of acute and chronic heart failure [175, 223]. Endothelial factors and mediators, whereupon endothelial relaxing factor (NO) activity represents a hallmark of endothelial function [236], contribute via para-, auto- and endocrine pathways to organize pivotal homeostasis and co-modulate cardiac and renal assignments and vascular properties in order to assure appropriate blood volume, cardiac output, perfusion pressure and blood distribution to the tissues and organs meeting cellular and tissue metabolic demands [192, 236].

Altered endothelial function, endothelial dysfunction (“should more appropriately considered as endothelial activation” [237]), implies a disturbed NO bioavailability, among other issues (ED displays pro-inflammatory, pro-coagulatory, and vasoconstrictive conditions [238]), as probably its most relevant pathobiological consequence. A disturbed NO bioavailability critically contributes to an imbalance of local (and potentially systemic as the endothelium is present in the whole body) vasoactive substances [239–241], precipitating significantly increased vascular tone, resulting in deranged (local) blood flow distribution and autoregulation [242]. The restricted bioavailability of NO is not only associated with vasoconstriction but causes increased stiffness in the systemic and pulmonary circulation and hence augments LV and RV systolic load [174]. Shortage of NO availability further favours ET-1 related vasoconstriction [243], increases sympathetic discharge including raised release of catecholamines [244], and contributes to diminished sodium excretion [245]. Dysfunctional cardiac microvascular endothelium may affect, via paracrine paths, diastolic LV properties [206] whereupon the already mentioned NO signalling pathway, considerably affected by ED, precipitates compromised endothelial cross-talk and disrupted phosphorylation paths [246, 247], including the cardiomyocyte NO-cGMP-PKG pathway leading to titin hypophosphorylation and thus acute cardiomyocyte stiffening [210, 218]. Accordingly, the effects of ED relevantly contribute to the clinical-hemodynamic profile characteristic in heart failure [248]. Moreover, ED is related to heart failure initiation and thus AHF [249]. ED is associated with adverse outcome in acute and chronic heart failure [250–252], correspondingly improvement of endothelial function is affiliated with a better outcome [253]. The worse ED the more severe the heart failure stage present and the more severe the functional limitation [254, 255]. ED independently predicts mortality risk [249, 251, 256] and major cardio-vascular events [252]. Hence, there is no doubt that ED has a major and crucial role in heart failure malady in both acute and chronic conditions, integrates the multi-facet signals arising [176], triggers, modulates and even perpetuates the cascades activated [257–259]. Indeed it orchestrates the adaptive and potentially morbid processes, and unquestionably causally contributes to initiate and to display acute heart failure [174, 260]. Notably, dysfunctional vascular endothelium is a recognized hallmark of human diseases in general [261].

Inflammation as evidenced by elevated serum levels of TNFα, IL-1, IL-6, and ST-2, an activated complement system and adhesion molecules verified in AHFS is part of the pathobiology [170, 171]. Inflammation per se is a protective response to injury of any kind, ensues and applies by interactions between cell surfaces, extracellular matrix, and pro-inflammatory mediators [262], and may basically be regarded as a vascular response to any threat or injury [263–265]. As such, vascular stretch as present in acute and chronic pressure or volume load exerts biomechanical stress on the mechanoreceptors of the endothelial cells, and thus initiates an at least mild inflammatory response [266–268]. Even physiological adaptions in vascular tone and tension are principally regulated and mediated by the same molecules, agents, and hormones involved in inflammatory processes [17] and in endothelial functions and effects. The endothelium is substantially involved in the innate [269–271] and adaptive [272]) immune response to injury, processes associated with inflammation, and as such is surely a fundamental feature in cardiovascular disease processes and may be considered as “linking” inflammation and cardiovascular diseases [174, 175, 206]. Indeed, a distinct correlation between inflammation and endothelial dysfunction is well established [273], confirming that inflammation and endothelial cells are closely intertwined and interconnected [273, 274]. Furthermore, since being characterized and accompanied by an increase in inflammatory markers including CRP, cytokines, adhesion molecules, and acute phase proteins, a more substantial and chronic inflammation has to be considered as a systemic process rather than “purely” a local reaction [275]. Accordingly, inflammation is recognized as taking a central position in the pathophysiology of cardiovascular diseases and hypertension [276]. As such, inflammation may, by causing endothelial dysfunction [277, 278], promote hypertension due to impaired endothelium-dependent vasodilation favouring vasoconstriction following an imbalance between vasoconstrictor and vasodilator mediator production and release [279], namely an impaired NO bioavailability [280, 281].

Especially remarkable and important to understand is that systemic inflammation such as severe infections, especially sepsis, may cause acute cardiac decompensations: The set of cardio-vascular responses associated with inflammatory activation may include a dissociated reply with enhanced peripheral vasodilation (due to reduced peripheral vascular resistance caused by vasodilative mediators). Although occurring in the presence of limited NO bioavailability, which implicates impaired NO-related vasodilation, and coexisting with enhanced arterial stiffness, which consecutively causes increased afterload [282, 283], the net result is a potential drop in blood pressure (largely determined by the resistance vessels), LV afterload is augmented [174, 219, 284, 285] and systolic LV-function is blunted [174, 219, 286].

To resume this issue, beside the tight and intertwined relation between ED and inflammation [273, 274], a close interrelation and interaction between the NHs, namely the autonomic nervous system and the AII effects, and endothelial function/dysfunction is quite evident [287–289], whereupon NO constitutes the decisive link [272]. Enhanced sympathetic drive induces shear stress on the vessel walls [290], even in case of minor discharge [291]. Shear stress is associated with ED [292–294]. On the other hand, (activated) endothelial cells may trigger NHs [287, 295]: Physiological and pathological (as e.g. in case of venous congestion) biomechanical forces affect the endothelial mechanoreceptors and subsequently stimulate endothelial cells and consecutively activate NHs [201, 261, 296]. Endothelial stretch (activating endothelial cells) [201, 261, 297], and as such even increasing ventricular filling pressures and myocardial stretch [160], directly evoke activation of the NHs, in case of SNS by altered autonomic reflexes [297]. Actually, elevated filling pressures and myocardial stretch are acknowledged as being among the most powerful impulses activating NHs [160]. Accordingly, NHs activation and endothelial dysfunction may be considered being a common path of the causative features contributing to incipient heart failure [186]. Furthermore, the tight interrelations and interconnections of the features and systems inevitably hold the risk to end up and to constitute a vicious cycle, potentially amplifying and perpetuating each other and as such facilitating disease progression [60, 104, 259, 297, 298].

Vascular properties and “function play a central role in the development and progression of heart failure” [174]. Albeit the elevated left-sided (and mostly right-sided as well) filling pressures, which are associated with central pulmonary and peripheral congestion [14, 15, 122, 123, 153], coin the clinical picture and give rise for hospital admission in the vast majority of acute heart failure cases [17, 30, 49, 50, 69], acute marked alterations in vascular tone, vasoconstrictions (affecting LV and RV loading conditions) are actually often the direct cause of incipient AHF [13, 113, 127, 137]. Indeed, AHF may be considered as a disorder of “pathologic vasoconstriction” [299]. AHF is almost always associated with both, elevated LVEDPs and generally (in cardiogenic shock as the most severe form of AHF, the SVR may be even abased – read more about this phenomenon in Chap. 3) substantially increased afterload, in daily practice usually indicated by augmented peripheral vascular resistance (SVR), whereupon CI/CO is indefinite [300].

The often considerable increase in afterload (respectively SVR as part of total afterload) in the presence of deficient systolic and/or diastolic myocardial properties [300] cannot be compensated, as the cardiac properties are neither capable of allowing compensation by increasing preload (at least not at the cost of still reasonable increases in filling pressures below the threshold of pulmonary congestion/edema formation) and consecutively applied Frank-Starling-mechanism nor by subsequent sufficient increase in contractility following and adapting to the rapid increase in aortic pressure (afterload), known and referred to as Anrep’s effect [301, 302]): This condition (a substantial rise in afterload in the presence of compromised systolic and/or diastolic capabilities) is referred to as afterload mismatch [303, 304]. Afterload mismatch causes a vicious cycle with secondary mitral regurgitation, reduced SV and increasing and elevated LVEDPs, and as the latter are being transmitted backward, pulmonary congestion/edema ensues [67, 305]. Notably, as a matter of fact, venoconstriction is part of the “generalized “vasoconstrictive transaction [60, 306, 307].

Cotter demonstrated that almost always systemic vascular resistance is enhanced in acute heart failure syndromes (AHFS) [13, 137] and argues that most episodes of AHF (about 70%) are attributed to increased aortic input impedance [308], which denotes enhanced afterload, with consecutively increased end-systolic LV-stiffness and reduced diastolic compliance [151], resulting in a noticeable rise in LVEDP [113, 127, 145, 146]. This opinion is agreed by Metra and co-workers [160] and supported by several facts, particularly:

(1) Relatively high systolic BPs are frequently seen in AHF patients [15, 69], at least 50% of all patients admitted with AHF are “hypertensive”—systolic BP > 140 mmHg [69, 309]. However, patients with systolic BPs of 140 mmHg or less may very well suffer from augmented afterload as in the setting of systemic inflammation/infection with increased central aortic stiffness and thus increased systolic LV-load [13, 282].

(2) Furthermore, AHF often develops rapidly, typically within hours [17] and without much previous complaints [4, 137], and as such is associated with acute alterations in arterial loading conditions directly affecting cardiac properties and function [160, 308]: “ LV performance is influenced by arterial load [284] (since systolic wall stress reflects afterload as defined by the law of LaPlace [310, 311]), and arterial properties are, in turn, influenced by LV performance” [284, 312]. Consequently, vascular properties (specifically vascular tone) play an essential role in the development and progression of HF [174]. Moreover, (worsening) vascular failure is considered to be a precipitant for AHF [313].

As evident from the above depicted setting, altered vascular properties are decisively causally responsible for incipient AHF, accordingly, this type of AHF is referred to as “vascular failure” or “vascular type of AHF” in contrast to “cardiac failure” [308]. The latter, in which predominantly the cardiac performance and/or the myocardial efficiency is/are considerably compromised, may further deteriorate (e.g. due to ischemia with hibernating or stunning myocardium and thus (further) afflicted contractile properties [314], a common reason in de novo AHFS [26, 33]), and consecutively provoke AHF [308]. Of prominent concern are elevated troponin levels indicating myocardial damage, found in about 50% of all patients admitted with AHFS [315]. These elevations are suggested to be largely attributed to improper and disproportionate myocardial perfusion provoking ischemia (subendocardial ischemia due to high filling pressures, dysregulated cardiac/myocardial autoregulation (altered microcirculation), metabolic imbalances, hypotension, application of vasodilatory substances treating AHF, etc.) [26, 66, 68, 316–318], and will, in any case, (further) weaken myocardial performance [319]. Characteristic for the cardiac pathway (cardiac failure) is a marked de novo fluid accumulation, developed often over weeks, and relevantly involved cardio-renal features [17, 54, 164, 308, 320].

The concept by Cotter takes into account that (A) the heart and the vessel system have to be acknowledged as a functional unit, an absolutely essential view for understanding and interpreting the basic physiological and pathophysiological features, affecting each other and are together responsible for sufficient cardio-vascular performance [147, 312, 321–325], and that (B) both, an afflicted heart and altered vascular properties are present in acute heart failure. However, while one part of the unit may predominantly malfunction in the acute condition, the unit as a whole precipitates the failure [326]. Metra emphasizes, it is even “essential for understanding and treatment of heart failure” to distinguish between both pathways, although they may be disrupted concomitantly and thus contribute equally at the same time to acute decompensation [160]. Further details of this new fundamental concept on AHFS by Cotter, meanwhile recognized and even endorsed by the ESC [5] are depicted in Fig. 2.1.

The vascular pathway is related to increased vascular stiffness/resistance with acute afterload mismatch and exacerbated filling pressures in the setting of activated NHs, resulting in (further) impaired systolic performance and redistribution of fluids from systemic (predominantly splanchnic veins, see below) to pulmonary circulation, rather than from general fluid accumulation. The cardiac pathway implies largely myocardial issues (due to acute ischemia, acute myocardial infarction, or acute myocarditis, but also due to sepsis and other threats affecting myocardium) in the setting of stimulated NHs (further) blunting and deteriorating systolic performance, to primarily responsible for the AHFS and is essentially associated with de novo fluid accumulation and cardiorenal dysfunction [104, 126, 154, 308].

Characteristic for the “vascular profile” of AHF development are rapid onset of clinical symptons and central fluid redistribution causing pulmonary congestion or edema rather than fluid accumulation, thus no or only marginal weight gain prior to AHF is seen, furthermore, most patients have preserved EF, suffer from diastolic dysfunction, and present with normal (sBP 100–140 mmHg) or elevated (sBP > 140 mmHg) blood pressure [17, 308]. Of course, especially affected are in general patients with pre-existing combined v-a stiffening, demonstrating amplified changes for any alteration in loading conditions [147], and ADHF arises due to temporary exacerbated/worsened diastolic dysfunction [127]. As such, acute increases in afterload (e.g. due to an increase in vascular resistance and / or in vascular stiffness) have a markedly unique impact on blood pressure and consecutively on filling pressures [145, 146] since blood pressure feeds back into (further) impairment of diastolic properties [151], potentially inducing pulmonary congestion [112, 327, 328]. Petrie established an inverse relationship between diastolic relaxation and afterload in hypertensive and non-hypertensive humans indicating cross-talk between arterial afterload and diastolic LV function [329]. Clinical pulmonary congestion (compared to hemodynamic congestion which is reflected by elevated LVEDPs but without clinical symptoms [153]) or even edema may apply in case of acutely increased LVEDPs already at relative low filling pressures, and consecutively, relatively lower pulmonary pressures than found in chronically elevated LVEDPs, as pulmonary lymphatics drain excess lung fluids in case of chronic overfilling more rapidly and efficient than in case of abruptly enhanced fluid onset [192, 330].

However, in conclusion, the classical vascular pathway relates to acutely altered vascular arterial impedance (due to increased vascular stiffness and/or resistance) associated with an acute afterload mismatch as the change in loading conditions cannot be compensated by adjusting cardiac performance, the latter in general due to compromised systolic cardiac performance or limited systolic reserve, further affecting systolic properties, and is accompanied by fluid redistribution (due to neurohormonal drive, read below) rather than by fluid retention [117, 154, 308, 331].

Highly remarkable, very recent study results provide evidence that even subtly altered hemodynamic conditions may provoke AHF from vascular type in predisposed subjects with abnormal cardio-vascular function, whereupon acute sympathetic discharge mediates acute changes in vascular properties with subsequently modified loading conditions thereby leading to acute heart failure [60, 123, 126, 332]. The neurohormonal systems are, as described above, decisively controlling and modulating cardio-circulatory function [183, 184], and may acutely affect cardiovascular conditions and function [164, 186]. Particularly the sympathetic nervous system (SNS) is reported to be able to instantaneously affect cardiopulmonary and arterial baroreflexes [333, 334], and to acutely release vasoactive agents such as noradrenaline into the circulation and thus mediate and induce rapidly changes in vascular arterial and venous resistance and compliance [60, 335]. As such, abruptly enhanced sympathetic drive is demonstrated to critically influence the pathogenesis and onset of AHFS [60, 126, 165, 224, 226]: Study results and considerations by Fallick and colleagues address sympathetically-mediated central fluid redistributions from the splanchnic venous blood reservoir, caused by acutely elevated sympathetic discharge resulting in ADHF [60]. More than 70% of total body blood volume is mainly residing in the veins and not involved in effective circulation, since the venous system is substantially more compliant (about 30 times) than the arteries [335]. Of which, the splanchnic veins are even more compliant than the other veins and are furthermore particularly densely equipped with α₁ and α₂ receptors [335]. These anatomic facilities translate into physiological consequences, displaying better storage abilities (reservoir veins) than other veins and a significant stronger degree of vasomotor response in case of sympathetic activation [336], which predominantly reduces venous compliance and as such diminishes the vessels’ capacitance [60]. Hence, even minor sympathetic discharges prevailing, translate into constriction of the splanchnic veins while there is no, or only a negligible, effect to be seen in the other veins and hardly any in the arteries. Furthermore, the amount of fluids shifted in case of constriction of the splanchnic veins is comparatively greater as with an equal strong constriction in other venous areas.

Moreover, while the capacitance of the peripheral veins is reported to be normal in heart failure patients [337], it is suggested that splanchnic veins behave dysfunctional in that patient group unable to properly buffer changes in effective circulating volume [60]: The inhibitory control mechanisms, in particular reflex control, attenuate and modulate SNS discharge and cause its effects to not properly apply [338–341]. Adamson provided evidence that imbalanced autonomic activities prefer sympathetic over parasympathetic activity [342], and as such result in sustained sympathetic influence and activism.

Accordingly, sympathetically-mediated and initiated reduction in splanchnic venous capacitance may provoke relevant fluid shifts from the venous reservoir into the effective circulating blood stream, subsequently increasing preload and consecutively enhancing LVEDPs: Indeed, pulmonary diastolic pressures are demonstrated to fluctuate markedly during the day, apparently attributed to sympathetic discharges in response to in principal physiologic matters like upright posture and exercise [332]. While many of these sympathetic discharges are uncritical, some may initiate a vicious cycle ending up in acute heart failure in susceptible persons [60]. Patients suffering from chronic heart failure show chronic endothelial dysfunction and low grade inflammation [80, 175, 261, 343, 344] and as such are predisposed to decompensate—the vast majority (about 75%) of patients with AHFS are acute decompensations of chronic heart failure [345, 346]—in case of a further threat/threats (e.g. temporary ischemia—cardiac pathway) or even minor alterations in loading conditions (vascular pathway) [297]. Accordingly, Fallick and co-authors suppose that acute (and maybe even “physiological“) sympathetic discharge, at least in the setting of dysfunctional splanchnic veins as found in (chronic) cardiac/cardiovascular dysfunction, alone has the potential to provoke AHF [60]. The concept is well consistent with other study results: Autonomic imbalance and elevated filling pressures become evident already days and weeks before acute decompensations turn into a clinically overt malady (display clinical congestion) [123, 342]. Furthermore, elevated pulmonary pressures are suspected to promote sympathetic excitation through pulmonary afferents [347], thereby amplifying sympathetic drive and thus may intensify venoconstriction and consecutively a fluid shift. The results from the COMPASS-HF study suggest, providing clinical evidence, that fluid shifts from the extracellular space into the effective circulation (expanding effective circulating volume) may underlie the development of AHF [348]. Moreover, the authors’ concept also explains very well why patients without weight gain (weight gain is acknowledged to indicate fluid accumulation in heart failure patients, although this is a relatively insensitive (and nonspecific) marker of fluid agglomeration with several limitation and restricted accuracy [160, 349–352]) may well develop AHFS without typical precipitants due to minor, elusory or even not comprehensible occasions initiating incipient acute heart [60, 126]. This pathogenesis explicates that the majority of patients presenting with AHF do not suffer from clinically comprehensible fluid accumulation and weight gain (inducing acute decompensations and AHF [123, 134, 353]), rather, fluid redistribution from peripheral, namely splanchnic venous, to central circulation is definitely an established pathway in AHF pathobiology [60, 126, 160, 308].

Furthermore, this approach broadens Cotter’s concept who attributed fluid redistribution to increased vascular resistance and stiffness, thereby referring vascular failure to altered arterial properties. Obviously, changes in venous tone and hence venous capacitance (namely in the compliance of the splanchnic veins reducing their capacitance due to acutely increased sympathetic drive) foremost apply, and are able to shift within seconds up to 800 mL of blood into the circulation [335], thereby augmenting effective circulating blood volume and concomitantly increasing preload, and thus cause acute heart failure [60, 126]. In summary, sympathetically–mediated veno-constriction, predominantly affecting the splanchnic veins, with subsequent considerable blood shift into the effective circulation and hence increased preload causing (further) elevations in filling and concomitantly pulmonary pressures, inducing pulmonary venous congestion, has to be considered primarily as a vascular pathway with fluid redistribution following Cotter’s concept.

Expansions, even very mild ones, of the effective circulating blood volume, inevitably increasing the preload, are in the setting of heart failure in any case accompanied by appreciable increases in filling pressures, actually even exponentially increases may be seen [354]. This condition is referred to as hemodynamic congestion [153]. As such, acute increases in venous return, due to reduced venous capacitance of the venous reservoir following sympathetic activation, are able to provoke (occasionally substantial) enhancements in LVEDP and RVEDP [60]. If the increase in cardiac filling and intravenous pressures (elevated left-sided pressures are usually responsible for increased systemic venous pressures [124, 355, 356]) become clinically obvious by precipitating acute pulmonary congestion/edema [60, 226] and systemic peripheral edema (the latter traditionally known and referred to as venous congestion [134, 139]), clinical congestion applies [153]. “Central (pulmonary and intrathoracic) and peripheral (venous) congestion usually exist together” [126, 155, 156]: Pulmonary and systemic congestion caused by elevated left- and right-heart filling pressures is almost a universal finding in AHFS [15].

Congestion is almost always associated with excess extracellular fluid and blood volume [60], whereupon most of the excess fluid will be located in the venous system [335]. However, increased intravascular fluid volume does not always reflect fluid accumulation or retention rather may be due to altered fluid distribution, redistribution, as described by Fallick and coworkers [60] and as conceptualized for AHFS by Cotter [308]. Indeed, elevations in filling pressures following fluid shifts from the venous reservoir may result in a failing heart in hemodynamic or even clinical congestion without any relevant (at least for us recognizable) supplementary retention of salt and water [357]. Consistent, weeks before overt AHF ensues, autonomic imbalance and elevated filling pressures are demonstrated [123, 342]. As such, inappropriate autonomic regulation of the vascular, namely of the venous tone, and the physiological fluctuations in SNS drive, may induce (repetitively) some degree of fluid shift especially from the splanchnic reservoir to the effective circulation thereby potentially provoking incipient AHF [297, 357].

Accordingly, although in the majority of AHFSs (acute) central fluid redistribution, rather than fluid accumulation, is the recognized flash point leading to acute clinically relevant and overt malady [126, 160, 308], at least some degree of fluid excess, often beyond clinical comprehensibleness, is universally present in all AHF patients [35, 126, 358, 359] and a “basic and fundamental mechanism of decompensation” [160]: (1) Sympathetic excitation is reported to facilitate sodium retention and as such may contribute to decompensation [60]—enhanced sympathetic drive is an acknowledged issue in heart failure [227]. (2) Diminished natriuresis is a hallmark of heart failure and thus fluid retention has to be anticipated in heart failure patients [104, 105]. Threats, often minor ones, or even intense physiological fluctuations in the concentrations of (circulating) neurohormones are demonstrated to promote fluid retention in patients suffering from chronic heart failure [55, 59], and may launch acute decompensations—remember, the vast majority (75% and more) are acute decompensations of chronic heart failure cases [346]. (3) Arginine- vasopressin- mediated reabsorption of free water is reported to be present in heart failure [224, 349]. (4) Not only Silva Androne could verify that intravascular volume indeed is elevated in patients with “stabile” chronic heart failure [360]. (5) Furthermore, renal dysfunction is common in heart failure resulting in salt and water retention [224, 349] and may contribute to fluid overload. Actually, in a large majority of heart failure patients, a shortened kidney function has to be recognized [35, 353, 361]. The complex pathophysiology of kidney dysfunction associated with heart failure, the cardio-renal-syndrome (CRS), is largely attributed to a decrease in renal perfusion pressure, altered intrarenal hemodynamics, and elevated renal venous pressures [362], basically a result of the effect of activated neurohormonal systems (SNS and AII !) and associated fluid retention [199, 363], and deficient/overwhelmed counter-regulatory systems and effects [186, 224]. Furthermore the signalling pathways of the natriuretic hormones must be affected in heart failure, since in case of increased natriuretic levels, physiologically an accelerated natriuresis applies [364]. Thus, in heart failure, salt excretion in general is disturbed [126]. (6) Moreover, in the setting of an increased vascular tone which is accompanied by a diminished (foremost splanchnic) venous capacitance [60, 335], the hemodynamic effect of sodium and (consecutively) water retention may be amplified [365, 366]. (7) Especially to be noted, “fluid redistribution can only happen on the basis of an existing elevated blood volume” [126]. Thus some degree of fluid accumulation is necessary for the concepts of Fallick and Cotter to work, explaining very well the pathophysiology in absolute consistency with the clinical findings and presentations.

Nonetheless, fluid accumulation as the typical, classical feature characterizing the cardiac pathway of AHFS following the concept by Cotter [308], applies predominantly in case of relevantly compromised cardiac function [308]. In the setting of markedly impaired, prevailing cardiac performance, progressive fluid accumulation occurs as the result of cardiac failure. The ensuing, often persisting and thereby maladaptive, compensatory mechanisms, including activated neurohormonal cascades and endothelial—inflammatory programs, affect salt and water balance and renal function, clinically manifesting in a more gradual increase in total body volume, with concomitant enhanced body weight and in the front peripheral edema, jugular venous congestion, hepatomegaly, and gut discomfort [5, 17, 50, 308]. As the renal dysfunction and the modified fluid—salt balance component are relevantly involved [124], some authors talk about a cardio-renal pathway (instead of cardiac pathway) [54, 164, 297]. This “slow” decompensation over days and often weeks [134, 342] has been traditionally attributed to non-adherence in diet (improper high salt and fluid intake) and medication, as well decreasing contractility due to ongoing myocardial injury (mainly ischemia) [17, 55, 308]. This pathway is related to largely altered systolic, myocardial properties while changes in, and the impact of, the vascular conditions are seen in these circumstances in the background [308, 311].

Increased intravascular, thus particularly intravenous fluid content exerts biomechanical stress on the vessel walls [259, 367, 368]: Biomechanical forces including shear and circumferential wall stress as well as increased intravascular fluid content precipitating hydrostatic pressure display endothelial stretch, sensed by the mechanoreceptors located on the surface of the endothelial cells [296, 369–371]. Consecutively, the endothelial cells will be activated and hence switch phenotypically, altering their synthetic profile, and as such, physiologically deploy a signalling cascade resulting in a minor degree of vasoconstrictive, pro-coagulatory and pro-inflammatory condition [296, 369–371]. The reaction may be somewhat more pronounced in case of already enhanced vascular tone as typically present in “compensated” chronic heart failure [183, 184, 227]. Moreover, excessive and sustained activation is in any case crucial for disease progression [183]. As such, environmental cues may cause apparent or subtle, unrecognizable biomechanical stress which is associated with endothelial and neurohormonal activation and concomitant generation of oxidative stress. Oxidative degradation of the ROS’s quenches NO (the key molecule of vasodilatation) activity despite elevated NO production and thus results in blunted NO bioavailability. This then affects vascular tone, causing (and amplifying) vasoconstriction [201, 261]. The vasoconstriction may be more distinct and amplified by other neurohormones modulated and released following vascular stretch, notably the renin-angiotensin-aldosterone—system with angiotensin II [259, 297] as its biologically most active representative, which, in turn, directly and indirectly promotes vasoconstriction [372]. Especially to be recognized, peripheral rather than central, cardio-pulmonary triggers are reported to be the decisive source of activating endothelial cells to generate and release vaso- and bioactive mediators [307, 373]. However, that is not surprising and absolutely consistent with the natural physiological conditions as most of the accumulated or retained excess fluids are “stored” within the venous system [335]. Accordingly, systemic, particularly local venous hemodynamic and finally clinical congestion (venous congestion, mainly a result of the activated compensatory mechanisms and cascades, is associated with circumferential stretch [259]) causally accompanies and potentially facilitates acute heart failure evolution [54, 164, 174, 186, 192], as congestion is considered to play a crucial role in provoking endothelial and neurohormonal activation [374, 375]: “Systemic venous congestion is sufficient to cause endothelial and neurohormonal activation” [297]. However, as Hayashi [307] could demonstrate in a human study model of patients with systolic heart failure (HFrEF), local venous congestion is also, by all means, able to “promote endothelial and neurohormonal activation, even exerting systemic effects, as evidenced by an increase in plasma ET-1, IL-6, and VCAM-1 in this patient population” [297]. The special input from venous congestion in the acute and chronic heart failure pathobiology is further supported by the fact that venous congestion commences, and can be observed, days and even weeks before clinically overt heart failure ensues [133]. Hence, venous congestion has to be considered as being itself a primary contributor and hemodynamic, pro-oxidative, and pro-inflammatory stimulator of acute decompensation, rather than an epiphenomenon and merely a consequence of poor cardiac performance [133, 297]. Accordingly, there is substantial evidence that venous endothelial stretch, associated with and caused by local (and systemic) venous congestion following fluid retention and accumulation [259, 297, 307], is able to activate particularly the local, peripheral venous endothelial cells to subsequently produce and release, in a paracrine/endocrine manner, a number of vaso- and bioactive mediators and substances including vasoactive and inflammatory neurohormones and cytokines [259, 297, 374, 375] in a composition compatible with results typically demonstrated in AHFSs [374, 376]: “The peripheral release of vasoactive and pro-inflammatory neurohormones and substances from stretched endothelial cells and perivascular congested tissues may offset the physiologic adaptive state and may promote further fluid retention (fluid accumulation) inducing a vicious cycle resulting in overt decompensation” [375].

Thus, in consequence of the extended and elevated intravascular, namely intravenous, fluid amount, a rise in filling pressures of both the right and the left ventricle ensues. Subsequently progressive central pulmonary and peripheral local and systemic venous congestion will be displayed [104, 117, 126, 377]. Pulmonary (left-sided) and systemic venous (right-sided) congestion are related to elevated left- respectively right- sided filling pressures [15], whereupon the elevated LVEDP is the characteristic consequence of the systolic and/or diastolic cardiac dysfunction causally present in heart failure syndromes [378]. Elevated right-sided filling pressures are the result of (a) the elevated LVEDP being transmitted backward to the pulmonary vessel network, causing pulmonary venous hypertension, consecutively increasing RV-afterload [379, 380], (b) the increased RV preload and (c) of diastolic ventricular interaction applying in the presence of (acute) heart failure and typically if intravascular fluids distinctly accumulate as in cardiac malfunction [131, 132]: In circumstances with relatively preserved RV function, the failing left ventricle, unable to properly accommodate with any accessory fluid without a rise in LVEDP [354], responds with a further (often inappropriate high) increase in LVEDP, even if the fluid amount offered by the RV is small [117, 125, 354] affecting markedly RV afterload and filling characteristics [380]. Accordingly, besides the enhanced right ventricular filling “inherently” promoting an increase in RVEDP [381, 382], and the backward transmission of elevated LVEDP first and foremost contributing to an enhancement of RVEDP [67, 383, 384], DVI will contribute to a recognizable, sometimes marked increase in RVEDP [132, 385, 386]. In case RV function is also altered, the increase in REVDP will be accentuated [385–387] and is typically higher than the rise in LVEDP [385, 386], as notably diastolic ventricular interdependence will decisively influence the filling pressures [131, 388, 389]. Accordingly, in most cases (≫80%), the increase in LVEDP is accompanied by a noticeably substantially elevated RV-filling pressure [121]. Indeed, Gheorghiade found that nearly all patients suffering from acute heart failure present with both, systemic and pulmonary congestion [153]. Anyhow, subsequently RV function [390, 391] as well as diastolic [392] and systolic [393–395]) LV properties will be further compromised.

Hence, a considerable increase in LVEDP following enhanced intravascular volume arises, potentially causing clinical pulmonary congestion or even provoking pulmonary edema [125, 396–399]. Pulmonary congestion is associated with reduced oxygen saturation and myocardial ischemia potentially arises if oxygen saturation is less than 90%, furthermore circulatory insufficiency results in metabolic acidosis which jeopardizes the heart [137].

In addition, venous congestion (which is affected by the amount of intravenous fluid volume, changes in venous tone and sympathetic activation [60, 400]) is demonstrated to impair cardiac function [125, 126, 401] (another hint that venous congestion is a contributor rather than simply an epiphenomenon of AHF), and increases in LV end-diastolic filling themselves inherently augment ventricular stiffness (and thus afterload) and decrease EF [126].

Hemodynamic congestion may be seen as fluid retention and occurs early in the course but is clinically imminent [153]. However, local peripheral venous distension and local tissue edema, both attributed to enhanced fluid content, result in venoconstriction, since endothelial stretch initiates local (but accompanied by systemic) neurohormonal and endothelial activation, where particularly A II, ET-1 and sympathetic discharge are responsible for the local venous venoconstriction [174, 261, 297, 402, 403]. This will precipitate further fluid influx, preferentially from the splanchnic veins, enhancing effective circulating blood volume [60] and promoting a further increase in venous return and thus preload, but as well amplifying venous congestion. As a matter of fact, there will arise a somewhat worsened/affected arterial stiffness due to the inflammatory effects displayed [282]. Both effects, venoconstriction with associated fluid shift and the (more) stiffened arteries (further) alter loading conditions and effect systolic and diastolic ventricular properties translating in a further increase in LVEDP (RVEDP respectively) and compromised LV and RV function [15, 60, 134, 153, 284, 285, 297, 354].

Very remarkable, these considerations are not only indicative for a vicious cycle being established and applied leading to acute decompensations and disease progression, but are rather well suggestive of a link between fluid accumulation and vasoconstriction, notably venoconstriction, the latter affiliated with fluid redistribution. Hence a link between the vascular and the cardio-renal pathway [297]: Venoconstriction due to neurohormonal, namely sympathetic discharge by reducing the venous capacitance [60, 335, 404], induces a fluid shift, preferentially from the splanchnic venous reservoir, into the effective blood circulation, hence central fluid redistribution applies. Subsequently a rise in preload and inevitably an, often marked, increase in filling pressures ensues, facilitating further venous congestion through fluid accumulation [60, 153, 297, 374]. On the other hand, fluid accumulation, primarily due to impaired (and during the course progressively worsening) cardiac performance, leads to (further) endothelial and neurohormonal activation, ending up in a pro-inflammatory, pro-coagulative and vasoconstrictive milieu, fostering vaso-, especially splanchnic venous, constriction. The splanchnic veins are shown to be exceptionally sensitive to even discrete sympathetic discharge, and as such shift and redistribute blood from the venous reservoir into the effective circulating stream. Augmented preload and concomitantly filling pressures result [60, 133, 297] (Fig. 2.2).

With these remarks it becomes obvious, that even mild, primarily natural and reasonable modifications, adaptations (e.g. to upright position) within the physiological range may offset (“just”) compensated conditions initiating a vicious cycle in which (further) sympathetic discharge and other regulatory cascades lead to and provoke acute heart failure [126, 297]. Furthermore, Fallick’s [60] and Colombo’s [297] considerations add a new aspect to the existing views and concepts, namely a special venocentric approach (in addition to cardiocentric, nephrocentric and arteriocentric): Venous congestion contributes (via triggering local and systemic endothelial-inflammatory response and compensatory mechanisms) to the heart failure pathobiology by promoting (further) increases in effective circulation blood volume with consecutively increased preload, filling pressures, aggravated congestion and additional fluid accumulation.

Furthermore, as exemplarily demonstrated by the link between the vascular (vasoconstriction and fluid redistribution) and cardiac/cardiorenal (fluid accumulation and venous congestion) pathway, and as demonstrated by the interconnections of the neurohormonal and endothelial-inflammatory features and systems involved, this condition bears a considerable potential of self-amplification and perpetuation of a vicious cycle driving the heart failure malady [186, 297]. As such, elevated, high LVEDPs and myocardial stretch, typically present in acute (and chronic) heart failure, are known to be very powerful biomechanical incentives. They cause neurohormonal activation including the adrenergic and cytokine pathways and the RAAS, [104, 160, 405], provoke subendocardial ischemia (further affecting the cardiac properties) [66, 68] and reduce coronary perfusion (potentially causing ischemia) [160], not at least facilitate changes in LV-shape and thus functional mitral regurgitation (affecting hemodynamics) [36, 406, 407]. Furthermore, simply ordinary stress may induce an increase in LAP/LVEDP causing further distress in predisposed patients with neurohormonal activation, and in consequence facilitate congestion [297]. Moreover, in the setting of an increased vascular tone which is accompanied by a diminished venous, foremost splanchnic, capacitance [60, 335, 404], the hemodynamic effect of sodium and (consecutively) water retention may be amplified [365, 366].

A clinical-hemodynamic, widely used in daily practice, and easy to perform assessment tool for patients with acute heart failure syndromes, allowing for a meaningful and crucial distinction of those patients [224], has been introduced by Nohria and Stevenson [158, 426] (see Fig. 2.4). It takes into consideration the most prominent clinical features and basic pathophysiological issues characterizing the nature of AHF, gives a clue about the severity of the actual situation and possible complications the physician may be faced with, like potentially ensuing shock, and provides hints to select therapeutic measures [16, 17, 433, 434].

Accordingly, most patients can be classified during that 2-min bedside assessment [158, 432, 435] into a hemodynamic profile with a corresponding treatment regimen [158]. The main hemodynamic abnormalities are related to filling pressure and peripheral perfusion. In the presence of elevated filling pressures the patient is said to be ‘wet’, in their absence ‘dry’; if the perfusion of the peripheries is adequate, the patient is ‘warm’, if critically reduced ‘cold’. Note that the assessment concerning a ‘cold’ patient due to hypoperfusion should be made by assessing the legs and forearms rather than the feet and the hands [435] (Fig. 2.4).

Haemodynamic profiles are:

Clinical symptoms and signs of congestion (wet) include: Pulmonary congestion (crackles and rales), jugular venous distension, peripheral oedema, hepatomegaly, orthopnoea, paroxysmal nocturnal dyspnea, gut congestion and ascites, hepatojugular reflux [4, 30].

Clinical signs of hypoperfusion/shock (cold) comprise the following [158, 437, 438]: Altered level of consciousness (confused, quiet, apathetic, dizzy), cold peripheries (forearms, lower leg), moist and clammy skin, mottled extremities, ↓ toe tip temperature, oliguria (renal dysfunction), narrow pulse pressure, ↓ MAP, hepatic dysfunction, low serum sodium.

Patients classified into profile 3 are reported to have a 6-month mortality rate up to 40% [16, 426].

Typical features precipitating acute decompensations may include:

[138, 139, 158, 159, 431, 439].

To identify an acute coronary syndrome is of critical importance as immediate coronary intervention is acknowledged to significantly reduce complications and mortality [437, 440, 441].

Echocardiography, considered the “gold standard” for the detection of LV dysfunction [442], is an essential tool which should be performed to evaluate LV-function, structure, and any alterations to this; confirmation of the diagnosis (acute) heart failure is essential as well as identifying potentially reversible causes [4, 443]. However, an immediate echocardiographic examination is “only” imperative in patients with hemodynamic instability and in case life threatening conditions are suggested [431]. In de novo AHF, heart ultrasound is recommended to be performed in otherwise stable patients within 48 h [431].

Of note, ultrasound of the lungs to identify congestion and pulmonary edema (and their severity), substantiate [156, 444–446] or even diagnose AHF [447–449] in case the diagnosis is uncertain, may be of great value as recent publications revealed [444, 445].

The chest radiograph will aid diagnosis of congestion and/or pulmonary oedema [42, 82], and may identify cardiomegaly. However, in up to 20% of cases, the chest X-ray in AHF patients may be nearly normal [119].

The electrocardiogram (ECG) will help to identify a precipitating ischemic event or the new onset of atrial fibrillation inducing the AHFS [4, 429]. A normal ECG in a clinically suggested case of acute heart failure virtually rules out this diagnosis [429].

As the symptoms of acute heart failure may be non-specific and as the physical findings are sometimes not particularly sensitive [432, 450], the Natriuretic Peptides, ANP and BNP, may be helpful in the diagnostic and differential diagnostic considerations, particularly in the emergency department [194, 451–453].

It is in particular the excellent negative predictive value of BNP which can be used to exclude heart failure and to differentiate potential cardiac failure from other underlying diseases [454]. On the other hand, elevated levels do not automatically confirm the diagnosis of AHF, as natriuretic peptide serum levels may be enhanced in quite a number of other cardiac (LV hypertrophy, myocarditis, tachyarrhythmias, pulmonary hypertension) and non-cardiac reasons including advanced age, cardiometabolic disorders, severe infections, anemia, renal and liver dysfunction, ischemic stroke and subarachnoid bleed, and in the paraneoplastic syndrome [455–457].

Troponin T and I are highly sensitive and specific parameters, allowing identification of myocardial injury and play a well-established key role in diagnosing acute coronary syndromes (ACS) [458], as well as in the risk stratification and management of patients suffering from ACS [459–462].

An elevation of cardiac troponin is found in about 40% of all patients with acute decompensated heart failure [463, 464], is associated with a low LV-EF [465, 466], and is said to predict a poor short term prognosis [465, 467].

You [468] has shown that troponin I is a strong predictor of all-cause mortality in patients with acute decompensated heart failure. The study shows an independent ‘dose’-response relationship between cardiac troponins and mortality in AHFS-patients. Thus, an association between elevated cardiac troponins and poor outcome in acute heart failure seems to be established [465, 467].

Cardiac output and cardiac index are undoubtedly the parameters widely used in daily practice. In 1989, Stevenson published a method remarkably reliable, able to estimate CI non-invasively: If the ratio [sBP–dBP]/sBP < 25% then CI is highly likely to be less than 2.2 L/min/m². This prediction shows a sensitivity of 91%, its specificity is 83% [432] (Table 2.3).

The patient should also be assessed according to the ABC (airway, breathing, circulation) method of resuscitation, which tends to be standard but with emphasis on particular areas:

The patient should sit upright;

However, some trials expressed concerns, morphine may show adverse effects [519–521].